A MANUAL of PLURIGLANDULAR THERAPY BY HENRY R. HARROWER, M.D. Founder and Director of The Harrow er Laboratory THE HARRO WER LABORATORY, Inc. GLENDALE, CALIFORNIA Copyright 1924, by The Harrower Laboratory, Inc. [All Rights Reserved.] Printed in U. S. A. W. B. Conkey Company Hammond, Indiana^ CONTENTS PAGE The Publishers' Preface . 5 I. Introduction: Fundamen- tals in Pluriglandular Therapy 7 II. Adrenal Support in As- thenic Conditions ... 15 III. Neurasthenia: A Solution of the Problem .... 26 IV. The Backward Child . . 34 V. Epilepsy and the Endo- crines 46 VI. Galactagogue Organother- apy 59 VII. Menstrual Irregularities . 72 VIII. The Menopause .... 85 IX. Sympathetic Sedation in Hyperthyroidism ... 99 X. Adjuvant Organotherapy in Indigestion 112 XI. Hemoglobin Therapy in Anemia 120 XII. The Control of Simple Goiter 127 XIII. Better Results in Mucous Colitis 134 XIV. Ulceration, Calcium Fixa- tion, and Parathyroid Therapy 144 CONTENTS-Continued PAG8 XV. Nutritional Control in Tuberculosis 157 XVI. Reducing High Blood-Pres- sure . . . 171 XVII. Mammary Therapy in Menorrhagia ..... 188 XVIII. Langerhansian Therapy in Diabetes 198 XIX. Endocrine Measures in Prostatic Dysfunction . 215 XX. Hyperemesis Gravidarum as an Anaphylaxis . . 227 XXI. The Hormones in Impo- tence, Asexualism, and Sterility 234 XXII. Organotherapy in E. N. and T. Work 245 XXIII. Pluriglandular Formulas: A Ready-Reference List 256 A Therapeutic Index . . 283 THE PUBLISHERS' PREFACE This little handbook contains some extremely valuable information which will be the more helpful now that it has been gathered between these cov- ers and indexed for reference. It happens that practically all of the chapters in this book have been pub- lished previously as individual booklets and used separately to carry their messages to the attention of the medi- cal profession. Through them, certain developments in organotherapy have been advertised, for which the .pro- fession (and many thousands of grate- ful patients) are indebted to Doctor narrower, whose aggressive work in this branch of therapeutics has been conceded by many to have been of conspicuous service to medicine. One of Mr. Thomas A. Edison's close associates recently said : " Without advertising one cannot sell the best goods in the world," and in view of the fact that we are fortunate in having certain " goods " to sell-quite the best of their kind in both quality and incep- tion-we take this opportunity to call the attention of the profession to many original ideas which have been devel- oped to a point of convenient applica- tion in clinical practice by the author, and which we are in a position to make available for application, either direct or through any druggist. In the meantime our present struggle is twofold-to broaden our field and seek out further useful applications of this method and to maintain ourselves against a veritable horde of imitators whose chief watchword is price. Their sole object seems to be to imitate my formulas, copy my writings, pirate my tradenames, and to use cheapness as their chief weapon. There is no fair comparison between cheaper imitations and the combination of quality and service offered by The Harrower Lab- oratory. Insist on having the products of this institution. There is a difference between manu- facturing and selling on a purely commercial basis and producing upon a scientific basis and selling on a com- mercial one. We simply cannot main- tain our present standards of perfec- tion and research and compete on a price basis. We might add that we have no in- terest whatever in dealing with the public direct, and that every attempt is made to conserve the high ethical standards which The Harrower Lab- oratory has adhered to these many years. On the other hand, correspon- dence with the profession is welcomed and to them we pledge our best efforts. The Harrower Laboratory, Inc., Glendale, California. I INTRODUCTION: FUNDAMENTALS IN PLURIGLAN- DULAR THERAPY Every-Day Endocrine Disorders-" The Interlocking ■ Directorate "-Hormone Selectivity-Destroyed by Digestion ? THERE are four essential funda- mentals in which I believe implic- itly-basic principles which seem to me so obvious that I have never quite understood how intelligent physicians could deny them and commit them- selves in the publications of medicine to such statements as have ap- peared time and again in the past decade. These principles have been estab- lished beyond peradventure and, while my faith in them has never once wavered, it is a great satisfaction to see to what extent their value is now being appreciated by such a large proportion of the practising section of the profession. Equally, it is just as pleasing to me to compare the present silence of most of the critics with their vociferous opposition of only a few years ago. Every-Day Endocrine Disorders. First and foremost, I believe that the glands of internal secretion are en- trusted with such vital functions that the common causes of disease, such as infection, toxemia, and stress, inevi- 7 tably must derange their service to the body. This being the case, the every- day functional disorders of the en- docrine glands must be far more important-because more frequent- than the essential " ductless glandular diseases," like myxedema or Addison's disease. Besides this, the early functional aberrations of these important little organs are much more easily controlled than when definite structural pathology has been brought about. Hypoadrenia, compared with the Addisonian syn- drome, is far more common, just as it is much more satisfactorily treated. Therefore, the search for these simpler difficulties is both rational and advan- tageous, for once appreciated they are so much more effectively con- trolled. " The Interlocking Directorate." The intimacy of the endocrine func- tions and their dependence upon one another is now accepted as a reality and not " the figment of a disordered imagination " that it was deemed to be not so far back. The interrelation of these glands has been likened aptly to an interlocking directorate, and so close is their dependence and co- operation that conditions which bring about an irregular function on the part of one endocrine organ inevitably must interfere with the functions of others in the system. When one is especially burdened as, for instance, the thyroid gland, by an acute infection, the abnormally increased demands upon it in this direction may lessen its .service in other directions, as, let us say, its well-known maintenance of ovarian function. Because of this, the thyroid 8 service to the ovaries is lessened with consequent menstrual irregularity and dependent disorders. Again, the tendency of the endocrines is to supplement one another, or to bring about a balance between their functional activities. When one is deficient another attempts to take up a part of its work. To revert to the. thyro-ovarian relationship just men- tioned, when a condition of this char- acter is brought about, not uncom- monly the pituitary gland-also a sex gland stimulant-may be prompted to increase its activities to make up for what the thyroid temporarily is pre- vented from doing. As a result, there is a hyperemia of this organ and, not at all rarely, a pituitary headache is brought about by a well-intended extra effort on the part of one endocrine to substitute for a share of the work of another that is incapacitated from accomplishing its full hormone service to a third. Tens of thousands of clinical experi- ences have served to prove how impor- tant are the relations of these glands and also have shown the advantage of considering the regulation of pluri- glandular dysfunction by a correspond- ing pluriglandular therapy. Revert again for a moment to the quite common type of dyscrinism used as an illustration above. If there is a thyro-pituitary-ovarian syndrome, such as has been mentioned, why not a thyro-pituitary-ovarian therapy, instead of thyroid therapy for the thyroid dis- order or ovarian therapy for the ova- rian insufficiency ? Usually a part of such syndrome is ignored-the pitui- tary aspect, for instance. Why not treat the patient rather than the most 9 obvious irregularity alone ? Why not take for granted that the intimacy of these endocrine functions predicates such a pluriglandular involvement as I have outlined, even though clear-cut evidence of each variety of glandular insufficiency may be lacking ? This idea, once derided as empirical and unscientific, has done as much to revolutionize organotherapy and bring it to its present state of clinical appre- ciation as any of the many advances made in this field. The third of these " four funda- mentals " concerns a more intangible factor. It relates to a theory which I outlined in a paper in the New York Medical Record some years ago ("A Hypothesis of Hormone Hunger," N. Y. Med. Rec., Aug. 16, 1919). Briefly, after referring to the accepted physio- logical principle of cell selectivity, I suggested that not merely do the cells appropriate the various hormones sent to them through the blood stream, but that they do so quantita- tively. For instance, to use the same illus- tration as previously, the ovarian cells receive from the thyroid through their blood supply a certain modicum of hormones which they actually need to bring about the functional activity expected of them. Given conditions which lessen this supply and it is rea- sonable to suppose that a " hunger " for the missing hormones exists. The degree of this demand predicates a corresponding increase in the avidity with which a later supply-normally produced or artificially augmented- is appropriated. When the hunger is Hormone Selectivity. 10 great or prolonged, the capacity to ap- preciate a renewed supply is supposed to be the greater. When the hunger is satisfied, it is as fair to presume that a reasonable excess is ignored and al- lowed to pass on in the blood for use elsewhere or later oxidization as it is to believe that not every bit of a given hormone found in the blood must posi- tively be appropriated by a given organ to which it is known to be serv- iceable and through which it may pass. I admit that this is purely a theory, just as is the very generally accepted " side-chain theory " of Ehrlich, and I have no way of proving it absolutely. I still think it a reasonable explana- tion of what happens with regard to the regulation of hormone appropria- tion, and even though, as my critics have insisted, an excess of thyroid can be administered to an organism with well-marked evidences of abnormal hormone appropriation, I still contend that this illustration is not effective, for the amounts used are quite ab- normal and also the excess of thyroxin, or whatever the substance is, acts as a poison just as we expect an excess of any good food or remedy to be detri- mental. My point is, then, that the variations in cellular hormone selectivity-the degrees of hormone hunger-determine in a quantitative fashion the avail- ability of the hormones present in the blood, including those that may reach there by direction of the therapist who wisely offers his patients a pluri- glandular menu. We have for years been offering suitable patients a selection of hor- mones in place of single-gland extracts, 11 in the hope that the body would avail itself of a part, or all, of the proffered supplies, and that it would do so with a quantitative selectivity. Clinical experience has proved that to ad- minister such pluriglandular formulas offers the organism several alterna- tives as against the one represented by a single, though needed, endocrine sub- stance. In this way we have increased our range of results and immeasurably broadened our prospects of clinical success. To those who once shouted " shot- gun therapy" we reply that, in view of our limitations with a rifle in this variety of hunting, we use the shot- gun and our " bags " are ever so much larger. If, in some fashion, the ultra- skilled physician can estimate the actual endocrine values and accurately supply the needs, well and good ; but persistent inquiry for many years in a dozen different countries has not yet brought me to the man who even claims to be able to accomplish this much-desired diagnostic feat. Such an accomplishment is virtually impossible ; but, for the sake of argu- ment, let us suppose that a true endocrine evaluation really can be made of a given case. While a corre- spondingly accurate endocrine formula is being prepared-"individualized to fit the patient " as some have put it- what is to prevent these endocrine values being changed, by a shock, due to toxemia, or resulting from a nor- mal variation such as we expect from the ovaries ? By the time that the " proper " formula is ready, the find- ings are changed! How much better to fit together an average formula, built upon years of experience with 12 thousands of cases, and hope that the body's powers of hormone selec- tion will make the most of what we are attempting to accomplish for it. I now come to the fourth funda- mental, which I confess has been assailed more than all the others combined. I thoroughly disbelieve the oft-repeated comment, " but these ex- tracts are destroyed by digestion ; they are protein meat products, and in the stomach or in the bowel they must be altered by digestion." To all such-and, of course, many of the comments made to me have been inquiries rather than assertions-I first ask if they have ever used thyroid extract. On hearing their reply, I next ask how it was administered. Practi- cally invariably the answer enables me to inquire next why the thyroid is not destroyed in the stomach and to ask if some of the other hormones may not be equally as resistant to the influence of the digestive ferments. As a matter of fact, the only way we know that these various endocrine formulas are effective when given by mouth, despite their necessary pass- age through the alimentary canal, is that they are effective ! For years it has been my privilege to struggle to maintain these four basic principles against attack. We have succeeded admirably. Now the only ones who deny them do so half- heartedly, continuing their opposition because they have committed them- selves in black and white and, quite humanly, they dislike to reverse them- selves. Most of these now agree, but tacitly ignore their one-time opposi- Destroyed by Digestion ? 13 tion, and some of them even are now writing papers containing as matter worthy of their reiteration these very things they once denied. Such is life! 14 II ADRENAL SUPPORT IN ASTHENIC CONDITIONS The Adrenal Functions-Post-Influen- zal Asthenia-Symptoms of Adrenal Depletion-Adrenal Aspects of Tuber- culosis-Neurasthenia of Endocrine Origin-Emotional Causes-Tropical Hypoadrenia-Points in the Diagnosis -Strychnia Contraindicated - Rein- forcing Adrenal Support-Hypoadrenia in the Daily Roiltine. THE adrenal glands, small pads of endocrine tissue lying above each kidney, exert a very important influence upon certain functions which are beyond the control of the will-those regulated by the sympathetic nervous system. A part of the function of these glands is to maintain the tonicity of unstriped muscle, including that of the heart, blood-vessel walls, and alimentary canal. In fact, the tone of all muscles, voluntary and involuntary, is affected by the adrenal hormone, which is called " adrenin. " The adrenals also are con- cerned in the regulation of the cell chemistry, as well as the harmonious function of the other associated glands of internal secretion. These glands are influenced very de- cidedly by toxic substances which may get into the circulation. A most im- portant part of their function is to respond immediately to toxic stimuli in order that the body's defensive and The Adrenal Functions. 15 detoxicating mechanism may com- mence its necessary work as soon as possible. For this reason, the admin- istration or production in the system of various poisons causes an increase in the work of the adrenal glands, with circulatory changes which are very well known, as well as other changes in oxidization made necessary by the toxemia. Since various forms of poisoning are among the commonest causes of dis- ease, the adrenal functions have a much greater importance than hitherto attributed to them. During the influenza epidemics the unusually severe toxemia resulted in many thousands of cases in serious depletion of the adrenals, and brought attention very forcibly to the tonic influences of these glands. Not merely influenza, but all acute infectious dis- eases and the accompanying toxemias, as well as all chronic foci of infection, are the commonest factors in over- stimulating the adrenal glands. If these glands were not stimulated, the body's defenses against such condi- tions would not be initiated properly, and death would ensue. It happens that adrenin is very easily oxidized in the body, and since there must be a continued supply of this principle in order to maintain the sympathetic and automatic functions of the body, febrile conditions espe- cially invariably are accompanied with abnormal adrenal functioning. If these glands are excessively stimulated nat- urally they become tired out or de- pleted. Sometimes the degree of depletion is very marked, just as the Post-Influenzal Asthenia. 16 degree of fatigue may be marked fol- lowing severe exertion. Because of this adrenal insufficiency, or hypoadrenia, a condition arises which is the result of the absence of a part or all of the all- important stimuli from this gland. In a general way. Dr. Emile Sergent, of Paris, defines adrenal insufficiency as " the suppression or diminution of the adrenal functions." According to this well-known teacher and indefatigable worker, the adrenal glands have two functions, an antitoxic function and an angiotonic function. The following statement gives his view-point regarding these functions: " Under the term antitoxic function is to be understood the property which the adrenals possess of exerting a neutralizing power in respect to exo- genous and endogenous poisons. Mus- cular activity engenders the production of toxic substances. The accumulation of these toxic substances-which is the cause of fatigue-when it is excessive, brings about physical overstrain, a veritable endogenous form of intoxi- cation. The adrenals exert a truly specific neutralizing action in respect to poisons of muscular origin, the ef- fects of which are analogous to those of curare. Should these glands happen to be destroyed, this neutralization is lacking and a condition of depression and muscular fatigue is seen to appear which, in man, we shall find in the form of the earlier symptoms of adrenal insufficiency-asthenia." Hypoadrenia is quite similar in its symptomatology to the more serious structural disease of the adrenals which was described first by Addison Symptoms of Adrenal Depletion. 17 in 1855. Addison's disease is believed to be a destruction of the adrenal glands usually by tuberculosis, while the hypo- adrenia to which attention is being directed here is rather a functional exhaustion of these glands due usually to the toxic stress described. The symptoms of adrenal insufficiency are essentially asthenic in character. In fact, -fatigue is the principal result, and it may be of a most severe char- acter. The patient is tired-out and unable to accomplish the usual mental or physical work. An aggravated de- gree of muscular asthenia extends to the involuntary muscles causing heart weakness (very commonly these cases are classed as " myocarditis," when in reality there is no real structural change in the heart muscle at the time), the vessel walls lose their tonic- ity and as a result there is a condition of low hlood-pressure which, in turn, causes cold hands and feet and other evidences of circulatory insufficiency. The muscles of the alimentary canal are equally atonic, and as a result there is constipation, indigestion, and the well-known intestinal stasis. Par- enthetically it may be stated that the toxemia from intestinal stasis nat- urally is just as much a cause of adrenal stimulation as that which re- sults from any other poisoning, and consequently a vicious circle is pro- duced and the adrenals are still further depleted with still more atonicity. Adrenal Aspects of Tuberculosis. Perhaps the most common of all the disorders in which there is a clear-cut adrenal aspect is pulmonary tubercu- losis. Strangely enough this phase of both diagnosis and treatment is not or- 18 dinarily appreciated. The fact remains, however, that the toxemia of tubercu- losis overstimulates and consequently depletes the adrenal glands. Hypoad- renia is an invariable concomitant of tuberculosis in practically every stage. The languor and lassitude of the earliest onset of tuberculosis are due to some infective process of toxemia acting in its expected manner upon the adrenals. This undue stimulation wears them out in time. I am not at all sure that this adrenal phase of tuber- culosis does not have a good deal to do with its cause. Certain it is that the symptoms of hypoadrenia are usual in the tuberculous. Further, adrenal sup- port is measurably efficient in these cases. One can actually measiire the changes from this treatment-the in- creased tension, better urea elimina- tion, and obviously increased strength and weight. Netirasthenia of Endocrine Origin. Neurasthenia, or nervous breakdown, commonly is the result of a protracted adrenal insufficiency, not merely be- cause of the ever accumulating poison- ing, with a resultant general atonicity of the body, but because of a direct detrimental influence upon the nerves. They, too, have lost their normal tonicity and are asthenic, just as the rest of the body is asthenic. Many forms of neurasthenia may be con- nected with the other glands of in- ternal secretion, especially the thyroid or the sex glands, but the most com- monly involved of all the endocrine glands undoubtedly are the adrenals, and 'practically every case of neuras- thenia is of an endocrine character, and involves the adrenal glands. 19 Perhaps the most important of all the asthenic manifestations of adrenal insufficiency is what has been called " chemasthenia." By this I mean an asthenic state of the cell which causes metabolic laziness or cellular ineffi- ciency. The chemistry of the cells most vital in its influence on the body is reduced, and in consequence the cells are unable to eliminate their own waste products, and cannot avail them- selves of the food substances brought to them by the blood. This causes malnu- trition and an added toxemia which is of very serious import. Chemasthenia invariably is present in severe cases of adrenal insufficiency ; and the urinary analysis, especially the study of the 24-hour output of urea, shows a marked reduction in elimination. Often the urea is reduced as much as two-thirds of the usual normal, and the accumula- tion of these wastes in the body com- plicates an already complex problem. Since most of the wastes of the body have an acid influence-that is to say, they lessen the reserve of alkaline salts which is maintained for just this pur- pose-demineralization and a tendency to acidosis is the rule in all these chronic cases. The subject is briefly mentioned on page 31, and it is well to supplement the treatment of these cases by apply- ing the principle of remineralization. Emotional Causes. Prof. W. B. Cannon, of Harvard University, has demonstrated quite conclusively that the every-day emo- tional factors stimulate the adrenals in a remarkable and uniform manner. Fear, rage, pain, and other emotions, including probably worry, act upon the adrenal glands almost identically as 20 do toxins, and adrenal depletion from shock or mental storms is almost as common as that due to actual poison- ing. The usual reaction which follows emotional overstimulation is a typical picture of adrenal depletion. Hence, the frequency of hypoadrenia is really very great-in fact, I believe that it is the most common endocrine disturbance. Tropical Hypoadrenia. The various fevers of tropical climates are enervating because of the adrenal depletion that inevitably must result. Malaria always depletes these glands. Typhus, intermittent fever, and even sprue act just like all toxemias ; they cause an overactivity of the adrenals, thereby quickly depleting them. The alimentary parasites which so fre- quently fasten themselves upon indi- viduals residing in the tropics-the en- tameba histolytica, giardia and lam- blia-all produce toxic waste products which aggravate the adrenal depletion, and treatment directed at the actual infection obviously should include the attempt to offset this particularly detrimental endocrine dysfunction. It has been conclusively proved that the marked fatigue, the seriously slowed cell activities, and the poor circulation, with its low blood-pressure and circu- latory stasis, which so commonly are sequelae of many tropical affections, are of unquestioned adrenal origin, and frequently respond to the principle of adrenal support under discussion here. Points. in the Diagnosis. It is not difficult to diagnose hypo- adrenia. The patient' invariably com- plains of a marked lack of energy and is " all run-down." Mentally, physi- 21 cally, and physiologically these unfortu- nate individuals are exhausted. There is evidence in the history of a chronic or acute toxemia, or there is other clin- ical proof that the fundamental causes which deplete the adrenals have been present. The blood-pressure in most cases is considerably below normal, usually it is around 100 mm. systolic though sometimes it has reached as low as 80 mm. The elimination of urinary solids is low, and nutrition ordinarily is reduced. As a result of this, anemia is not uncommon, and the patient's powers of resistance are considerably less than usual, while he is subject to all sorts of aches and pains and discomfort of a functional type. Strychnia Contraindicated. It just happens that most of these cases of hypoadrenia are in the large class for whom the average medical man prescribes a tonic. Now, most of the tonics are of the strychnia type- that is, they are alkaloidal poisons and are tonics in that they stimulate the adrenals to produce more of its chemi- cal substance and thereby to increase circulation, muscular tone, and nervous tone. In cases of adrenal insufficiency, however, the adrenals have had too much stimulation and are virtually ex- hausted. Therefore, the administration of strychnia or similar substances is merely a means of aggravating the al- ready serious adrenal insufficiency. For this reason strychnia and alkaloidal tonics, including coffee, rarely should be given to an individual with depleted adrenals. Remove as best one can all sources of toxic stimulation of these glands and allow them to rest and while doing so support them. 22 ■ It is well known that organotherapy depends very largely upon a funda- mental principle described by Professor Hallion, of Paris, which is called " the law of homostimulation." This is as follows : " Extracts of an organ exert on the same organ an exciting influ- ence which lasts for a longer or shorter time. When an organ is insufficient, it is conceivable that this influence aug- ments its action, and when it is in- jured, that it favors its restoration." This homostimulation is not at all com- parable to the stimulation that results from drugs. As a matter of fact, or- ganotherapy actually supplies a suit- ably prepared pabulum that can be made available and used at once by the cells that correspond to those from which the extract was made. In other words, adrenal support by means of adrenal substance is a satisfactory means of antagonizing hypoadrenia, just exactly as the administration of thyroid substance to a person with thy- roid insufficiency is likely to modify conditions due to hypothyroidism. The administration of adrenal sub- stance is known to exert a musculo- tonic effect. It slows, steadies, and strengthens the heart ; it raises the blood-pressure, and, by actual measure- ment, increases elimination. Therefore, adrenal support is a rational means of modifying the results of hypoadrenia, and with it, of course, other things may be done simultaneously that are equally advantageous. Chief among these is the removal of all forms of toxemia-from foci of infection, from the alimentary canal, from the food in- gested, and from any other source that Reinforcing Adrenal Support. 23 can be discovered and modified. Added to this, remineralization by means of suitable alkaline salts to replace those that are deficient in the body, is always desirable. Still further, the cellular in- fluence of products from other endo- crine glands, which cooperate with the adrenals, very properly may be used. Practically every individual with adrenal insufficiency also has a greater or less degree of hypothyroidism. Since oxidization is so obviously deficient, every effort should be made to increase, the cellular activities of the body. Small doses of thyroid are helpful in accom- plishing this, for it is well known that the thyroid has the power to increase cellular chemistry and to encourage detoxication. Hence, in many cases of hypoadrenia, small doses of desiccated thyroid, perhaps a quarter of a grain a day, may be added to adrenal feeding. Still another endocrine product is used with great success in conditions of the adynamic type. Spermin, the endo- crine principle from thh interstitial cells of Leydig of the sex glands, is a muscular tonic ; it stimulates muscular contractility and also the chemistry of the muscle cells and perhaps other cells also. It has been recommended for many years as a means of increasing energy and the general tone of the body ; and is distinctly called for in the cases of muscular asthenia with hypoadrenia. A suitable dose of total adrenal gland is reinforced by a small amount of thyroid and spermin (made from the Leydig cells of the gonads). This original formula is combined with an excipient-calcium glycerophosphate- which also has some therapeutic value. Adreno-Spermin Co. (Harrower). 24 Under the name Adreno-Spermin Co. (Harrower), this formula has been used successfully for several years. It is a rational and efficient remedy because it is based upon sound physiology ; and the experiences of thousands of phy- sicians have proved its value as a means of causing effective adrenal support. Look for the asthenic findings of hypoadrenia. Remove the causes as best you can and, simultaneously, pre- scribe : Adreno-Spermin Co. (nar- rower), one q.i.d., at meals and at bed- time. In long-standing cases and where the need for such support is great, the foregoing treatment may be enhanced by hypodermic injections of Sol. Adreno-Spermin Co. (Harrower), once daily or every other day. Hypoadrenia in the Daily Routine. In conclusion, I urge the considera- tion of the adrenal aspect of the every- day disorders which come to our attention. Since asthenia is so essen- tially a symptom of adrenal origin, let every history which embodies this common statement prompt us to inves- tigate the factors mentioned herein, which are believed to be related to adrenal functioning. If the asthenia is accompanied with low systolic tension, subnormal temperature, low 24-hour urea and solids, and a tendency to acidosis, the diagnosis is clear. The de- velopment of the history will have given reason for this adrenal deple- tion; and its treatment should be add- ed to every effort to modify the toxic or infective causes, as well as the other indicated hygienic and eliminative measures. Adrenal support is a rational adjuvant measure in the majority of cases which come to us from day to day. 25 Ill NEURASTHENIA: A SOLUTION OF THE PROBLEM Adrenal Insufficiency - Customary Adrenal Symptoms-Organotherapeutic Possibilities - Adrenal Stipport - A Usual Method of Procedure-A Warn- ing-Contraindications. THE nervous breakdown or, as it is often called, neurasthenia, is a very real clinical entity, even though many neurologists now believe that the term neurasthenia is but a " cloak to cover shortcomings in diagnosis." There is no doubt that the condition commonly understood as neurasthenia is a decidedly variable complex, the factors of which differ widely in their origin. Naturally, the diagnosis " neu- rasthenia " is an incomplete one, and satisfactory treatment is attainable only when fundamental causes are un- derstood and properly disposed of. In my monograph, " Neurasthenia as an Endocrine Syndrome," a large amount of evidence has been gathered from the literature to indicate that the run-down neurasthenic patient prac- tically always has an endocrine syn- drome even though it may not stand out above all the other symptoms. Adrenal Insufficiency. As we have already seen, all forms of stimuli to the endocrine glands first increase their functioning and then, provided their physiological elasticity is not unlimited, play them out. Over- 26 stimulation must cause depletion. It happens that the adrenal glands are extremely important in maintaining the tone of the sympathetic nervous system as well as of unstriped muscle. Many of the subtle chemical reactions of the body, such as detoxication and immunity, depend upon the harmonic encouragement of the adrenals. (Strangely enough, in addition to this, the sympathetic system stimulates the adrenal glands; therefore, both cause and effect are related.) Consequently, toxemia such as one finds accompany- ing chronic foci of infection or acute infectious disease, causes an undue functional activity of the adrenal system, and the greater or more seri- ous the stimulus, the more likely the resultant hypoadrenia. It happens also that emotional stimuli exert their principal influence on the adrenals and, through them, upon the thyroid and other endocrine organs. A very common cause of adre- nal irritation and later adrenal insuf- ficiency is emotional overstimulation. Hence it can be readily seen that the adrenal glands are likely to be involved in a large number of cases; and, dependent upon their resilience and capacity to come back, the body is lia- ble to lack their service, at least during the maximum period of hypoadrenia. Customary Adrenal Symptoms. When the ordinary symptoms of hypoadrenia are enumerated, it will be quickly apparent that there is some intimate relationship between this condition and neurasthenia, for the symptoms of both manifestations are practically identical. This is so uni- formly the case that Dr. Leonard 27 Williams, of London, once said: "I boldly call attention to the practical identity in the symptomatology of the real neurasthenia with that of adrenal insufficiency." Let us recall the picture of the patient with adrenal insufficiency. The first and transcendently important fea- ture of such a case is that he is " all tired-out " and has neither initiative, reserve, nor that attribute so commonly called " pep." Besides this asthenia, there is a remarkably reduced circula- tory efficacy. The patient suffers from cold, especially in the hands and feet, he has other evidence of circulatory stasis, and still more important, the blood-pressure in most instances is much below the average normal. From the standpoint of oxidization, the tem- perature usually is subnormal, and the elimination of wastes is carried out just as half-heartedly as every other function of the body is performed. A re- duction of 50 to 75 per cent, in the 24- hour urea figure is not at all unusual. These people are atonic; and, since the atonicity involves the alimentary musculature equally with the muscula- ture of the cardiovascular mechanism, intestinal stasis is the rule, and, naturally, auto-intoxication is aggra- vated. This atonic picture often may as- sume most distressing forms-apathy, disinterestedness, and even insanity being built upon this same essential foundation. In passing it may be mentioned that adrenal dysfunction, as well as actual adrenal pathology, is often found in insane persons, and Sir Frederick Mott recently reported (Brit. Med. Jour., July 21, 1923, p. 95) that in 143 cases of 28 dementia praecox the average blood- pressure was comparatively low, and in 100 cases brought to autopsy " the adrenals were smaller than in any other class of cases studied to date." All functions dependent upon sym- pathetic maintenance, or in the regula- tion of which the autonomic nervous system plays a part, become deranged as a result of this serious chemical irregularity, and bad inevitably be- comes worse with inexorable swiftness. The neurasthenic syndrome always appears " hopeless " to the sufferer, and too often to his physician as well. So, for our encouragement, let us re- member that the Harley Street neu- rologist, Dr. S. Kinnier Wilson, once said: " The sympathetic tone is de- pendent on adrenal support; and until the glandular equilibrium is once more attained, sympathetic symptoms are likely to occur." Organotherapcutic Possibilities. Until the endocrine aspect of neur- asthenia was brought to the attention of the profession (the writer, reiter- ating things which he had been taught in France years ago, made the state- ment that " Neurasthenia of all condi- tions deserves to he studied and treated as a condition in which dysadrenia is the most important fundamental fac- tor"), the treatment of neurasthenia always was essentially a negative treat- ment. By this I mean that a change of surroundings, increased elimination, and enforced rest, both physical and mental, were the customary measures employed. This is negative treatment merely because it removes factors which are fundamental, leaving the body to recuperate as best it can. Of 29 course, such treatment is perfectly rational, because fatigue-and neur- asthenia is endocrinasthenia or adrenal fatigue-demands rest; and it cannot be overcome without rest. However, what to my mind is far better, is treat- ment which is more positive in its action, i. e., while the causes are being con- trolled advantageously, and the over- worked organs are being rested as much as possible, why not also encour- age the depleted endocrine mechanism which is so fundamentally at the bottom of this syndrome! This is indeed a direct and positive measure, and clinical ex- perience has proved it to be " a revolu- tion in the consideration as well as in the treatment of neurasthenia." Adrenal Sxi/pport. The fundamental therapeutic princi- ple of adrenal support applies in neur- asthenia just as it does in any of the other manifestations of hypoadrenia. The administration of an organotherapy calculated to encourage the exhausted adrenal system is just as rational as to offer other forms of homostimulative organotherapy in the hope of increasing the ovarian function, the thyroid func- tion, or any other endocrine function. Since the adrenal aspects of the majority of cases of neurasthenia are of paramount importance-first, as we have seen, in the study of these diffi- cult cases; and, secondly, as I am now attempting to show, in their successful treatment-considerable emphasis has been given to the value of adrenal sup- port by an extended experience with Adreno-Spermin Co. (Harrower). The remarkable results following its use in neurasthenia have clinically proved its value in a very large number of cases. 30 The tired-out, run-down patient invariably manifests evidence of endo- crine disorder. The ductless glands are just as depleted as the rest of the organism as a whole. Since it is of capital importance, particularly when there is hypocrinism-generalized en- docrine insufficiency-that these endo- crine organs should deliver to the body the vital chemical messengers which initiate and maintain so many im- portant functions, a corresponding pluriglandular support is in order. When the neurasthenic syndrome in- cludes myasthenia and cardiac tire, with hypotension, cold extremities, poor elimination, and cellular lazi- ness, Adreno-Spermin Co. (narrower) should be prescribed, for this original pluriglandular treatment of neur- asthenia is given with the expectation of encouraging the endocrine glands so uniformly depleted in just such cases. Recapitulation. A Usual Method of Procedure. Every neurasthenic is toxic; there- fore, an essential part of the treatment of every such individual is the mitiga- tion as far as possible of this etiologic factor. Reduce the intake of easily putrifiable protein ; unload the stag- nating contents of the asthenic, flaccid alimentary canal, and neutralize the tendency to acidosis so obviously pres- ent in such cases. This is quite satis- factorily accomplished by the adminis- tration of a remineralizing formula containing magnesium phosphate, calcium phosphate, calcium glycero- phosphate, and potassium and sodium bicarbonates in suitable combination, known as Calcium-Phosphorus Co. 31 (Harrower)-Dose: 3 one-gram tablets, crushed, with much water, an hour before food, twice a day for three or four weeks, and thereafter on alternate weeks for perhaps a month longer. The removal of as many interfering factors of an emotional character as possible and the maintenance of a rest- ful environment should be carried out in conjunction with the pluriglandular therapy, which is as follows: In both sexes the formula Adreno- Spermin Co. (Harrower)-a carefully worked out combination of total adrenal substance, spermin from the interstitial cells of Leydig, and a small dose of thyroid-is prescribed: one sanitablet at meals and at bedtime. Usually this dose is large enough, though in certain cases it may be advantageous to give two sanitablets three times a day, or even two, four times a day during part of the treat- ment. Every case should receive this formula for at least two months, even though the results may seem to be entirely satisfactory before the expira- tion of this time. In grave cases, and particularly when it seems advisable to watch the patient carefully, the oral administration of this formula may be supplemented with hypodermic injec- tions of a corresponding solution. Sol. Adreno-Spermin Co. (Harrower) is put up in boxes of 15 ampules, and usually one intramuscular injection is given every other day for a month. It is not advisable to give these injections with- out the simultaneous oral adminis- tration of the corresponding formula. In neurasthenic women, in whom the ovarian factor is marked, the problem almost always involves dysovarism; and this subject is considered more 32 fully in several subsequent chapters. The formula Adreno-Ovarian Co. (narrower) is preferable in such cases. During the menstrual life it is given as follows: During menstruation, and perhaps for just a few days afterwards, omit the formula altogether; then prescribe one sanitablet at meals and at bedtime for ten days. Then until the onset of the next period, give two, three times a day. In such cases, pluriglandular therapy must be con- tinued during three or four menstrual periods. If there is no notable dysovarism, Adreno-Spermin Co. (nar- rower) is the remedy of choice, just as it is preferable in women with post- climacteric neurasthenia. A Warning-Contraindications. Certain cases of so-called " neuras- thenia " are complicated by sympa- theticotonus, a condition quite the opposite of asthenia. The usual apathy, inactivity, and cellular torpor are replaced by irritability, nervousness, and hypersensitiveness. Often, the unusually low tension of hypoadrenia is absent. These cases do not require this type of endocrine stimulation. The estimation of the basal metabolic rate or recourse to my Thyroid Function Test usually will show them to be cases of latent hyperthyroidism, and in such event Adreno-Spermin Co. (narrower) is contraindicated. Best results in such cases follow the use of the sympathetic sedative pluriglandular formula known as Pancreas Co. (narrower), coupled with the therapeutic routine suggested in my article, "Sympathetic Sedation in Hyperthyroidism" (see Chap- ter IX). 33 IV THE BACKWARD CHILD An Essentially Endocrine Problem-• The Glands Involved-Differential Diag- nosis-Criteria of Abnormality-Im- portance of Pluriglandular Therapy- A Time-tried Formula--Persistence in Treatment - Clinical Reports - Trust- worthy Preparations. Organotherapy has given to medicine some of its most remark- able surprises. What greater astound- mentthan to see a patient moribund in diabetic coma literally brought back to life by an injection of insulin? Is any- thing more wonderful than the re- sponse to adrenalin in shock or the apnea of asthma? Does not every obstetrician feel a thrill of apprecia- tion every time the application of the posterior pituitary solution " does the work " ? And " the original surprise " is just as amazing to-day as it was nearly thirty-five years ago when Dr. George Murray, then of Newcastle-on- Tyne, caused a backward child to grow and develop by the administration of an extract of sheep's thyroids. The passage of years has not dimmed the luster of this achievement. It is just as wonderful to-day to be able to offer hope to the parents of the help- less cretin or the mongoloid child. In fact, the possibilities of organotherapy are greater to-day than ever, for we have learned to appreciate the influ- ence of the other endocrine glands; and, based on this new knowledge, we 34 have been able to fit together several glandular substances which enable us to reach still farther toward the goal of the complete solution of the difficult problem of the mentally and develop- mentally defective child. An Essentially Endocrine Problem. The problems of abnormal growth and development, especially in children requiring special attention, constitute a very serious and difficult problem in medicine. Every so often the general practitioner runs across a child that is " different," backward, defective, or abnormal, whose disabilities range from a simple tardiness in certain of the functions of the body to a develop- mental dystrophy which has caused a material reduction in the size of the body, its normal development, or in the inherent power to direct it normally. Naturally, the broad classification, "backward children," includes a very wide range of disturbances, and their consideration here necessarily must be fragmentary. There can no longer be any doubt that the endocrine glands play a very important part both in the normal unfolding of mental and physical growth and the physiological changes associated with the metamorphosis from infant to adult, as well as in the pathological modifications of these changes. Since the glands of internal secretion are so definitely concerned in the normal growth of the individual, we must expect abnormalities in these glands to accompany defective develop- ment; and if the basic principles of organotherapy hold good, we should be able to modify some of these defects by applying them. 35 First and foremost among the glands which control growth and mentality is the thyroid gland. Its influence upon development is paramount. It has aptly been called " the keystone of the endocrine arch," and its relation to developmental dystrophies has been studied longer and better than any of the other endocrine organs. The literature on the subject is absolutely tremendous. As a result of this, the thyroid feature of the disorder under- lying the syndrome seems to have overshadowed the associated features. Because we know what an important role the thyroid plays, the rest of the cast is not appreciated as it should be. Yet the support which the thyroid receives from the pituitary gland, especially the glandular (anterior) lobe and the thymus, is, to say the least, essential. And later, as the endocrine influences of the gonads replace those of the thymus, the reciprocal relation between the sex glands and the thyro- pituitary mechanism is of extreme importance. We can be assured, then, that while the thyroid is an important and essential regulator of growth and mentality and that the backward child invariably has an important thyroid defect in his make-up, the closely associated glands deserve equal consideration, and that pluriglandular treatment is likely to accomplish far more than may result from the use of the single gland alone. The Glands Involved. Differential Diagnosis. The differentiation between those defective children that are likely to respond to organotherapy, and those in 36 whom there is no likelihood of benefit, is very difficult; and it is a very serious thing to doom a child to lifelong dis- ability by saying that this method of prospective merit, or that, need not be employed because it is useless. A source of trouble concerns the determi- nation of cerebral difficulties. If there are definite changes in the character of the cerebral cortex, or if there are de- velopmental defects in the cranium, which naturally would influence cere- bralgrowth and function, the prospects are not good; and it is for this particu- lar reason that the prognosis of many idiotic children is quite hopeless. The hypocrine child, on the other hand, is merely sluggish-not idiotic or de- mented-and his physiology is merely retarded. It has been shown that growth is not permanently arrested, as proved by the fact that thyroid, or other organotherapy, may bring about a complete change in all the clinical features. There is always the possibility, how- ever, that even in the child who is definitely defective from a cerebral standpoint, there may be an associated endocrine phase of sufficient impor- tance to warrant the attempt to modify it. Surely it is more proper to attempt organotherapy in such' cases than to deny both the child and its parents a chance at this " last straw." Criteria of Abnormality. The signs of functional dyscrinism are not marked in the young, except, of course, in the cretins and mongols, and yet this is just the time when such dyscrasias are beginning to develop. One of the most important matters to consider in the diagnosis of dyscrinism 37 is a review of the incidents of the developmental years, noting the occur- rence of severe infectious diseases or other prostrations, the rate of growth, the time of walking, of cutting the teeth, the onset of puberty (age, irregularities, etc.), and other signifi- cant features. In these factors are often found the criteria of abnormality. Thus we may see in retrospect the onset of metabolic changes of an abnormal nature, the development of endocrine toxemias from imbalance, etc., all of which may lead to a complex which can be controlled only by recourse to measures calculated to reestablish a more nearly normal endocrine func- tioning. This is not the place to outline the clinical findings in the obvious con- ditions such as cretinism, mongolism, or infantilism. Such information is easily found in practically all text- books. Rather do I prefer to devote this space to emphasizing the necessity for broadening our treatment of such cases, and for extending the control of this large class of developmental dys- trophies by pluriglandular measures, so much more than has been possible by thyroid therapy. Importance of pluriglandular Therapy. While I claim to have had a hand in securing a better appreciation of the importance of the pluriglandular idea, I did not originate it. It is Claude and Gougerot, of Paris, who should have credit for uncovering this great ad- vance in organotherapy in 1907. While I believe that my pluriglandular formula for the treatment of backward children was the first preparation of its kind to be recommended in this 38 country, it was by no means the original endocrine formula recommended in place of thyroid or to supplement it. As far back as 1912, Dr. R. Dupuy (Jour, de med. de Par., 1912), who had made an extended study of the treat- ment of backward and defective chil- dren, used pluriglandular therapy with very encouraging results, which he summarized as follows: " (1) A rapid increase in stature, which had been slow to show itself with thyroid treat- ment, and a reduction in the rapid growth in those which seemed to be suffering from gigantism. (2) A less marked reduction in emaciation than with thyroid treatment alone, and a more decided tendency to regain the initial weight than when thyroid alone had been allowed. (3) An extraor- dinarily rapid modification of the urinary elimination, clearly indicating that metabolism is reestablished on a more nearly normal basis and that assimilation has become regular. (4) A beneficial effect on the disorders due to morbid phenomena as well as on those lesions of a sympathetic character which are found in the backward (and which thyroid treatment often does not influence), including troubles in vision, incontinence, visceral ptoses, umbilical hernia, etc. (5) A general physical metamorphosis and reestablishment of the sexual functions (menstruation, ovulation, etc.). (6) A psychic and sensory metamorphosis and a reduc- tion of asthenia and excitability, as well as a noticeable progress in the in- tellectual capacity, thus allowing these unfortunates to take their proper place in society." I submit that if such a catalog of ameliorations can be obtained as the 39 result of pluriglandular therapy, then a very good case has been made out for the much more extensive treatment of thesp unfortunates by such means. At all events, the pluriglandular therapy of defective children has been a good deal more successful in my hands, as well as in the hands of a good many of my friends, than thyroid or pituitary or thymus feeding alone, all of which have been recommended in the litera- ture as of use in these cases. I have therefore combined these preparations in suitable amounts in a formula known as Antero-Pituitary Co. (Harrower), each dose of which contains 2 grains of the desiccated anterior lobe of the pituitary body, 1 grain of thymus, 1/12 grain of thyroid, with the mineral salts which correspond to those found in the blood. This has been used in many cases of defective development, and I have seen a number of children in whom it was eminently successful-a child of two or three years, previously unable even to sit up, who has not only learned to sit and crawl, but to walk; children of five to seven who had never been able to speak who, in six or eight months, were able to make intelligible sentences of five or six words; a child of eight years who had been persistently constipated from birth and who " had never had a normal bowel movement in his life," whose alimentary condition was modified and the constipation en- tirely controlled without cathartics. (Parenthetically it may be well to state that one of the common manifes- tations of endocrine deficiency is cellu- lar infiltration, muscular atonicity, and asthenia-all of which very definitely A Time-Tried Formula. 40 favor chronic alimentary insufficiency and stasis.) I have seen individuals, fifteen or sixteen years old, who had not grown a fraction of an inch for five or more years, suddenly begin to grow and change, following the application of this formula. I recall one boy in particular who was fifteen and a half when I first saw him; height four feet four inches; general contour stubby and ugly; with a temperament that was very unfortunate-it was almost impossible to get on with him. His liver was stimulated with Bile Salts Co. (Harrower), and Antero-Pituitary Co. (Harrower) was given, with the result that within four months he grew two inches and, better still, his tem- peramental difficulties disappeared. I have seen infantilism in children at puberty modified by this formula, or another similar to it containing ex- tracts of the gonads. Persistence in Treatment. The real attempt in all these cases is to reestablish the deficient functions, to educate certain glands; and, as with all other forms of education, this takes time. Pluriglandular therapy should be continued for a minimum of six months. It must be given regularly and the results watched carefully and, if necessary, the treatment modified to suit the changing conditions. Natur- ally, every associated effort to facili- tate the desired outcome should be advised. Particular attention should be paid to elimination and to the metabolism of the mineral salts, by the use, for instance, of Calcium Phos- phorus Co. (Harrower). The usual dosage of Antero-Pituitary Co. (Harrower) is two or three tablets 41 a day, the former for children under six and the latter for older ones. I am in the habit of prescribing them to be taken for four out of every five weeks. Clinical Reports. Clinical experience is the best teacher. One can never predict the outcome prior to treating a case of this type. The results are variable and do not always show themselves early. The time element is most important and persistence must be fostered by the physician-in fact, no case should commence this treatment for a shorter time than six months. Many cases do not respond; but when they do, usually after months' or years' treat- ment with thyroid alone, the outstand- ing value of pluriglandular therapy is obvious, as the subjoined cases show: "A defective girl, age nine, who had never spoken, and who could take only a few steps by having the body supported under the arms, came under my care. When I first took the case, the tongue seemed to fill the whole mouth and rested on the lip; there was constant drooling and it was with difficulty that she swallowed. It was quite impossible to see the tonsils. Her elbows and wrists were semi-flexed, and she could stand only by being propped up in the corner. Apparently, impressions were taken through the ears. Her parents had had the best specialists in Baltimore, and their prognosis was that she ' might walk, but would never talk.' I put her on your Antero-Pituitary Co. two months ago. Already the tongue has come down to normal size, and the soft palate has been taken up to its proper height. The whole expression of her face has 42 improved and, by the way, she is a very good-looking child. Unfortu- nately, the head is about two inches too small, but I am hoping there may be an energizing of the whole skull; certainly the seeming exostosis above the eyes has vastly improved in ap- pearance, and while there is life there is hope. She has better accommodation of vision, and now sees about 12 inches from the eyes. The guttural sounds that she makes have taken on a higher pitch and she can stand on both feet with fairly good arches. This is a great improvement." " You will be interested in a case of very pronounced sporadic cretinism in a small child three years of age, who had never walked, talked, or even laughed when I started treatment. Nearly all of the physicians in the country round previously had given this little boy treatments to put him on his feet, but he still remained the same little baby with the appearance of a typical cretin. I prescribed your Antero-Pituitary Co. and to date they have given him 150 doses, with perhaps 50 grams of the remineralizing formula, Calcium Phos- phorus Co. (Harrower). This treatment has been continued for three months, with the result that the baby walks with a walker and satisfactorily makes the turns. He now cries if the parents do not notice him and speak to him, but the most remarkable thing has been the change in the appearance. I am delighted to tell you that the family is fully satisfied. Of course, I shall con- tinue treatment for months to come." "A miniature girl, age nine, came for consideration some time ago. At that time her weight was about 32 pounds and her length was 26 inches. She had 43 never walked and could not talk, al- though she had learned to make certain noises which were partially intelligible to those who lived with her. She had a double curvature of the spine; her left foot was turned in and her legs and arms were extraordinarily small, and I could span the leg above the knee with my fingers. She was undoubtedly an unusual type of cretin and there had been no improvement in her condition despite desultory treatment over a period of years. I gave Antero-Pituitary Co. (Harrower), with occasional addi- tional doses of anterior pituitary sub- stance. In a year the girl gained over 30 pounds, virtually doubling her weight. She now stands, walks, and runs well. The curvature of her spine has been greatly straightened and she talks in a way that is quite encour- aging. Her mother says that about two-thirds of her words are intelligible. Her height is now 37 inches-a gain of 11 inches-and her mentality has im- proved a thousand per cent." " For the past nine months I have had my son (eighteen years) on your Antero-Pituitary Co. for arrested phys- ical and mental development. For the first two months I could see no results, and became somewhat discouraged. I was about to discontinue the treatment when the boy began to grow, so it was continued for seven months. He has not been taking the sanitablets for three months now, but during the past year he has grown 6 inches. His mentality is normal, he weighs 155 pounds, and seems normal in every way-even beginning to grow a mustache! " " I am pleased to submit a brief clinical report of an experience that 44 I have had with a backward boy of eighteen. This boy, who is fairly well developed and especially muscular, has been subject to attacks of grand mal since he was four years of age. He has been given many forms of treatment customary in this disease, but there has been no permanent benefit. For years he has had several grand mal attacks each day and the record shows that there have been as many as sixteen in twenty-four hours. I have had him on Antero-Pituitary Co. (Harrower) now for three and a half months, and I am pleased to be able to state that there have been no spells after the first forty-eight hours of treatment, and I am assured that during the past fourteen years this lad had never gone over forty-eight hours without an attack." It is particularly important to get a trustworthy preparation. There is more than one value of glandular products on the market. My own formula, in addition to being the orig- inal application of pluriglandular therapy for the treatment of develop- mentally defective children, is made up of ingredients of maximum quality and in suitable dosage. Please note the dose of anterior pituitary substance- 2 grains, or approximately 12 grains of fresh anterior lobe; and this means (interior lobe, not connective tissue, fat, or other portions of the gland. Prescribe Antero-Pituitary Co. (nar- rower), one t.i.d. for four out of every five weeks. Continue for at least six months. (In very small children, under three years, give only two doses a day.) Trustworthy Preparations. 45 V EPILEPSY AND THE ENDOCRINES Endocrine Therapy Better Than Bro- mides-Thyroid Considerations-Is the Pituitary Involved?-Epilepsy in De- fective Children-Ovarian Epilepsy-• A Pituitary-Ovarian Complex-The Use of Sedatives-Diagnosis of Endocrine Epilepsy-Ideal Method of Procedure. DESPITE all the advances of the past few years, epilepsy still remains a big problem. We have by no means reached the ultimate in our knowledge of the etiology of this disease or of its treatment. The application of the ideas of those who have attempted to connect epilepsy with disordered endocrine function seems to be as worth-while a way to progress as any of which we have knowledge. Endocrine Therapy Better Than Bromides. Much of the advance along this line has come as a result of empirical study. It has been said that the attempt to apply glandular therapy by the use of extracts of the pituitary gland, the thyroid, or the sex glands (alone or suitably associated) is subject to criticism; but to my mind such procedures are better than the use of bromides, which, as we all know, are merely makeshifts. There are still those physicians who, when confronted with an epileptic, automatically write a prescription for 46 " triple bromides, gr. xv, t.i.d." Whether this is a beneficial procedure or not, it certainly is not scientific. On the other hand, it is known that epilepsy is a central nervous reaction to toxemia (much stress has rightly been laid upon the intoxication due to the usual hepato-biliary-enteric derangement so common in epileptics), and the ductless glands have much to do with the regulation of metabolism and detoxication. In fact, dyscrinism may be responsible for enough of the underlying conditions in epilepsy to make possible a revolution in its treat- ment, and to enable us actually to cure the epileptic manifestations in a fair proportion of cases. This applies particularly to epilepsy associated with definite endocrine dis- turbance, especially of the ovaries. As we shall see shortly, epilepsy associated with menstrual difficulties has been entirely removed by organotherapeutic regulation of disturbed ovarian activity. Thyroid, Considerations. Let us first consider the possible relations between " the chief endocrine gland ''-the thyroid-and the epileptic groundwork. It has been shown in many com- munications that disorders of the thyroid gland may be accompanied with epilepsy. In a paper published in 1916, entitled " The Relation of the Thyroid Gland to Epilepsy," I collected a good deal of information which seemed to establish the belief that hypothyroidism is a factor in the cause of epilepsy, and that when an epileptic has an associated hypo- thyroidism, treatment by the obvious organotherapy might have some bene- 47 ficial influence upon the epilepsy as well as upon the thyroid condition. From the information gathered in this article I drew some conclusions which I still believe to be fundamental: 1. Thyroid insufficiency is likely to be a frequent factor in the etiology of epilepsy for several reasons: (a) It favors toxemia; (b) it produces cellu- lar infiltration and edema, which may affect the brain in the manner de- scribed by Hertoghe, Reed, and others; and (c) it usually causes other symp- toms in epilepsy which have been defi- nitely attributed to hypothyroidism. 2. Thyroid therapy is a rational therapeutic adjunct in the treatment of epilepsy accompanied with other signs of hypothyroidism. 3. Favorable results following the use of thyroid extract in certain cases of epilepsy should be considered as confirmation of these conclusions. Is the Pituitary Involved? Pituitary dystrophies have been con- nected with epilepsy by many writers. Several of the papers which show an evident relationship between dys- pituitarism and epilepsy are doubly interesting because they include re- ports of good results following suitable organotherapy. The effort to modify this feature of the underlying dys- crinism has been of simultaneous bene- fit to the accompanying epilepsy. Just why the pituitary should be involved in the etiology of epilepsy does not seem to be very clear, save only as increased intracranial pressure from an enlarged gland might cause pressure upon local structures which, in turn, might cause the typical experiences which we call epilepsy. I frequently 48 have seen cases in whom I was confi- dent that the suggested relationship between the pituitary and epilepsy, which was discussed so interestingly by Dr. Harvey Cushing, of Harvard, in his book, was a reality. As to whether such a syndrome can be modified by organotherapy must always remain to be seen, for each individual is a law unto himself. Cushing gives six reasons why pituitary insufficiency is related to epilepsy. In brief, they are as follows: (1) Sir Victor Horsley, of London, noted increased excitability of the motor cortex in hypophysectomized dogs. (2) Epileptiform convulsions were frequently seen in animals which survived for long periods after partial removal of the pituitary. (3) Epilepsy is a frequent accompaniment of clinical conditions in which an insufficiency of the pituitary is manifest. (4) The pituitary may be damaged from a bursting fracture of the base of the skull. (5) It is believed that the posterior lobe secretion enters the spinal fluid, thereby bathing the cortex with a substance essential to the functional stability of the cortical cells. (6) Many individuals, supposed to be suffering from so-called genuine epilepsy, present symptoms of pituitary insufficiency, and in some of these, pituitary extract has served to moder- ate the seizures. Epilepsy in Defective Children. My consideration of epilepsy from the endocrine standpoint naturally has been connected with the possibilities of pluriglandular therapy. My first interest in the subject came as a result of the coincidental betterment of 49 several cases of epilepsy in children who were receiving pluriglandular therapy for developmental dystrophies which clearly were of endocrine origin. The fact that epilepsy commonly is found in the young, seems to indicate that something which takes place during the developmental period may be at fault. It is worth while investi- gating whether or not some endocrine factor may be related to this; for it is in the young that the developmental processes are most active and that the endocrine glands which have to do with development render their most important service. It is during this period also that these all-important organs may show evidence of imperfect action. It is well known that the large class of children who require special atten- tion, who are backward, or in whom there is some developmental defect, as well as those who are in some more definite endocrine class, as the cretins or mongols, not infrequently have a tendency to epilepsy. Many of these children have been treated with thy- roid, and in some instances the better- ment extended considerably beyond the developmental feature, and the epi- lepsy itself was improved. Experiences with the combination of anterior pitui- tary, thyroid, and thymus, known as Antero-Pituitary Co. (Harrower), in the treatment of a very large number of developmentally deficient children indi- cate that the aggregate of results from its use has been very encouraging. Not a few of the children thus treated had epilepsy also, and with the general betterment there has come a fortunate change in the epileptic manifestations. The reduction in' both the number and 50 the severity of the attacks indicates that the endocrine therapy is fully as advantageous in controlling this type of epilepsy as it is in modifying the as- sociated endocrine irregularities which cause the developmental and mental defects. It is admitted that such pro- cedures are empirical, and I confess that not always has there been a clear- cut demand for each of the three en- docrine products that I have routinely recommended. However, despite the criticism which naturally comes to those who are not afraid to lean toward an intelligent empiricism, great prog- ress in the study and the treatment of epilepsy has resulted ; and, best of all, many parents are rejoicing to-day over the marked improvements secured in their children by this treatment. It was quite natural for a physician having obtained good results with this method in children, to extend the same treatment to older persons. While the aggregate of results has not been so good in adults, there has been marked benefit in many cases,, and not a few physicians have been encouraged to make a trial of this form of treatment whenever they are confronted with this difficult problem. There is enough clinical benefit to indicate the far- reaching results of endocrine impair- ment, and it is confidently believed that the consideration and treatment of this important factor in many cases of epilepsy, especially in children and youth, by means of this same pluri- glandular therapy, contain the best hope of therapeutic success. Ovarian Epilepsy. There is another form of epilepsy which is related so closely to ovarian 51 functioning that it is more decidedly an ovarian problem than anything else. It is called " ovarian epilepsy " because the epileptic attacks, both of the grand mal and the petit mal type, are related either in the time of their onset or in the degree of severity to the ovarian function, and particularly to ovarian dysfunction. In other words, certain women develop typical epilepsy, which on careful investigation is found to be connected with a pelvic difficulty, the attacks having been initiated in connection with some menstrual, ob- stetric, or postpartum experience. Further, the study of these cases by means of the diary and chart, indicates that the number of attacks and their severity have a wave-like character which closely follows the wave on the menstrual chart. A number of suggestions have been voiced as to the actual cause of the difficulty, and it is the writer's opinion that the cause is not necessarily ova- rian in origin, although clinical experi- ence certainly relates the disordered endocrine function of dysovarism with ovarian epilepsy. Some writers believe that the pituitary gland is the princi- pal factor and that irregularities in its size and functioning come about as a result of greater demands put upon it by ovarian functional irregularities, for it is well known that the pituitary plays an important role in the regula- tion of ovarian function. Again, the thyroid has been consid- ered to be an important etiological factor in some of these cases, largely because thyroid irregularities often have been uncovered in the study of these cases ; but practically always the ovarian feature appears to be equally 52 important. As a matter of fact, the reader will quickly recall that of all the endocrine glands connected with ovarian functioning, the thyroid is quite the most important ; and, as Dr. Oliver T. Osborne, of Yale University, said, " The thyroid is typically a fe- male gland, entering constantly into the woman's sexual life. Menstruation cannot properly occur without the ac- tivity of the thyroid." To revert for the moment to the role which the pituitary plays in such conditions, an article by Drs. Lisser and Nixon, of San Francisco, entitled " Dyspituitarism and Epilepsy" (Med. Clin. N. Amer., 1923, vi, p. 1471), indi- cates the close connection between endo- crine, and especially pituitary, dys- function and " idiopathic " epilepsy. Of the six cases reported in this article, five had reached or passed puberty and " all presented menstrual disturbances especially characterized by a scanty flow and an abnormally prolonged interval." Mental retardation, espe- cially impaired memory, was fairly marked in practically all the cases and emotional disturbances common to dyscrinism were seen in all. The inter- esting conclusion, as quoted in Endo- crinology (Sept.-Nov., 1923, vii, p. 855) is that " organotherapy was adminis- tered to all six patients with strikingly beneficial results in the menstrual dis- turbances, obesity, and mental and emo- tional status. In the five patients under treatment for a long enough period of time, epileptic seizures either ceased entirely or became far less fre- quent and much milder. . . . The authors emphasize the importance of A Pituitary-Ovarian Complex. 53 early apprehension and treatment of endocrine abnormalities." Many experiences confirm this posi- tion. I have personally prescribed ovarian substance alone, anterior pituitary substance alone, thyroid sub- stance alone, and various combinations of these three endocrines in at least fifty cases of epilepsy connected with dysovarism, and, while we have not had so satisfactory an average of re- sults as Lisser and Nixon report, bene- fit was secured in more than half of these cases and an apparent cure in thirteen. When it is recalled that epi- lepsy is one of the most serious neuro- logical problems, and that just one at- tack is an experience through which no reader of this little book would care to go, any change which permits an individual who has had from two to ten attacks a day to go along with no further attacks at all, or perhaps with only one or two a month, is very cor- rectly indicated as " nothing short of marvelous." The Use of Sedatives. Many of my colleagues have had occasion to experiment with sedatives in a number of these cases. In some of them, sedatives (bromides and lumi- nal) were continued. In others the dosage was modified, and in still others it was discontinued altogether. From these experiments we can advise the continuance of sedative medication during the early part of the treatment until the influence from the organo- therapy begins to show itself, at which time the sedative part of the treatment may be tapered off. Manifestly, an endocrine treatment can have little or no neurosedative effect upon the 54 irritability of the motor cortex such as we expect from the administration of drugs. Organotherapy has revolutionized our conceptions of epilepsy. It has opened the door of hope to every phy- sician confronted with this " strangest of diseases," as Spratling once called it ; and if we are not mistaken, the types of epilepsy under discussion here are most likely to have a fundamental endocrine basis and to respond most satisfactorily to this form of treatment. The subjoined letter is worth quot- ing because of the question it contains and for the excellent clinical report that my correspondent included : " That I am interested in your prod- ucts you already know. My experi- ences with your Antero-Pituitary Co. in a number of cases of epilepsy prompt me to ask this question : How can you determine in advance in which cases you may expect results from this treatment ? " You may be interested in the fol- lowing recent experience : A man, age twenty-eight, began to have epi- lepsy which for ten years gradually became worse in spite of treatment by a number of physicians. He had gone over the usual bromide road, and when I saw him a year ago, at the age of thirty-nine, he was having five to eight heavy grand mal attacks daily. For a year now he has been taking Antero- Pituitary Co. (Harrower). After the first month's treatment the character of the attacks changed. After two and a half months my record reads, ' A few petit mal attacks daily.' Occasion- ally he would have a complete attack. Diagnosis of Endocrine Epilepsy. 55 Now he goes six weeks or two months without any seizure. He is not cured yet, but he is certainly a different man." The answer to this inquiry is re- printed from The Organotherapeutic Review: "Your experience was the more in- teresting because of the age of the man and the number and severity of his attacks. So far as I know, there is no way definitely to determine in ad- vance whether a given case of epilepsy is an endocrine one and likely to bene- fit from organotherapy or not. Nat- urally, if there are clear-cut signs of thyroid insufficiency or the appearance indicates a pituitary case, one would be justified in presuming that it might be an endocrine case. But even this does not give one the kind of impres- sion that you must be seeking. " Suppose that a given case clearly has the thyroid-pituitary dystrophy. A half a dozen or more indications establish this to your satisfaction. This, however, is no therapeutic cri- terion. Merely because the case may very clearly involve the ductless glands, does not prove that the endocrine aspect is at the bottom of the epilepsy, for all endocrine cases do not have epilepsy. "As a matter of fact, while it is well to discover as many facts as possi- ble about the endocrine side of a given case, this only supports the supposi- tion that the case may respond to the treatment of the endocrine feature ; it does not by any means establish it in advance. Frankly, while I am being surprised continually by the re- ports I hear of epileptics who have been treated successfully with Antero- 56 Pituitary Co. (Harrower), I am equally discouraged about the very problem that you bring up, for so far as I know, we are no farther ahead to-day in determining the prospects from organotherapy and the prognosis of a case than we were before we began, these clinical experiments. As things stand we know very positively that many epileptics, chiefly the young, but also older people, have been benefited by the use of this pluriglandular therapy. The attacks have been ended entirely or their frequency remarkably changed ; attacks occurring from ten. to twenty or more times a day have been modified so that seizures occur once a week ; or, again, very severe seizures have been modified, i.e., grand mal attacks have been lessened to petit mal. " We know that with the changes in the epileptic aspects many times there has been benefit to other aspects as well, with a general increase in health and nutrition. I know these results have occurred in many hundreds of cases, but our figures do not allow us to determine the relation between results and failure ; and, of course, of the latter there have been fully as many as the former. " As I see it, the frank answer to your inquiry is, ' There is no way to determine this in advance,' but I must say that I never see an epileptic with- out wanting to give him the benefit of the doubt and treat him from this standpoint. Even if we do fail after four or five months we have done no worse than ten thousand other doctors have done with bromides." There can be no denying the fact that treatment of this character is 57 neither inconvenient to the physician nor harmful to the patient, and besides the very fair prospect for good results, it has an undoubted diagnostic value, which hardly can be said of the bro- mides and other drugs commonly used in the treatment of epilepsy. Manifestly, " everything " should be done for the epileptic. Dietetic control, detoxication, alkalinization, and ali- mentary stimulation-all are essential. Pluriglandular therapy is indeed an adjuvant measure. So, in addition to the best of care and advice, prescribe Antero-Pituitary Co. (Harrower), one at meals and at bedtime (in small chil- dren, one, two or three times a day with food) for several months. Give it without hope of results. Promise nothing. It is effective only in endocrine cases and can have no effect upon an essentially organic, nervous difficulty. In girls and women use Thyro- Ovarian Co. (Harrower), provided there is evidence of a relation between dysovarism and the epilepsy. The fol- lowing is the ideal method of admin- istration : Ten days after menstrua- tion begins, give one sanitablet t.i.d. During the ten days prior to the flow double the dose. Omit for ten days beginning with onset of the flow. Re- peat this step-ladder procedure for at least four menstrual experiences. Gonad-Ovarian Co. (Harrower) is a similar formula with a much larger dose of anterior pituitary substance. It may be used after the first two months of treatment with Thyro- Ovarian Co. and is given in the same cyclic fashion. Ideal Method of Procedure. 58 VI GALACTAGOGUE ORGANO- THERAPY Hormone Control of Milk Production- Value of Mammary Extract-Galacta- gogue Effects of Pituitary-Influence of Placenta Substance-Uterine Subinvo- lution-An Original Galactagogue For- mula-Some Convincing Experiences. THERE should be no necessity for emphasizing the advantages of breast-feeding-both to mother and in- fant-nor of the disadvantages and even dangers of agalactia-both to mother and infant. Nursing is a phys- iological advantage (I might almost say a necessity) to the mother, since it assists uterine involution, thus obviat- ing many pelvic disorders which de- velop where there is a boggy, atonic uterus. Consequently any remedy which is' of benefit in producing an abundant supply of milk is a godsend to mothers. Before endocrine therapy was well known there was but one drug in use for its galactagogue action. This some- what rare agent is extractum gossypii seminis, and it has been used with vari- able results. Other than this the usual admonition to drink plenty of milk and cream-or in Great Britain, ale and stout-was the sole measure adopted. Hormone Control of Milk Production. Experiments with preparations of animal origin have been carried out by many investigators. There are some references to the use of fetal tissue as a galactagogue, but the work is of only 59 technical interest. Extracts of thymus, ovaries, and corpus luteum have all been injected experimentally, but the milk-producing results have been varied, and provide no basis for the therapeutic use of these extracts. As incontrovertible evidence of the hormone control of galactogenesis, I will cite the remarkable experience of the famous Blazek twins. It may be remembered that this pair of pygopa- gous female twins matured and one of them married. In due time she became pregnant and was successfully confined and after delivery the secretion of milk occurred in the non-puerperal sister. In other words, both were able to nurse the infant, and obviously the influ- ences which stimulated mammary ac- tivity in the unmarried sister were of a hormone nature. The three organotherapeutic sub- stances which have been found to be most effective and which are now being employed in the treatment of agalactia are prepared from mammary tissue, the pituitary gland, and the placenta. They offer the best prospects for galac- tagogue effects of all the possible therapeutic measures, whether of die- tetic, drug, or endocrine origin. The mammary glands and the ovaries are physiological antagonists. While these organs begin their activity at puberty, and retrograde at the meno- pause, during their functional period they oppose each other. Mammary ac- tivity during pregnancy is balanced by complete cessation of the menstrual function, the outward evidence of the ovarian incretory activity. Usually menstruation does not occur during Value of Mammary Extract. 60 lactation, at least, it is not normal dur- ing this period. Nursing opposes the return of the menses, just as it favors postpartum involution of the uterus. Additional evidence is found from the effects of ovariotomy in animals during pregnancy. In his book Dr. Wilhelm Falta says : " The ovaries are not necessary for the pregnancy-hyper- plasia of the mammae, for in spite of castration undertaken in the early stages of pregnancy, the development of the breasts proceeds in a normal manner, and the women are able to suckle their children. Mainzer has col- lected sixteen such cases from the lit- erature and Halban has added three more. It looks very much now as though the removal cf the ovaries later exercises a favorable influence on milk production, as breeders state that cas- trated cows yield abundant milk." In his " Internal Secretions and the Ductless Glands," Prof. Swale Vincent reiterates the same fact: " Foges came to the conclusion that the ovary is, by its internal secretion, necessary for the development of the mammary gland, but not for the secretion of milk. Rather does the absence of ovarian function (in the view of Foges) in- crease the secretion of milk." In March, 1915, in an article in the Woman's Medical Journal, I made the statement that the mammary glands have come to be classed as organs with a dual function-the production of both external and internal secre- tions. The fundamentals upon which my paper was based are as follows : (1) The mamma, in addition to their galactogenic function, produce an in- ternal secretion ; are themselves sub- ject to hormone influences and hence 61 must be considered as part of the endo- crine system. (2) Suitably prepared extracts of the mammary parenchyma contain a principle (presumably a hormone) which exerts a definite physiologic action, and hence contains inherent therapeutic possibilities. The latest comprehensive work on the internal secretions is the five- volume series, " Endocrinology and Metabolism," edited by Hrs. Barker, Hoskins, and Mosenthal (1922). Sev- eral references will be made to various chapters, but first I will take a short quotation from the chapter by Freder- ick S. Hammett, supporting the previ- ous statements : " Further observations tending to demonstrate such an influ- ence have been made by Muller and by Hermann and Stolper, who found that puerperal involution occurs sooner when the breasts are sucked than when not. In addition, the fact that continued lactation leads to hyperinvolution, as demonstrated by Frommel, Gruner, Vineburg, Engstrom, and others, adds still more evidence of an underlying relationship between uterus and mam- mae ; whether or not this is neural, hormonal, or accomplished through some other intermediary is a matter for further investigation." From a therapeutic standpoint mam- mary substance has long been used with success in the control of ovarian hyperactivity, and, on the principle of homostimulation, mammary substance also should increase mammary activ- ity. One of the most remarkable ex- periments performed at University College, London, by Prof. E. H. Star- ling and his associate, Miss Lane-Clay- pon, was the establishment of lactation in virgin rabbits by the administration 62 of mammary extract. Previously to this, Hibbert, in 1898, had shown that the development of the mammary glands was not controlled by the nerv- ous system. He transplanted a portion of the mamma from a virgin rabbit into a pregnant one, and the trans- planted gland developed and secreted milk. Most physiologists are agreed that glandular development and func- tion occur as a result of a chemical stimulus due to a hormone carried into the blood, although some of them, nota- bly Luciani, do not yet appear to be convinced of this. It is clear from the experiences mentioned above, that the hormones which develop and acti- vate the mammary glands are not spe- cific for the species from which they are taken ; but their action, as noted by numerous authors, is quite similar to that of other internal secretions. In two different references, Dr. Ivo Geikie Cobb, of London, calls attention to the fact that mammary therapy pro- duces mammary stimulation. The first is found in his book, " Organs of Internal Secretion," and is as follows : " From the therapeutic standpoint, moreover, the balance of evidence is in favour of administering mammary extract to promote lactation." Again, in "Aids to Organotherapy," he says : " The therapeutics of the mammary gland can be described briefly. In 1896, Bell, of Glasgow, showed that extracts of the mammae of cows had a galacta- gogic effect, and since then other observers have confirmed this. Apart from this action, mammary extract has been prescribed to neutralize ovarian over-activity, as it is believed that an antagonism exists between the mam- mary and ovarian hormones." 63 Galactagogue Effects of Pituitary. The pituitary gland next deserves brief consideration. 21 1 eport in the British Medical Journal, for July 24, 1915, called attention to the fact that the use of posterior lobe of the pitui- tary caused an increased secretion of milk. There is considerable discussion in regard to the real action shown. It is known that the pituitary principle has a powerful musculo-tonic effect, and its action as a galactagogue is at- tributed by some to this ability to expel the milk already present. How- ever, there has been some very inter- esting work done which seems to prove that pituitary extract really has a defi- nite effect upon mammary activity. Dr. Hugo Ehrenfest, of St. Louis, makes this statement: "Ott and Scott, of Philadelphia, in 1910, reported that an extract from the posterior lobe of the hypophysis (infundibulin) has a very powerful galactagogue effect on the se- creting mammary gland. . . . The pituitary extract is the most active, and it is active whether from lactating or non-lactating animals, whether from the same or a different species, and even when the hypophysis was taken from birds, in which, of course, no galactagogue effect can be a natural function of the gland. These findings later have been confirmed by Sir Ed- ward Schaefer, who believes that the largest quantity of the galactagogue hormones is supplied by the posterior lobe of the pituitary body, but . also is yielded by the corpus luteum, by the involuting uterus, by the lactating mammary gland itself, and perhaps by other organs." The fact that the pituitary has a 64 galactagogue effect has been confirmed by a number of other writers. Swale Vincent goes so far as to state that " of all the substances used to increase the milk supply, the pituitary body produces the most marked results." Bandler is more conservative in his statements regarding the pituitary. He says: " Whether the hypophysis has anything to do with this before or after labor is not known, but some consider the hypophysis secretion a re- markable galactagogue." Remarkably enough, it is the pla- centa which contains the most power- ful galactagogue principle. From time immemorial certain animals have been accustomed, to devour this organ. Evi- dently this is not due to instincts of cleanliness alone. Again, the placenta has been known to be used in past ages as a means of starting the milk flow ; and certain races in Brazil and remote districts of Asiatic Russia feed the placenta routinely for this purpose. A hormone with a galactagogue ac- tion has been found in the placenta, which Basch proved had no connection with the nerve supply of the breasts. He showed that its administration in animals, as well as its influence upon transplanted portions of the mam- mary gland, was unquestioned, the cells hypertrophying and producing milk. Teresa Bianchini, in an article ap- pearing in the Gazetta Italiana delle Levatrici (abs. in Brit. Med. Jour., Feb. 10, 1917), reports five cases in which placenta therapy was used with good results. In the same article the advantages to the mother, from the Influence of Placenta Substance. 65 involutant effects of placental extract, are reiterated. Robert T. Frank, of Denver (Jour. Cancer Research, ii, p. 515), showed that placental extract " experimentally stimulates the breasts, increasing the area and developing the ducts, acini, and nipples." S. W. Handler, in Endocrinology for June, 1919, includes mammary extract and placental sub- stance among " the valuable opothera- peutic products." Some convincing work along this line has been accomplished by Dr. Bertha Van Hoosen, of Chicago. A very interesting article by her appeared in the 'Woman's Medical Journal for July, 1921. From a knowledge of the in- stincts in the lower animals which causes them to ingest the placenta,, the doctor reasoned that this tissue must supply an active and immediate galac- tagogue. She carried out quite a large series of experiments with nursing mothers, giving to some dried placenta obtained from the cow, and using others as controls. It was determined that even in very large doses placental extract caused no deleterious effect, and that 40 to 60 grains administered during the first hours after delivery would stimulate a secretion of milk which would continue for three or four days. In this way painful tur- gescence of the breasts was obviated. Dr. Van Hoosen's conclusions about placental extract are concise and to the point : " I therefore classify the placental hormone as a physiological galactagogue, both on account of its production in the body and of its con- sumption by the animal. Our knowl- edge of the placenta is too meager to allow one to say that it furnishes an 66 internal secretion and is one of the endocrine organs, but it is upon that hypothesis that the administration of placental hormone is based." Another very important side-effect follows placental therapy. Besides exerting its most acceptable galacta- gogue influence, it also affects the involution of the uterus. Okintschits found that the administration of ex- tract of placenta prevented the atrophy of the uterine walls which so uni- formly follows extirpation of both ovaries. This gave an idea to Iscovesco, who shortly afterwards tried placental extract in an attempt to modify uterine subinvolution. He records several ob- servations in which this remedy ex- erted a beneficial influence upon uterine involution, and especially in certain cases of chronic hyperplastic metritis which followed accouchement. Ehrenfest has written quite fully on this subject and has compiled an inter- esting bibliography of convincing re- ports. He refers frequently to the work done by Basch, since he was probably the first investigator to initi- ate milk secretion by recourse to placental extracts. Basch contends that the development of the mammary glands is due to ovarian influences, but that the actual secretion results from the effects of the placental hormone. As a result of his study and observa- tion he feels justified in making the positive statement that " increased secretion of the breasts can be obtained by means of injection of placental extracts." The placental extracts of commerce usually are made from the fresh Uterine Subinvolution. 67 placentas of ewes, although occasion- ally those of cows are used. They are deprived of their blood, washed, chopped, and dried in vacuo, as in the preparation of other animal extracts. The dry powder represents approxi- mately 15 per cent, by weight of the fresh substance, and is quite innocuous when given internally. Over ten years ago I suggested that a combination of mammary, pituitary, and placental extracts should provide an efficient and rational means of stimulating milk production. If each of the ingredients is good, the com- bination should be better since the in- fluence of each of the aforementioned endocrine products is active through different channels. My original pluri- glandular formula, called Placento- Mammary Co. (narrower) has since been used by many thousands of phy- sicians throughout the world with un- usual success, both as a prophylactic measure and as a means of restoring a gradually subsiding milk flow. It is proper to emphasize the origi- nality of this endocrine galactagogue formula. It is the most effective prod- uct of its kind, and has been used with satisfaction for many years. The galac- tagogue value of this preparation is materially supported by its utero-tonic value. Its use frequently has stopped postpartum oozing and prevented early menstruation. In other words, its utero-tonic effect is as advantageous as its effect upon milk production. Many clinical experiences with this pluri- glandular formula have demonstrated that it is as beneficial to the mother herself as to the infant, and while it An Original Galactagogue Formula. 68 is a most satisfactory galactagogue remedy, its use should not preclude recourse to every hygienic considera- tion. Its effects, however, far out- weigh any results obtained by diet and other measures alone. Prescribe a package of 100 sanitab- lets-a smaller number rarely will suf- fice. It is advisable to commence the administration of Placento-Mammary Co. (Harrower) as early as possible- it is a prophylactic measure also. The initial dosage should be two sanitab- lets four times a day, preferably at meals and at bedtime. After two weeks, usually the dosage may be re- duced to one, four times a day. Con- tinue for a minimum of three weeks. Some Convincing Experiences. Subjoined are some clinical reports which may carry almost as much con- viction to the reader as they have to the physicians who render them and to their grateful patients : " Placento-Mammary Co. (narrower) is a real galactagogue. It has given me more consistent results than any treatment that I have previously used in twenty-five years of practice. You are to be congratulated on having de- veloped such an effective method of treatment." " A young primipara was not able to nurse her infant and we were ' not get- ting anywhere.' While I had never tried Placento-Mammary Co. (nar- rower) I had heard of it and did not think that it could do any harm, so I prescribed it. The next day the patient began to notice results, and within three days her breasts filled up so that they almost hurt her, and now both she and her baby are getting along beautifully." 69 " After taking only twelve sanitab- lets, the milk came in abundance. I have seen the same thing happen many times in my local practice. Placento- Mammary Co. (narrower) easily is the most dependable formula you put up." " I am glad to state that I have used Placento-Mammary Co. (narrower) as a galactagogue with very fine results in two cases. It has made me a thor- ough convert to this whole method of treatment." " I have used your No. 3 (Placento- Mammary Co. narrower) in a little woman whose baby was just starving. The mother's milk seemed to have virtually no food value. Very shortly after commencing the treatment, the breasts began to fill up and the results were really wonderful. This mother is now giving milk as good as any Jersey cow's. I have used this formula in a number of other cases, and have never failed to have good success fol- lowing its use." " Here is a report of some remark- able results from the use of your Placento-Mammary Co. Not only has this been of value as a galactagogue, but I recall a case in which it con- trolled an early menstruation (in a colleague's wife who had had heavy menstrual experiences commencing a short time after her baby was born). This lady calls Placento-Mammary Co. ' the magic tablets,' and I am glad to say that this experience has converted her husband to the use of several of your pluriglandular formulas." " I am pleased to report a remark- able experience with the use of your Placento-Mammary Co. Some months ago I delivered a woman of her ninth 70 child. She has never been able to nurse a single one of her other chil- dren ; but I told her she had to nurse this one, so I secured a supply, and sure enough the milk came ! Later this woman went away to visit a friend and forgot to take her tablets. Her milk immediately stopped and she had to order an additional supply by long distance telephone, and very shortly after it was taken, the situation was relieved. I have used Placento-Mam- mary Co. (narrower) in quite a large number of cases and have secured ex- cellent results from its use in at least 60 per cent, of them." "A woman whose baby had to be delivered by Csesarean section was un- able to nurse her infant. She received Placento-Mammary Co. (Harrower) and within a short time had plenty of milk, and finally it was necessary to discontinue the formula because she had too much milk." " I am glad to report a remarkable experience with Placento-Mammary Co. (Harrower) in a young mother who lost her milk because of the fact that her five-months-old baby had pneu- monia and, therefore, could not nurse. We pumped both breasts and massaged them, but the milk disappeared en- tirely. Matters were complicated by the fact that she constantly worried about losing her milk and about the condition of her baby. I gave this mother one sanitablet of Placento- Mammary Co. every three hours. It did not take more than twenty-four hours to start the flow again and now both breasts are well filled, while she takes one sanitablet four times a day." 71 VII MENSTRUAL IRREGULARITIES Causes of Menstrual Disorders-Clin- ical Fundamentals-The Endocrine Glands Involved-A Typical Case De- scribed-Neurasthenia a Common Re- sult-The Interdependent Glands-The Thyroid - The PiUtitary - Pituitary Headache-Climacteric Disturbances- A Thyro-Ovarian Formula-Mammary Tenderness-Varied Formulas for Dysovarism-Some Reasonable Con- clusions. COMPETENT authorities assert that no less than one-half of all women, from puberty to the climac- teric, suffer from menstrual irregulari- ties. These disorders vary as greatly in degree as they do in their etiology. On the one hand we find the simple and brief discomfort lasting for a few hours prior to, or at the onset of the flow ; while on the other, serious, pro- tracted disability results, which puts the patient to bed for several days, or even a week, each month, and the unfortunate sufferer is barely over her trouble before the next period brings it back again. The incidence of such disorders is greatest at the commence- ment and at the close of menstrual life. The study of this subject, from the endocrine standpoint, is intensely prac- tical because it broadens so very de- cidedly our possibilities for therapeu- tic service. The development of our knowledge of organotherapy has in- creased our information so much that 72 " things are now possible that before the advent of this new knowledge were quite beyond us." This applies particu- larly to the use of the principle of gland stimulation made possible by the use, as remedies, of extracts of cer- tain of the endocrine glands. Cause of Menstrual Disorders. Numerous factors are responsible for menstrual irregularities, and it is pro- posed to discuss briefly the endocrine features of menstrual disorders. Our consideration will ignore the organic derangements, since they are rarely endocrine in character, and even where this exception is encountered, a treat- ment that is directed at a functional disturbance is not likely to benefit a structural difficulty. It is my opinion that the majority of functional menstrual irregularities are essentially endocrine in their etiology. By this I do not mean that the cause lies solely in the incretory glands, but that the essential difficulty involves the production of these vital internal secretions. It should be remembered that the most common underlying causes of dyscrinism-disturbed endo- crine functions-are toxemia, malnutri- tion, and infections, while sympathetic or emotional factors frequently are involved. Regarding these underlying causes little can be said here, save that a careful search should be made for such disturbances and, naturally, the treat- ment should embody every effort to detoxicate, neutralize, and increase the nutrition of the organism, for it is now well known that these conditions can- not exist without derangement of the endocrine activities. 73 Clinical Fundamentals. Ovarian hormone function begins at puberty, and is responsible for the deep-seated changes of this epoch, in- cluding menstruation ; hence a large share of the disturbances of menstrua- tion necessarily must be of an endo- crine character. Amenorrhea, dysmen- orrhea, and the disturbances of circu- lation, nutrition, and resistance that are related to the monthly flow are dependent in greater or less degree upon the normal functioning of the ovaries and related glands. The various manifestations of amenorrhea range from long-standing absence of the menses through irregu- lar menstruation to a somewhat de- layed or scanty menstruation. Fri- gidity, sexual apathy, and sterility are also important. Pelvic congestion, dysmenorrhea and its varying mani- festations, and, occasionally, menor- rhagia, often are of the same origin. The Endocrine Glands Involved. The endocrine disorders which so often are at the bottom of menstrual Irregularities involve the ovaries them- selves, the thyroid, and the pituitary body, probably in the order mentioned. Ovarian dysfunction results from an inherent lack in the actual incretory power of the corpora lutea, and when the regular production of the luteal hormone is modified, not only do we find menstrual insufficiency, but a les- sened utero-ovarian circulation and nu- trition. With this, one often finds defective development with modifica- tions in the usual mental and physical out-folding of the secondary sex char- 74 acteristics, or infantilism. The results of this complex upon the menstruation invariably include amenorrhea, either complete, or, more usually, an irregu- lar menstrual insufficiency. By " irregular " menstruation is meant a monthly flow indeterminate both in point of time and amount, ranging from periods of complete amenorrhea, with not even a molimen, through a varying degree of menstrual discomfort with little or no flow, to a menstruation which lasts for a very short time and may occasionally be quite profuse. Rarely is this condition present without some more extended influence upon the organism as a whole. If we visualize a typical case, we can see how other concomitant dis- orders are built upon a foundation of dysovarism. A Typical Case Described. Here is a brief description of a more or less typical case of dysovarism. The patient complains of uncomfortable sensations, such as pelvic heaviness, vague nervous manifestations, and a feeling of general malaise of varying degree, for a longer or shorter time prior to each expected menstruation. Delay is the rule. Irregularity of onset and a scant flow are customary. During the period of delay, the patient often suffers from severe colds; an old ton- sillitis reawakens; headaches of quite decided severity are common ; in fact, the patient is so tired and below par at these periods that during them any latent condition may become aggra- vated because of the temporarily low- ered resistance. This is particularly true of those who are tuberculous, and it may be said with emphasis that the 75 regulation of dysovarism invariably should be undertaken in all women with tuberculosis. When the menses do begin and are properly started, these troubles disappear-until the next pre- menstrual delay. And so on. Frequently this element of delay lays the foundation for a condition of neurasthenia, and it is common to find neuroses in those suffering from dys- ovarism. Many cases called " neur- asthenia " and many associated mental and physical ills are connected in some direct or remote way with the men- strual function. In many sympathetic nervous disorders, well-defined as well as vague, the ovarian element is pro- foundly important. There is a rela- tionship between ovarian functioning and the adrenals, probably through the thyro-pituitary mechanism. No matter how this connection is maintained, symptoms of severe adrenal depletion often accompany dysovarism and " the fatigue syndrome " may predominate. The principle of adrenal support referred to in Chapters II and III often must be applied with the ovarian regulation (see especially pages 32- 33). Ovarian therapy is an accepted method of encouraging a more nearly normal ovarian function. By this means we can increase the pelvic cir- culation and ovarian nutrition. Scores of articles in the medical literature of the past ten years, as well as thou- sands of clinical experiences, empha- size the advantages of ovarian homo- stimulation. I propose to show that one can accomplish more by pluri- glandular therapy. Neurasthenia a Common Result. 76 The Interdependent Glands. Endocrine interrelationships are par- ticularly important in gynecology. The influence that other members of the ductless glandular system exert upon the initiation and maintenance of nor- mal ovarian activity is vital. Physiologists have shown very defi- nitely, and clinical experience likewise proves, that the ovaries are function- ally related to others of the glands of internal secretion. Undoubtedly the thyroid actually controls ovarian function. Its hormone encourages menstruation, and condi- tions of hypothyroidism very com- monly determine a lack of sexual de- velopment and amenorrhea. It is well known that cretins do not develop sexually and that myxedema commonly is accompanied by varying degrees of menstrual insufficiency. Recall also the frequent " sympathetic " enlargement of the thyroid during pregnancy, when ovarian hormone production rests ; and, too, the very common association of menstrual difficulties with goiter, especially in girls. Again, the pituitary gland also is functionally intimate with the ovaries. The adiposo-genital dystrophy of Frohlich is a condition of hypo- pituitarism and ovarian insufficiency is a customary part of this syndrome. In fact, this influence is so marked that there is not merely a functional insufficiency, but a distinct atrophy not merely of the ovaries, but also of the uterus and external genitalia. Many cases of amenorrhea have a minor pituitary aspect, and pituitary feeding often has caused a marked betterment in conditions of this type. 77 Pituitary Headache. Pituitary headache is now known to be connected many times with dis- turbed ovarian function. For instance, the individual with typical ovarian insufficiency and delayed and irregular menses frequently complains of a severe pressure headache just prior to the menstruation, which disappears as soon as the flow is thoroughly estab- lished. Is it unreasonable to suppose that the pituitary gland, known to stimulate ovarian function, is vicari- ously attempting to encourage the ova- ries just exactly as the thyroid many times enlarges in order to do this very thing ? And since the gland is limited in its bony cup, the sella turcica, the congestion causes a slight increase in its size with a resulting temporary pressure, which is really the cause of the headache. As soon as pituitary therapy is instituted or the ovarian function is reestablished, the necessity for this pituitary engorgement is re- moved and the headache ceases. Climacteric Disturbances. At the menopause the ovarian hor- mone production ceases, slowly or sud- denly, and the delicate hornionic mech- anisms of the body are unbalanced. Since each of the glands of internal secretion is in such intimate depend- ence upon one another, to remove a factor to which the body has accus- tomed itself for, say, thirty years, usually causes trouble, the extent of which depends largely upon (1) the previous ovarian hormone production, (2) the rapidity of the completion of this function (a sudden menopause, like a " surgical menopause," is liable to 78 be more severe than when the transi- tion is more gradual), and (3) the sensitiveness of the associated glands, especially the adrenal glands, due to toxemia, acidosis, and also emotional factors. Suffice it to say that there is preponderating evidence that ovarian therapy is a rational means of miti- gating the circulatory and nervous im- balance of the climacteric ; and when this potent measure is reinforced by synergistic extracts, the benefit is so much the greater, because of the at- tempt which is thus made to modify a functional disturbance which cannot help extending to other intimately de- pendent endocrine organs. (The subject is given more extended consideration in the next chapter.) From the foregoing statements, it is very clear that to combine thyroid and pituitary in proper doses with ovarian substance is not wanting in physio- logical basis, and innumerable experi- ences have decisively shown how much superior is the pluriglandular method as represented by a formula directed at the series of defaulting organs, com- pared with the uniglandular therapy directed at the ovaries alone. Such a formula is my original Thyro- Ovarian Co. To a suitable dose of ovarian substance particularly rich in corpora lutea is added a small dose (gr. 1/12) of thyroid extract and total pituitary. It should be remarked that these figures are based upon finished products and represent from five to eight times more than those preparations that are dosed on a basis of fresh glands. The cyclic method of administration A Thyro-Ovarian Formula. 79 Which I have recommended is very- satisfactory and less expensive. The idea is to push the dosage at that part of the menstrual cycle during which the ovaries have to accomplish their greatest work, while during a part of the month the treatment can be dis- continued. This should be advised at the onset of menstruation, for it is believed that the principal hormone function of the gland is consummated with the establishment of the monthly flow. Here is a procedure found to be very convenient: For 10 days from the beginning of menstruation omit the formula entirely. During the next 10 days take one sanitablet three times a day, at meals, or when convenient. For the remainder of the month, i.e., until menstruation begins again, double the dose, or take two sanitablets three times a day, omitting again as soon as the menstruation is manifest. It is necessary to urge persistence in this treatment, for obviously the object of such a measure is to educate the ovaries and associated glands to the production of their respective hor- mones, and since the ovarian function is virtually suppressed during part of each month it is not always possible to accomplish results rapidly. It should be continued for a minimum of three periods. Mammary Tenderness. For some inexplicable reason one of the manifestations of ovarian dysfunc- tion in certain cases is what is known as mammalgia or painful breasts. Often in the history of a patient one learns that the onset of the premenstrual dif- ficulties is marked, regularly each month or occasionally, by a tenderness 80 or even serious aching in the breasts. There is a reflex relationship connect- ing the breasts and the pelvis, and just as the mammalgia is a definite ovari- an symptom so may ovarian therapy relieve it. Several cases which have come to my notice have suffered more from the mammalgia itself than from menstrual discomfort, and not infre- quently the pain is most severe and discomforting. Treatment of these cases as dysovarism-with Thyro- Ovarian Co. (Harrower)-has not failed to bring about benefit, thus establishing the more decisively the etiologic connection between this dif- ficulty and the endocrine glands. While my original Thyro-Ovarian formula has been used successfully in a large number of cases, it has seemed advisable to make some modifications of it, as well as other formulas, for the treatment of varying phases of ovarian dysfunction. Adreno-Ovarian Co. (Harrower) is the same preparation, plus a suitable dose of adrenal substance. Its chief indication is ovarian dysfunction with which there is a marked degree of asthenia. In menstrual neuroses, and particularly in psychoses, it has been found to be capable of " working miracles." It is in the treatment of the menstrual or climacteric fatigue syn- drome that this formula is preferable. Another modification of this funda- mental formula is Gonad-Ovarian Co. (Harrower). This is the Thyro-Ovarian formula with a generous dose of anterior pituitary substance and spermin. This is likely to be more active in the more definitely organic conditions, as, for Varied Formulas for Dysovarism. 81 example, infantilism, sterility, and developmental disturbances, which are more definite and decided in their symptoms and permanence than the functional disturbances for which Thyro-Ovarian Co. (Harrower) ordi- narily is used. Occasionally the latter treatment may have accomplished a good, share of what is desired of it, but does not complete the work. For exam- ple, in girls who have not menstruated for years, the Thyro-Ovarian treatment modifies the nervous conditions and renders very obvious service, but if the result is not as thorough as might be desired, the addition of the pituitary preparation as in Gonad-Ovarian Co. (Harrower) sometimes suffices to make all the difference between partial and complete success. The same is true in the endocrine treatment of sterility. Functional high blood-pressure may be connected with the menopause, and a preparation called Thyro-Pancreas Co. with Ovary (Harrower) has been developed for the treatment of climac- teric disturbances in which high arterial tension is prominent. This sometimes has served permanently to reduce the systolic blood-pressure from 20 to 60 points, and to bring about other changes for the better which are very encouraging. (See also Chapter XVI.) Two other formulas should be men- tioned here: The one, Mamma-Ovary Co. (Harrower), is used in girls and young women where the menstruation is prolonged and excessive. The mammary ingredient seems to reduce the pelvic congestion and the accom- panying conditions more satisfactorily. On the other hand, Mamma-Pituitary Co. (Harrower) is essentially a remedy for hyperovarism and menorrhagia. It 82 is used chiefly in women at or near the change of life. It is a combination of mammary substance, pituitary gland, and ergotin, and is a splendid prepara- tion for menorrhagia, with or without fibroids. (See also Chapter XVII.) Some Reasonable Conclusions. I. It is accepted that the ovarian function involves the production of one or more internal secretions. 2. Ovarian function is influenced by the other endocrines and in turn exerts an influence upon them. 3. The thyroid encourages and favors ovarian activity-the cretin does not develop sexually and acquired hypothyroidism usually causes ovarian insufficiency. 4. On the other hand, hypo-ovarism, especially at the menopause, favors hypothyroidism-myxedema is more common in women and " nine out of ten cases occur in the decade from 40 to 50." 5. The pituitary is related to ovarian disorders-hypopituitarism causes sex dystrophies. The Frohlich syndrome includes amenorrhea, obesity, and atrophy of the sex organs. 6. In functional ovarian insufficiency other glands may attempt to aid vicari- ously, causing goiter, or pituitary headache. 7. Therefore, the intimacy of these glands predicates pluriglandular diffi- culties when any one of them happens to be affected, and hypo-ovarism (amenorrhea or dysmenorrhea as well as sterility and asexualism) is practi- cally never an ovarian disorder pure and simple. 8. Ovarian dysfunction usually in- 83 eludes thyroid and pituitary dys- trophies as well, either as cause or effect. The opposite is equally true. If organotherapy is advisable-and it is- pluriglandular therapy is more likely to reach a pluriglandular disorder than, corpus luteum or ovary alone. This, in brief, is why the Thyro- Ovarian Co. (narrower)-an original combination of corpus luteum, ovarian substance, thyroid, and total pituitary gland in proper proportions-is far superior to corpus luteum or ovarian substance alone. It explains, un- doubtedly, why this preparation is being carefully specified-by adding the name " narrower "-by over fifty thousand medical men in all parts of the world. Prescribe thus: R Thyro-Ovarian Co. (narrower) Sig. One thrice daily, a.c. for ten days; double for ten days before and omit during flow and for a week after. Repeat. (Always prescribe an original package of 100 sanitablets. Smaller amounts increase the cost and can but begin the treatment.) 84 VIII THE MENOPAUSE More Than an Ovarian Problem Alone- Aggravating Factors-Usual Time of Onset-Symptoms of the Menopause- Blood-Pressure Irregularities-Nervous Manifestations-Compensatory Endo- crine Action-Rheumatic Symptoms- Flooding at the Menopause-Virilism and Hypertrichosis-Essential Therapy of the Menopause-Routine Dosage. THE change of life, or " the critical age," is known by two names- the climacteric and the menopause. I prefer to use the former as an adjec- tive' and the latter as a noun. It is a period of imbalance in the life of woman resulting from the removal of a link in the hormonic chain, with consequent derangement of the func- tion and balance of the related and dependent organs. More Than an Ovarian Problem Alone. The menopause is, of course, mani- fested by menstrual irregularities and includes dysovarism as its central disorder; but it is far more than these. In view of the fact that this period so commonly is one of stress and trial and, too, that quite the most encourag- ing aspect of its study and control is connected with applied endocrinology, I propose to marshal some facts here which I hope may enable my readers to give greater aid to many who find themselves at this critical period. 85 Let me commence by asserting that the symptoms of the menopause are not essentially ovarian. The reduction in menstruation, it is true, is an ovarian manifestation, but it is by no means a discomfort to the patient. On the other hand, the chief symptoms of this period-mental, physical, circulatory, and metabolic-involve practically all the endocrine organs, and in propor- tion as they are functionally related to the ovaries. Aggravating Factors. After about thirty years of activity, nature ends the essential ovarian service to the organism. This "pause " is usually initiated very gradually, and in really normal women there are practically no symptoms other than the gradual lessening of the monthly flow. But, unfortunately, nowadays very few women are normal. Their environments, tendencies, and physi- ology are far from those of our ances- tors. And in proportion as the life has been abnormal, so usually is the meno- pause. Women whose sexual life has been generous, especially those who have borne many children, commonly have a late menopause, as though Nature were in hopes that reproduction might proceed as long as possible. On the other hand, in the spinster and the asexual wife, often the period of ovarian activity declines early-per- haps as much as ten years before that of her fertile sisters. Usual Time of Onset. The age of climacteric changes varies widely, ranging perhaps from 35 to 45, and averaging about 42 or 43. All sorts of wide variations from 86 these ages are on record. In addition to the factors already mentioned, climate and heredity play an obvious part in controlling the length of ovarian activity. Just as in warm climates puberty is initiated much earlier than in cold ones, so the menopause may be early or late for the same reason. Heredity exerts a still more marked effect. The women in certain families menstruate early and continue late, while in others the opposite is true. Yet there are no rules that can be depended upon absolutely. Certain organic changes begin to take place at this time. Atrophy of the ovaries brings with it a general aging and the breasts are reduced in size or firmness. These retrograde anatomical changes need not be dwelt upon, since the functional irregulari- tiesaremuch more important clinically. Almost every kind of neuro- circulatory manifestation can result from this imbalance. The most common discomfort is what is usually known as " hot flushes "-an irregu- larity of vasomotor control believed to be due to temporary abnormality of the thyro-adrenal share in the control of the sympathetic system. The circulatory instability is the preponderating manifestation of the menopause and may bring about widely differing symptoms. The flushes of heat already mentioned, with the imbalance of vasomotor control of the skin and irregular blushing, or even more permanent reddening of the skin, especially of the nose, are often accompanied with cold hands and feet, Symptoms of the Menopause. 87 while, on the other hand, a burning sen- sation in the soles severe enough to be most uncomfortable is not infrequent. Blood-Pressure Irregularities. With all this it is common, to find changes in the blood-pressure. Certain women who lean to the plethoric often have alarming increases in the systolic pressure due altogether to functional causes. The tension in these cases may reach 200 or more milli- meters, and usually no organic cause is discoverable. It is believed that this is due to a compensatory over- activity of the adrenals, and with this in mind antiadrenal therapy (pancreas) has been used with great success in the reduction of these abnor- mal pressures. The subject is given further consideration in Chapter XVI. Quite an opposite condition-the menopause is essentially a conglomera- tion of opposites-is noted in certain women, especially of the asthenic, badly nourished type. Instead of the excessively increased tension, they have- very low blood-pressure. The systolic tension may be as low as 80 mm. With this one finds the symptoms of adrenal insufficiency outlined in Chapter II, and their treatment is naturally quite different from that of the opposite type. Nervous Manifestations. Fleeting, indefinite pains are very- common and annoying symptoms of this period. Other sensory disturbances are encountered, such as formication, numbness, and even sensory paralyses. There are two types of headache that are common. The thyroid type is a dull, prolonged, indefinite ache, worse 88 in the morning and wearing off as the* day progresses. The pituitary type is quite different and, as has been men- tioned elsewhere, is a severe, throb- bing, pressure headache, believed to be due to a hyperemia of the pituitary body brought about as a compensatory effort to stimulate the waning ovarian endocrine function. These two types of climacteric headache are quite dissimilar and the obviously indicated organotherapy is infinitely more effec- tive than headache powders and other treatment. Neurasthenia is common at the menopause. Beside the actual dys- crinism expected at this time, the emotions, fear and worry, are not always well controlled and their influence upon adrenal functioning complicates matters. The explanations made regarding the endocrine aspects- of neurasthenia (Chapter III) apply in the cases under consideration, and climacteric neuroses must be con- sidered and treated as endocrine irregularities. Occasionally the diffi- culty is more serious and a real psychosis develops. Melancholia, mania, and what often has been diag- nosed as manic-depressive insanity, have been built upon the unstable con- ditions of the menopause. While such developments are serious, the prognosis is better than in similar psychoses not of endocrine origin, for a good per- centage of climacteric psychoses re- spond favorably to the needed pluri- glandular regulation. For instance, I recall a remarkable, but fairly typical, case of a woman, age 46, who, in the course of a stormy menopause, became quite insane. Unfortunately, she was not treated. 89 properly-at least, she had never received organotherapy-and when I was asked to consider her case she had been in an institution for nearly a year with little, if any, improve- ment. She was put under treatment with Adreno-0 varian Co. (Harrower), one t.i.d. for one week and two t.i.d. the next. This alternating dosage was continued almost without a break for four or five months. Within three months she was at home again and apparently had recovered completely. Certainly the organotherapy was an advantage, and the symptomatic better- ment very acceptable. However, it was suggested by one of the physicians who had had plenty of chance to rec- ommend this treatment before I did, that some climacteric psychoses get well in time without treatment; and this I admit. It should be remembered that the tendency of these hormone-producing organs is to cooperate with one another, therefore compensatory func- tioning is to be expected when for any reason one of these organs fails. Hence, several conditions encountered at the menopause may be traced to compensatory endocrine action by the principally associated glands. We have already mentioned the proba- bility that adrenal Irritability may be brought about with sympathetic irri- tability and blood-pressure changes. Also the pituitary headache referred to above obviously is the result of a com- pensatory hyperfunction. Hyperthyroidism is possible as a result of climacteric changes, but it is quite rare. As a matter of fact, hypo- Compensatory Endocrine Action. 90 thyroidism is much more usual; and it is a peculiar fact that 90 per cent, of all cases of myxedema occur in women and, more remarkable still, that 95 per cent, of these occur between the ages of 40 and 50. Major forms of hypo- thyroidism, then, are essentially related to the menopause and, therefore, it is necessary to recall some of the clinical findings of myxedema, so as to see which of them are essentially climac- teric in character. I have already referred to the thyroid type of headache which is, perhaps, the most common symptom of all. We all know how frequently obesity and metabolic insufficiency occur both in hypothyroidism and at the meno- pause. It is often solely a thyro- ovarian manifestation. Constipation is a very usual finding both in thyroid insufficiency and at the change. The most uniform of all the results of the serious forms of thyroid insufficiency is cellular infiltration. The cells of the body as a whole are not able to carry on their chemical duties at the normal rate, and the result is an accumulation of their wastes until, by the law of osmosis, they become puffed out, or infiltrated, by the body fluids which are thus drawn to the cells to maintain the osmotic tension in the cell equal with that in the surrounding lymph. This infiltration is inevitable in hypo- thyroidism and with it may come an extremely wide range of symptoms which I can only mention here: Deaf- ness and buzzing in the ears; headache, as previously mentioned; disturbances of vision, especially muscle tone, with asthenopia; asthmatic manifestations (not true asthma); cardiac tire and breathlessness- slowed digestion and, 91 especially, alimentary atonicity; gall- bladder infiltration and consequent con- gestion which paves the way to biliary stasis and, probably, gall-stones. I be- lieve that many of the bladder difficul- ties which occur in this period can be traced to this same infiltration of the bladder walls, with consequent abnor- mal desquamation and denudation and sensitiveness, etc. Remember that this infiltration is not localized, and that it is an invariable concomitant of well- defined hypothyroidism. The estimation of the basal meta- bolic rate is an accurate measure of the extent of this fundamental change; and the almost magic fashion in which the chemical exchanges are reestab- lished following the indicated thyroid therapy, with the unloading of these puffy cells, the reduction in the size and weight of these patients, and the simultaneous control of many symp- toms, is clear-cut evidence of the cor- rectness of our premises. Rheumatic Symptoms. As a result of this slowed chemistry we may expect conditions to develop allied to rheumatism. I have else- where expressed my belief in the thyroid causation of several of the dis- orders that are called " rheumatism." I am by no means alone in this opinion. It happens that some writers, including Dr. G. Maranon, of Madrid, believe in an essentially climacteric type of rheu- matism. It is immaterial whether this classification is correct; for it is incon- trovertible that the customary climac- teric hypothyroidism brings about a condition of cellular toxemia and acidosis which causes rheumatic symp- toms in nerves, muscles, and joints. 92 In passing, I might state that I am convinced that there is an essen- tially ovarian type of rheumatism-not necessarily at the menopause-which I have explained to the satisfaction of some in the following manner: The ovaries require certain stimuli from the thyroid. The thyroid having many varied tasks to perform may become functionally played out, as, for example, following an infection or acute infec- tious disease. In consequence its gonad- stimulating function, or its detoxicating function, may be defective. Or, again, there may be an essentially ovarian cause for additional thyroid hormone service, with a resultant limitation in its other powers, with increased toxemia and acidosis resulting in the manifest tations we often call rheumatism. At all events, Dr. Leopold-Levi, of Paris, once wrote: "From the prac- tical point of view, in all forms of rheumatism in which the cause is obscure, it is well to apply thyroid therapy. ... In those cases in whom there is a decided thyroid influence the initial results of such treatment will be rapid and sometimes immediate." Flooding at the Menopause. Finally, there is another result of this infiltration which may be respon- sible for a most usual climacteric symptom-menorrhagia. If the uterus is infiltrated and boggy there is an actual mechanical interference to the closing up of the vessels broken at menstruation. There is deficient tone, and the menstruation is prolonged and oozing. Still, another entirely dissimi- lar cause may be responsible for the frequently heavy menstrual losses at the menopause. This particular func- 93 tion is being accomplished with diffi- culty. The pelvic congestion is greater than usual, just as the effort on the part of all the organs involved is greater. As a result of both these factors the ovarian vessels are flaccid and overdistended, and when the time comes the loss of blood is so much the greater. It would almost seem as though the body hoped by an extra effort to force the ovaries to continue their work. This misdirected ovarian stimulation has to be overruled and fortunately organotherapy offers us some encouraging prospects. Mammary therapy is the indicated procedure. It opposes pelvic conges- tion, antagonizes ovarian activity, and lessens the abnormal menstrual loss. More extended consideration is given to this and other forms of flooding in Chapter XVII, and a more complete explanation is given of the philosophy of mammary therapy as well as of synergistic measures. The antimenorrhagic preparation, Mamma-Pituitary Co. (Harrower), is particularly efficacious in flooding accompanying the menopause, and it is surprising how effective it may be even in extreme cases. For example, a woman in the late thirties for years had suffered from an increasing men- strual flow. Like the woman in the Bible story (with a similar ailment) she had " spent all her living upon physicians, neither could be healed of any." She had been curetted, tam- poned, had taken hot vinegar douches, injections of ergotin and stypticin and, as her physician told me, " all sorts of treatment for years." Her flow lasted for three weeks, and was intensely heavy, requiring her to remain in bed 94 more than half the time. She was exsanguinated and no sooner had she partly recovered from one flow than the next began. In three months, dur- ing which she took my formula in amounts ranging from three to eight sanitablets a day, the menstrual flow lasted five days, and " was more nor- mal than it had been in many years." Virilism and Hypertrichosis. Mention must be made of a manifes- tation of dyscrinism which is quite rare, but is essentially a postclimacteric development. I refer to the peculiar establishment of masculine traits with the growth of beard and mustache (hypertrichosis), and the retrogressive changes in the breasts and other essentially feminine characteristics. This condition is known as virilism, and in view of the fact that the majority of cases occur after the menopause has commenced, it is properly classed as an endocrine disorder. It is believed to be due to an undue compensatory function (and later pathological development) of the adrenal cortex and is not satis- factorily treated by any known method. I have reports of several cases of sim- ple hypertrichosis in whom there was benefit from thyro-ovarian organo- therapy, but these could not be classi- fied as true virilism. Essential Therapy of the Menopause. There are three important aims in the treatment of the wide range of dis- orders dependent upon the endocrine derangement of the menopause: (1) To lessen the suddenness and extremity of the imbalance by substi- tutive organotherapy. (2) To give the organism a longer 95 time and consequently a better chance to align itself to the inevitable. (3) To remove as best one may the stress upon the overstrained organs. The last of these is essentially a fundamental hygienic recommendation ■embodying rest, elimination, neutrali- zation, and as suitable an environment as possible; but a part of this stress may be lessened by the measures I shall now recommend to accomplish the first two of these aims. Ovarian therapy is the ideal method of accomplishing this. It enables one to " substitute " certain principles of which the body has been deprived. Also it encourages, by the principle of homostimulation, a renewed functional activity on the part of the waning ovarian cells. This postpones the end of the change and thereby mitigates the seriousness of the symptoms. In the meantime the organism has a longer opportunity to accustom itself to the loss it is called upon to bear. It should not be necessary to explain why ovarian organotherapy is so effectively supplemented by associated remedies from the related glands- particularly the thyroid and the pit- uitary and, not infrequently, also the adrenals. The statements regarding the transcendent importance of hypo- thyroidism and its extraordinary fre- quency in women at this time of life are good enough reasons. The same applies with almost equal reason to the pituitary. The pluriglandular therapy which I have recommended for many years has been used success- fully in innumerable cases, and, still more interesting, it has been followed by results in thousands of cases that had been treated previously with 96 ovarian or luteal therapy with only limited benefit. May I reiterate that corpus luteum is not a particularly helpful remedy for hypothyroidism? Clearly, then, if there is a large and important thy- roid feature in a given case obviously in need of ovarian therapy, we must combine them. Rotitine Endocrine Dosage. I have two routine procedures, which vary with the conditions present and the reaction of the patient. Thyro- Ovarian Co. (narrower) is the usual formula, although many of the asthenic, hypotensive type of cases do better on Adreno-Ovarian Co. (nar- rower). The dose of either is one sani- tablet three times a day, the amount to be increased prior to an expected flow or, where the flow is ended, during "the worst time" of each month (for often there is an unusually unpleasant time in place of the molimen or menses). During this time the dose is two, t.i.d., and usually it is left to the patient her- self to plan where this customary in- crease in dosage is made. At all events, I try to arrange for a period of heavy dosage and also a free period, by ask- ing the patient to divide the month into three equal parts, to take one, t.i.d. during one ten-day period; two, t.i.d. for the next; and then to omit it for ten days prior to commencing over again. If the patient can distinguish a re- current time when conditions are worse, the double dose is best taken during it. Such treatment will have to be con- tinued for a number of months; in simple cases, say, three or four months; in the serious, aggravated cases, as those with neuroses, or psychoses, or 97 rheumatism, for at least six months or longer. The organotherapy should be tapered off and not stopped suddenly. The greater the lack and the more serious its effect, the greater the need and amount of remedy required. The slower the control exerted by the treat- ment, the larger the dosage and the longer its use. Absence of the one-time disconcerting symptoms is not an indication to stop treatment, if it has been applied only for a few weeks. If it is discontinued the trouble will re- turn and the measure must be used again. In certain extreme cases, additional pituitary is an advantage, in which case Gonad-Ovarian Co. (Harrower) is the choice. It is used ordinarily only after several months of treatment with the one or the other of the two for- mulas mentioned previously. The successful control of the serious problems of the menopause comes from a full appreciation of the syndrome with which we are confronted, fol- lowed by the application of a complete, rational therapy, maintained with per- sistence and perseverance. 98 IX SYMPATHETIC SEDATION IN HYPERTHYROIDISM A Stubborn Disorder-Focal Infection the Chief Cause-Underlying Emotional Causes - Endocrine Interreactions -- Diagnostic Measures-Find and Re- move Infective Foci-Protein Sensitiza- tion-Study Possible Endocrine Causes -A Routine Method of Treatment. THE condition known as hyper- thyroidism is one of the most complex and most resistant of the endocrine syndromes. For these reasons it is one of the serious problems of medicine. A study of the very exten- sive literature on the subject quickly brings us to the conclusion that there is much diversity of opinion in regard to its cause, clinical relations, and, especially, its treatment. Many writers still insist that the origin of this disease remains a mys- tery, though without doubt toxemia-• chemical, bacterial, endocrine, or emotional-is the real cause. Yet, as we shall shortly see, the complicated associated factors are the real reasons for the complexity of the problem and the chief sources of difficulty in its treatment. The frequent stubbornness with which hyperthyroidism responds to treatment, whether medical or surgical, makes study of the subject so much the more necessary. The facts that the A Stubborn Disorder. 99 prognosis is not good and that radical cures are by no means the rule, should impel the rank and file of the profes- sion-the ones who, by the way, see the most cases of hyperthyroidism-to study this subject still more thoroughly. The word " hyperthyroidism," as here used, is intended to denote a condition dependent upon, or related to, an excessive functional activity of the thyroid gland. It does not neces- sarily mean exophthalmic goiter, though hyperthyroidism is, indeed, a fundamental part of that disease; nor does it solely indicate the serious cases of thyrotoxicosis which we occasionally encounter. Hyperthyroidism is essentially a dis- ease of women, and especially of young women. From 80 to 90 per cent, of all cases occur in women, and the disease is most frequently found during the period of reproductive activity, being rare in older persons, and still more rare in children. From this we may suspect that the thyroid is not alone in its involvement. Focal Infection the Chief Cause. The most common single cause of hyperthyroidism undoubtedly is focal infection, especially of the structures near the thyroid gland. It seems that bacterial toxemia not merely can arouse and irritate the thyroid through the blood stream (and indirectly through the adrenal mechanism), but the transmission of irritating sub- stances through the lymphatics is also possible. Many experiences of my own, as well as a few reports in the recent literature, emphasize this. Bergh, of Christiania, reports that it is his opin- ion that the primary source of infection, 100 which most often causes the thyroid derangement responsible for the exophthalmic goiter, is in the tonsils, nose, or throat. All his own cases indi- cated this as a large part of the etiology. He cites Soiling's report on ninety-seven cases, no less than sixty of which dis- played a tendency toward infectious sore-throat. In sixty-two of these ninety-seven cases, the hyperthyroidism began evidently as a local process in the thyroid. This sustains Bergh's as- sertion that chronic catarrh of the nasal mucosa is not the superficial, harmless condition commonly sup- posed, but that it may spread along the lymphatics and involve the thyroid. The ear, nose, and throat specialist has plenty of opportunity to find a latent, early hyperthyroidism as a complication of the conditions which interest him especially. There are many comparatively recent papers on this subject, a notable one being that by Squier. Infections of the naso- pharyngeal fossae and the related sinuses, including the eustachian tubes and the middle ear itself, are believed by him to be the most frequent causes of this disease. To put it succinctly, the study of the etiology of hyper- thyroidism begins with a search for foci of bacterial infection, especially in the head. Another common and similar cause is pyorrhea and subdental infection. Dr. Florence A. Stoney, of Bourne- mouth, reports her extensive war-time experiences in full confirmation of this. It is bad practice to neglect such oral sepsis, "while the more needful therapy is inaugurated." Both measures are called for and rarely is it impossible to attend to both at the same time. 101 The aspects of hyperthyroidism that are related to the emotions are as prominent as they are important. Emotional instability almost invariably is a part of the syndrome, and it is one of its earliest manifestations. One cannot study this disease properly without a full knowledge of this phase of its etiology, nor can one treat hyperthyroidism successfully without taking this instability carefully into consideration. Certain individuals of the emotional type-those high-strung persons who are unduly susceptible to all sorts of external impressions-are fit subjects for hyperthyroidism. In fact, some assert that there are transmissible tendencies to this form of thyroid instability which permit an etiologic stimulus to cause hyperthyroidism in such an individual, whereas far worse stimuli have no such effect upon others " with a more stable sympathetic background." Fear, the tendency to worry, an unstable temper, and strain -physical as well as mental-are important predisposing causes. I admit that I do not know whether these fac- tors actually cause hyperthyroidism or whether it is this latent tendency to thyroid instability which favors the fundamental changes in the emotional balance and makes these persons especially emotional or temperamental. Suffice it to say that hyperemotivity and hyperthyroidism are very closely related. Underlying Emotional Causes. There is much evidence which would indicate that the pancreas and the Endocrine Interreactions. 102 thyroid produce antagonistic hormones. The thyroid inhibits the pancreas and vice versa. Parenthetically, it will be recalled that the Langerhansian (pan- creas) endocrine principle has been called by Gley, Schaefer, and others, an " antihormone," for, as von Noorden says, it is " a brake to the sugar mechanism," and its chief service is not to " arouse or set in motion." In hyperthyroidism there is frequently an increase in the blood-sugar and occasionally even glycosuria. On the contrary, in the opposite condition, myxedema, there is a high degree of sugar tolerance. The relation of the thyroid to the sex glands is sufficiently important to require some consideration. It is well known that the thyroid is largely responsible for the initiation of the sex function and that genital atrophy is one of the recognized results of inactivity of the thyroid and correlated endocrine glands. The fact that hyperthyroidism essentially is a disease of women points to a definite relation- ship between this and ovarian function. It is also well known that there is a predisposition to the onset of hyper- thyroidism both early in sexual life and at the menopause, as well as a tendency to exacerbation of an already existing disease during menstruation and pregnancy. There are two aspects to this particular relationship: On the one hand, the thyroid may have to work overtime in order to establish a more nearly normal ovarian function in hypo-ovarism. Incidentally, Leopold- Ldvi and de Rothschild refer to good therapeutic results in hyperthyroidism from an effective organotherapy of an associated ovarian insufficiency. On 103 the other hand, the related glands-• the adrenals and the pituitary-may be attempting to do the extra work, and their hyperactivity may unduly stimulate the thyroid. More and more the impression is gaining ground that the condition known as hyperthyroidism is really hypercrinism, especially of the sym- pathetic-stimulating endocrine organs. Liek considers that in hyperthyroidism the disorder is not so much of the thyroid as of the entire endocrine sys- tem, including the central nervous system. This German authority also believes that hyperthyroidism is de- veloped upon " a faulty groundwork (degenerative constitution), which fre- quently is found to be inherited." Having eliminated such other causal conditions, aside from variations in thyroid function, which may produce fluctuations of the metabolism-such as fever, severe cardiorenal disease, pernicious anemia, etc.-the basal metabolic rate should be taken before making any final decision as to the functional state of the thyroid gland. My own gland-feeding test (Har- rower's Thyroid Function Test) has been used quite extensively in deter- mining the pre-hyperthyroid state, and also in checking up clinically on the capacity of the thyroid gland to respond to endocrine stimuli. However, it is not of value in obvious cases of hyper- thyroidism since its value is greatest in uncovering latent forms, especially of thyroid insufficiency. A detailed explanation of this test is given else- where, though it may be well to cover the most salient points here and let Diagnostic Measures. 104 the reader's own interest carry him further into the literature. The test is based upon the fact that thyroid influence makes its early manifesta- tions by way of the heart, i. e., an in- creased pulse-rate. If the thyroid is irritable the pulse will show an early rise and will continue to be more rapid for two or more days following the test. A normal thyroid will be but mildly surprised and react accordingly -a slight, fleeting increased rate. The hyposecreting gland pays but little attention to the nudge given it by the active principle in the graduated doses of glandular substance, and little or no change is observed. The prognosis of hyperthyroidism is not good. Despite the statements of some, I am pessimistic about the possibility of real and unqualified " cures." It is true that there are many reports in the literature giving figures which introduce a feeling of genuine satisfaction at the outcome of the treatment, especially if it is sur- gical; but I cannot bring myself to a state of enthusiasm regarding the end- results of any method of treatment. Find and Remove Infective Foci. Too much emphasis cannot be laid upon the fact that hyperthyroidism is not merely an irritability of the thyroid gland, with a corresponding increase in the production of its hormones. It is really a manifestation of a much more subtle and deeply rooted disturbance in the functions of the body. May I recapitulate? As I see it, there are three fundamental causes-toxic, emo- tional, and endocrine-any or all of which may be related to the onset of the thyroid irritability. The first of 105 these may consist of various foci of infection, and every case of hyper- thyroidism must be very carefully examined from every possible stand- point so as to exclude conditions which would allow the absorption, into the system, of bacterial poisons. The teeth, tonsils, sinuses, lungs, gall- bladder, intestines, appendix, and pelvis should be carefully studied with this in mind, and if there is a condi- tion of focal bacterial toxemia, obvi- ously it must be taken care of; for no treatment, whether surgery of the thyroid or the very best medical regimen, could possibly have any direct influence upon a focal infection. Inci- dentally, herein lies the great sin of some surgeons! The thyroid gland so obviously is at the root of the serious sympathetic imbalance that they think it must be removed forthwith, while the real underlying difficulty remains to cause just as much trouble later on by irritation of the remainder of the thyroid, which must necessarily be left behind. This does not mean that I am opposed to surgery under certain circumstances, for undoubtedly it is occasionally necessary and decidedly helpful, but I have seen too many post- operative cases of hyperthyroidism to believe that the thyroid is the chief offender. It is merely the victim of circumstances. Another form of toxemia which is receiving increasing attention is allergy, or food poisoning, and ana- phylaxis, or protein sensitization. Certain individuals have an undue sensitiveness to strawberries, eggs, shell-fish, to mention several of the Protein Sensitization. 106 foods; or again, they may be subjects of asthma, hay fever, and allied forms of anaphylaxis. If a certain protein is a virulent poison to a given case and, through ignorance, it is allowed to get into the organism, it will surely aggravate a hyperthyroidism that may be present. I have never seen a case that I felt was caused by protein sensitization; but I have run across many who were unconsciously over- stimulating their thyroids by such means. Several of these cases had been operated on previously, and this contributing factor had never been appreciated. Not infrequently the discovery and discarding of such " poisons " make a very salutary difference in the condition under discussion. Incidentally, may I dare to hint that coffee contains a sympa- thetic stimulant known as caffeine, and that it' is bad practice to try to sedate the irritated sympathetic mechanism while a stimulant of this kind is being taken right along? Finally, under this head we must briefly consider the possibility of absorbing from the alimentary canal certain protein split products, the result of putrefaction, as well as the waste products of certain protozoa which may inhabit the intestines. The presence of ameba coli, giardia, and other alimentary parasites is a con- tributory cause (it might even be the essential cause) of this thyroid irrita- bility. Rational treatment mist in- clude the search for and disposal of such factors. Study Possible Endocrine Causes. As we have seen, the intimate relationship of the glands of internal 107 secretion enters very definitely into hyperthyroidism, from the standpoint of both cause and effect. The function of the thyroid gland is bound up with that of the other endocrines-two of which are particularly likely to enter into the etiology of hyperthyroidism. One of these is the thymus, which may be both persistent and enlarged, thereby adding to the complex by what properly should be called hyperthym- ism. A number of prominent investi- gators have found that a large percentage of patients suffering from hyperthyroidism have a persistent thy- mus and that treatment calculated to reduce the thymus (suitable exposure to the X-ray or radium, perhaps half a dozen times) not merely disposes of the thymus, but mitigates the symptoms of the hyperthyroidism very materially. Hence a condition of this kind should be looked for in every case and con- trolled when it is found. The other endocrine organs often closely related to dysthyroidism are the ovaries, and when one appreciates the dependence of the thyroid upon the ovaries, and of the ovaries upon the thyroid, it is apparent how a disturbed function of the ovaries may react upon the thyroid sufficiently to derange its normal routine. Personally, I do not believe that hyperthyroidism is related to ovarian dysfunction so often as ovarian dysfunction is related to hypothyroidism, but there is a relation. When there is a disturbed ovarian function it should be sought for and controlled, and this usually is best accomplished by suitable organo- therapy. It was evidently with this in mind that Dr. Andrd Crotti added the dose of ovarian substance to the 108 pluriglandular formula which I use in these cases, and to which I now direct attention. A Routine Method of Treatment. During and following the previously- advised search for, and control of, etiologic factors, I have found that the following therapeutic outline will be quite satisfactory in a great many cases: Absolute Rest Imperative. As soon as possible, and during your efforts at both diagnosis and treatment, prescribe as complete muscular and mental rest as circumstances will permit. In serious cases, rest is so imperative that nothing must be left undone to facilitate it. Care and worries must be discarded, and quiet insured. It is easy to advise this, but extremely hard to main- tain it. An Extra Good Diet. Naturally, patients in this category are in a state of metabolic imbalance, and while it is advisable to simplify the diet as much as possible, since the chemistry is usually increased, the food should be generous in amount and of an easily assimilable character. In addition to three well-balanced meals, it is proper to add an extra lunch and perhaps give a glass of hot malted milk, or some such thing, at bedtime. In addi- tion to its nutritive value, this latter is often helpful in controlling the insomnia which sometimes is found in these cases. Alkalimzation. While acidosis is more common in hypothyroidism than in hyperthyroidism, I have found con- siderable advantage from administer- ing the alkaline mineral salts which replace the reserve so often depleted 109 in chronic endocrine difficulties. For this purpose I use, as an average dose, three grams of a mixture of magnesium phosphate 2, calcium phosphate 8, calcium glycero-phosphate 8, potassium bicarbonate 32, and sodium bicarbonate 50. (It is very necessary to give this on an empty stomach in order' that the gastric acid may not nullify the alka- linity, and vice versa.) I advise the continuance of this part of the treat- ment for at least three or four weeks, and sometimes longer. Crotti's Sedative Formula. Another procedure in the line of active treat- ment involves the use of a pluri- glandular formula which frequently exerts a sympathetic sedative effect. This is a modification of a formula suggested some years ago by Dr. Andrfi Crotti, of Columbus, Ohio. This formula contains pituitary (total), adrenal, pancreas (notpancreatin), and ovary. The main difference between my modification of the Crotti formula and the original is that the amount of pancreas substance is increased three- fold. The fundamental value of this preparation lies in its capacity to slow and strengthen the heart action; to modify the tendency to dysovarism, not unusual in these cases (it may be noted that no objection has been found to administering this formula to a large number of male patients, despite the fact that the ovarian element may not be of particular value); and to antagonize or sedate the excessive sympathetic irritability, which is the chief manifestation of hyperthyroidism. Such treatment needs to be carried out for several months, and, naturally, the influence is purely symptomatic. 110 Prescribe Pancreas Co. (narrower) -specifying "Harrower " invariably-- 100 sanitablets, with instructions to take one at meals and at bedtime for three weeks, or, depending upon cir- cumstances, to increase the dosage to two, t.i.d., and later reduce it to one, t.i.d. for at least three months. With this the remineralizing tablet, Calcium- Phosphorus Co. (Harrower), the for- mula of which has been mentioned, is ordered (boxes of 100), and the patient is instructed to take three 1-gram tab- lets, crushed, with much water, one hour before food, twice a day, for three weeks, and thereafter on alternate weeks. In conclusion, let me impress that no matter what may be the cause of hyperthyroidism, and no matter if one use medicine, organotherapy, or the X-ray, the suggestions made above are perfectly in order; for while they may not directly attack the cause, they have many hundreds of times brought about a satisfactory control of the effect. This procedure is rational provided that, while it is being em- ployed, the cause is being sought for and eradicated as far as possible. I cannot refrain from emphasizing this because many physicians have failed in cases of this kind, and on analysis of the circumstances later on, I found that some subtle irritating element- infective, toxic, endocrine, or emotional -was still at work undoing the good that might have come from the organo- therapy, or whatever other measures might have been used. Usual Dosage. 111 X ADJUVANT ORGANOTHERAPY IN INDIGESTION Fundamentals in Treatment-Malnu- trition and Hepatic Torpor-Digestive Ferment Products-Pancreas Stimula- tion by Secretin - Indigestion in Diabetics-Ovarian Indigestion. NO single form of medication can be considered as " the treatment " of digestive disorders. Experts in the control of digestive disorders first develop a sensible appreciation of what is wrong, and spend their great efforts in the removal of those funda- mental factors which are at the root of the trouble. Therefore, all forms of drug therapy must be considered as adjuvant measures in the treatment of gastro-intestinal disorders. The ferment remedies like pepsin and pancreatin are merely makeshifts. The intestinal antiseptics can have only a minor and temporary influence. The stimulants-hepatic, muscular, and mucosal-are largely limited in their effects by the predominance of the opposing influences which cause hepatic torpor, alimentary atonicity, and mucosal sluggishness. Equally, organo- therapy is but an adjunct measure. Fundamentals in Treatment. I have not space here to discuss the fundamentals which the successful control of digestive difficulties pre- suppose. These " first works " are all essential, and should be carried on 112 from the very beginning of the diagnostic study through the period of clinical study to the hoped-for ending of the difficulty. To mention these fundamentals must suffice here: Rest from food, thorough evacuation of the contents of the entire tract, alimentary flushing (by having the patient drink a quart of normal saline solution before rising for several days in succession), and a replacement of the vicious intestinal . flora by the use of fruit juices, bacterial cultures, etc. These measures are a part of every well-regulated regimen, and they can- not be dispensed with-so much the less, when we are confronted with chronic and stubborn indigestions that have been treated first by one method and then another for, perhaps, years. In such cases, the prescribed routine must be insisted on, and while efforts are being made to alter anatomical, neurologic, and sympathetic features of these cases, organotherapy may prove to be a substantial adjunct, and alter the whole outlook for ultimate control of the difficulty. I shall attempt to explain several organotherapeutic procedures which have been developed in conjunction with the work at The narrower Labora- tory, and to differentiate between their indications and their advantages. Malnutrition and Hepatic Torpor. Many individuals suffer from a half- hearted liver service. Besides being constipated and subject to occasional exacerbation of indigestion, they are sallow, occasionally jaundiced, have bad tempers, and it is clear that hepatic torpor is a prominent part of their make-up. Two formulas are 113 available in such cases: the one is Bile-Salts Co. (narrower), which is given in the hope of increasing the production of bile by adding to the amount of bile salts present in the blood (after absorption of the bile from the bowel) which it is well known are made over again into fresh bile. The value of Bile-Salts Co. (Narrower) is discussed more fully in the con- sideration of mucous colitis (see Chapter XIII), and special attention is called to an unusual step-ladder method of dosage which is particularly helpful. After a more normal biliary produc- tion has been encouraged, it is possible to maintain a better hepatic activity by the continued use of hepatic sub- stance, and the other formula entitled Hepato-Splenic Co. (Narrower) often is beneficial in accomplishing this. It offers a means of modifying the internal and external secretory ca- pacity of the liver, for it is now under- stood that this organ in addition to its bile-producing capacity brings about certain phases of detoxication through an internal secretory influence. The principal influence of Hepato-Splenic Co. (Narrower) is through the liver upon nutrition, and it must not be given as a cathartic, for it has no such effect. In fact, in individuals who require cathartics, their special remedy should be continued while this formula is given, gradually lessening the amount of cathartics taken. Digestive Ferment Products. The administration of ferment prod- ucts is done with the expectation of assisting digestion in the upper part of the alimentary tract. It is a make- 114 shift procedure, and if used for any length of time, as, for example, the Indefinite administration of pepsin, it is believed that the digestive organs become accustomed to the artificial presence of this substance, and lose a part of their interest in producing their own quota of it. Digestive ferment preparations always are used temporarily and to supplement other associated treatment. My formula, Amylo-Trypsin Co. (Harrower), con- tains no pepsin, but its place is taken by papain, a " vegetable pepsin," which is active in both acid and alkaline media. To it are added amylopsin, the starch-splitting ferment of the pancreas, and a pancreatin particularly rich in the proteid-digest- ing ferment, trypsin. The formula is completed by the addition of an accepted mucosal tonic, berberine hydrochloride, and the well-known plant carminatives-cinnamon, nut- meg and ginger-as excipients. This is a most useful digestant remedy, and is given wherever alimentary enzyme medication is called for, especially in atonic gastric insufficiency, gastro- intestinal indigestion with achlor- hydria, flatulence, and fermentation. Pancreas Stimulation by Secretin. Another more fundamental method of treating indigestion is by the stimu- lation of digestive ferment production. This is far better than the use of ferments (though the latter are capable of immediately assisting di- gestion in the stomach) and is accom- plished by the administration of an acid extract of the duodenal walls rich in secretin. Secretin is the essential alimentary hormone discov- 115 ered by Prof. E. H. Starling, of London, in 1902, and it has the faculty of stimulating the production of pan- creatic enzymes. It is also believed that it influences the production of digestive juices by the stomach and intestines. At all events, secretin stimulates not merely the correspond- ing production on the part of the body, i.e., more secretin production, but it has been shown that it actually combines with the precursors of the pancreatic ferments, and thereby as- sists in maintaining a more active ferment production on the part of this, the chief of the digestive glands. Secretin has no immediate effect such as one expects from the digestive ferments, which it is well known are active immediately in the stomach or even in the test-tube. Scrapings of the upper eighteen inches of the small intestines are ex- tracted with hydrochloric acid, puri- fied and desiccated. To this extract is added a suitable dose of bile salts and, since the adrenals exert such a salu- tary effect upon circulatory and ali- mentary tone, adrenal gland is also included in my formula, Secretin Co. (Harrower). This is recommended to increase functional pancreas activity especially of the enzyme production. Unlike the ferment remedies, its effect comes about through the organs of the patient, any benefit following its use being brought about by increased func- tional capacity on the part of the pre- viously deficient organs. The dosage varies with conditions. Moderate amounts, such as one sani- tablet of this formula between meals, over a prolonged period, are better than larger doses for a limited 116 time, though two, or even three, sani- tablets may be given between meals for a part of the time. Indigestion in Diabetics. For more than fifteen years, secretin has been thought of in connection with the treatment of diabetes. Half a dozen or more articles on the subject have appeared in the literature. Kingsley (N. Y. Med. Jour., July 24, 1915) stated that secretin has been tried many times in diabetes " because its characteristic action on the pan- creas was supposed to extend beyond its well-known enzyme-stimulating ef- fects and to increase the internal secretory powers of this gland." It has not been found to have any uni- form or lasting effect upon glycosuria, but " diabetics using it gained in weight from ten to twenty pounds and were greatly improved in general health." My own experience often has confirmed this. If one considers diabetes mellitus as an aggravated, specialized form of indigestion-and it is-it is proper to attempt to encourage pancreatic diges- tive capacity by recourse to secretin just as in non-diabetic case£. Why not, then, attempt to increase the pancreatic enzyme production while en- couraging Langerhansian endocrine function ? It is for precisely this reason that I originally suggested the combination of secretin with an extract of the tail of the pancreas-Pan-Secre- tin Co. (Harrower)-as a valuable measure in the control of both these important features of pancreatic dia- betes. (In this connection read Chap- ter XVIII-" Langerhansian Therapy in Diabetes.") 117 Ovarian Indigestion. The intimacy of the essential endo- crine functions such as that of the ovaries with other functions, either through the related glands of internal secretion or through the sympathetic system, is no more remarkably shown than in the frequency with which chronic gastro-intestinal disorders are caused or aggravated by functional ovarian troubles. The monthly stress that so com- monly is found where there is ovarian dysfunction and menstrual irregularity often includes digestive manifestations. The connection between the thyro- adrenal mechanism and the ovaries on the one hand, and the thyro-adrenal influence upon alimentary tone on the other, favors constipation when the abnormal ovarian demands upon this mechanism prevent full service in the other directions. Clinically, digestive disorders often accompany ovarian problems, and my point is that it is almost useless to attempt to treat the digestive troubles and ignore the ovarian ones. Let me recall an experience in illus- tration. A certain young lady of nine- teen had a bad digestion for years. After six weeks in a prominent Phila- delphia hospital, under a renowned gastro-enterologist, she returned to her home and soon was as bad as ever. Her physician remembered having read a hint of mine emphasizing the close relationship between these two functions-menstrual and alimentary. He therefore carefully considered the ovarian aspects and found periods of amenorrhea and occasional dys- menorrhea, which apparently had not 118 been sufficiently important to have been considered as having any connec- tion with the much more obvious gastro-intestinal irregularities. The treatment consisted of the same care in a dietetic and hygienic way plus Thyro-Ovarian Co. (nar- rower), with entire and speedy control of both the menstrual and the digestive difficulties. This has happened so many times that I state as an axiom : All women with chronic digestive disorders de- serve to be studied and simultaneously treated for any ovarian dysfunction which may be present. 119 XI HEMOGLOBIN THERAPY IN ANEMIA Anemia and Endocrine Treatment-A Dependable Form of Organic Iron- Hemoglobin in Combination-Clinical Experience the Test of Value-Method of Administration-A Word on Cancer and Pernicious Anemia. THE production of blood-cells, both red and white, and the mainte- nance of the hemoglobin color-index undoubtedly are influenced by the endo- crine glands. Dyscrinism, as, for in- stance, ovarian dysfunction, commonly causes anemia as the well-known chlo- rosis in girls. Or again, hypothyroidism of the more serious types always causes a greater or less degree of change in the blood findings if only due to the in- evitably increased toxemia and the in- filtration of the tissues explained else- where (see especially page 91), which results from thyroid insufficiency. This must involve the hemopoietic organs with the rest of the body and naturally interferes with their work. Anemia and Endocrine Treatment. Anemia, then, is not infrequent in endocrine practice ; and the proper treatment of the particular variety of dyscrinism very probably will bring about a coincidental benefit to the anemia. It is equally true that any treatment of anemia that does not take into consideration fundamental dis- orders, such as those of the endocrine 120 glands, is destined to be limited in its scope and of reduced perma- nence. The discovery of essential forms of ductless glandular function opens up corresponding lines of treatment which it is not the place to discuss here. But since it is our duty to accomplish the greatest amount of good for our patients in the shortest possible time, it behooves us to supplement the right kind of endocrine therapy with the best hematinic or hemopoietic encour- agement that may be possible. Given a case of anemia, of whatever origin or degree, and the subjoined suggestions will be of great supple- mentary value. And let me say here that my recommendations include every means that can be of direct or indirect value to the patient, rather than " his disease." I will now attempt to rivet attention to as valuable a measure as I know of for increase of the blood values. A Dependable Form of Organic Iron. There is no better and more thor- oughly dependable form of therapeutic iron than hemoglobin, prepared from the blood of the steer. This proteid- molecule is an easily assimilable, non-constipating hematinic. It is rec- ommended as a rational substitute for Bland's mass, tincture of ferric chlor- ide, and citrate of iron. It has been said many times to be unsurpassed for the administration of iron by mouth. Cacodylate of iron, hypo- dermically, may be a better hematinic in what might be called " acute anemias," those rapidly developing conditions of anemia due to toxic and nutritional derangements, and in such 121 cases it may be given as well. How- ever, even here hemoglobin is a much more satisfactory remedy under con- ditions in which hypodermics are not acceptable. Not only is the iron-content .in hemoglobin more easily absorbed and hence more serviceable than other iron in the mineral form, but, according to several French observers, hemo- globin is believed to bring about an actual homostimulant effect, compar- able to the effects of other organo- therapeutic products, i.e., it definitely stimulates the hemopoietic organs, just as thyroid extract is known to stimu- late the thyroid gland or adrenal sub- stance exerts a direct effect upon the adrenals. This may or may not be ; but it has been proved that iron in the form of hemoglobin is not so quickly eliminated from the body as other organic forms of iron, which, of course, are superior to the mineral form, of which ferrous carbonate is perhaps the most used type. It is said that the eosinophile count may be considered as an index of the hemopoietic regenerative capacity of the organism and, especially, the medullary substance of the long bones, where red cell production is believed to have its chief seat. With this in mind, it is interesting to note that Matzner found the eosinophile count nearly two and a half times as great in a series of hemoglobin-fed animals as compared with several controls. Certainly in the treatment of the simple forms of anemia, as well as in chlorosis and the secondary anemias in lesser degree, the Hgb.-index is re- markably raised following a course of hemoglobin by mouth. 122 Hemoglobin in Combination. Hemoglobin may be very properly combined with other remedies which reinforce its hematinic and recon- structant value. After many experi- ments I have devised a formula con- taining in each six-grain sanitablet, Repurified Oxyhemoglobin, gr. 4, Desiccated Spleen Parenchyma, gr. 1, and Nucleinic Acid (Nuclein), gr. This combination has been found to be far superior to its individual in- gredients for several reasons. First of all, iron does not have any special effect upon leucocytosis. Blaud's mass will not affect the white-cell count, nor, for that matter, will hemo- globin ; but nuclein (originally pre- pared from the thymus) is a most re- markable stimulant of leucocytic ac- tivity and is used in conditions where an enhanced white-cell service would be acceptable, e.g., in practically all the fundamental conditions which cause anemia. There are many reports of its value and the majority of them agree in drawing particular attention to the resistance-increasing effects of nuclein. This therapeutic influence fits in splen- didly with that of hemoglobin, and to my mind the combination is made still better by adding a suitable dose of spleen substance. Clinical Experience the Test of Value. Clinical reports with Hemoglobin Co. (Harrower) are numerous. Atten- tion is frequently called to the evident advantage of the nuclein in modifying the conditions of infection and low resistance so commonly associated with the anemias. Many letters tell of good results, not merely as indicated by the blood-counts, but often there has been 123 an increase of weight and recuperation which was not credited to the hemo- globin alone. The hematinic value of this formula is also broadened by the addition of spleen substance, which in addition to the homostimulative effect upon the spleen attributed to this substance by Prof. Paul Carnot, L. Hallion, and other French authorities, is believed by Schiff and others to assist in " fixing " iron in the cells, as well as to stimulate nutrition, espe- cially in cachectic and tuberculous con- ditions. There is an increasing faith being placed in spleen therapy as " a nutrient hematinic," and recent work with the spleen nucleo-protein (out- lined quite fully in my consideration of " Nutritional Control in Tuberculosis " -Chapter XV) shows that its influ- ence upon ionic calcium is remark- able. Several reports tell of unusual blood changes. Not so long ago a physician mentioned an increase of 1,000,000 red cells per cu. mm. with other associated clinical progress in a month ! One of the earliest experiences with this formula was in the treatment of a case of most severe anemia with the Hgb. at 15 per cent, and the red-cell count at about 800,000, in which, after about seven weeks, the Hgb. had been increased to 65 per cent, and the red count to 3,700,000. And this was in a case that had been virtually given up. Many other most encouraging experi- ences could be related, but space for- bids. Suffice it to say that Hemoglobin Co. (Harrower) has made many friends for our work, because of the uniformly good and sometimes unex- pected results that have been secured in all shades of anemia. 124 Method of Administration. This formula is usually prescribed thus : Hemoglobin Co. (Harrower), Sig : One or two sanitablets three or four times a day at meals or whenever convenient. This is a sensible, reconstructive hematinic in postoperative, post- febrile, and postpartum conditions, and is suggested as a routine prescrip- tion in all anemias where the first thought is " iron." Where asthenia is marked and conditions seem to call for the application of the principle of adrenal support (see Chapter II), it is suggested that the formula Spermin- Hemoglobin Co. (Harrower) be sub- stituted, since it contains a gener- ous proportion of the adrenal-encour- aging cellular tonic formula, Adreno- Spermin Co. (Harrower) already dis- cussed. A Word on Cancer and Pernicious Anemia. In the course of the past eight years quite a number of cases of cancer (secondary anemia) and true perni- cious anemia have received either of these formulas - usually Spermin- Hemoglobin Co. I have recommended it often with confidence that it is a fundamentally sound procedure, even though I have never hoped that it could cure either of these diseases. In fact, one of my most serious critics once asserted in public that it was wrong for me " to recommend such a remedy as a cure for what every well- informed physician knows is incur- able." Shall we then refrain from treating these poor souls ? What does my critic and his colleagues do for 125 their cases of cancer or of pernicious anemia ? Fairly close to what I do, I imagine ; but I believe in doing as much as possible for every case, so I add hemoglobin therapy. When I rec- ommend it in consultation I always emphasize it as a supplementary meas- ure, adding something to the effect that " we must do everything we can- simultaneously." And what have been the results ? Cases of pernicious anemia " cured " even though the most meticulous blood- tests, more than once checked by a second laboratory, had established an unmistakable diagnosis. I confess that I have felt like agreeing with a critic who said, when confronted with the laboratory findings taken before, dur- ing, and after treatment, that " it couldn't have been true pernicious anemia, then." What odds, so long as we help the patient ? In cancer the advantage that I claim for this particular form of adrenal supportive, hematinic organotherapy, is that it mitigates the blood-cell loss and increases the hemoglobin index; therefore, it is a needed restorative measure. That it " cures " cancer is, I regret, too much to expect ; but let us use such measures in the treatment of our patients, rather than of their cancers. One can never hope to cure a cancer by treating it-the only hope lies in changing the conditions which permit it. 126 XII THE CONTROL OF SIMPLE GOITER The Endemic Type of Goiter-Thyroid Stress at Puberty-The Thyroid Func- tion Test-Iodine as an Essential Food -Two Endocrine Formulas. SIMPLE goiter, as its name indicates, is an enlargement of the thyroid gland that is not complicated by symp- toms associated with other forms of thyroid enlargement, as, for example, exophthalmic goiter or thyrotoxicosis. The thyroid gland is slightly en- larged, and to the touch appears to be fairly firm but not nodular, practically never tender, and without symptoms of hyperthyroidism such as have been mentioned elsewhere. The Endemic Type of Goiter. There is a form of simple goiter known as endemic goiter which is a geographical problem, evidently involv- ing some localized factor in the nutri- tion, which makes it necessary for the thyroid to enlarge itself. There has been a great deal of writing done on this subject and a number of theories have been submitted as to the cause of this disease, which the student of the literature will have learned is endemic in certain parts of Switzerland, India, the midlands of England, and the States of Washington and Ohio, to mention the two principal " goiter belts " in the United States. It has been thought possible that this form of endemic goiter was due to an infection in the Water, and Colonel McCarrison has 127 contributed some most fascinating studies to the literature, based upon his experience with the study of this condition in India. He believes that certain forms of goiter may be due to certain micro-organisms which are swallowed with the water supply. A very great deal of interesting mass study has been given to this subject, and it can now be said without ques- tion that simple goiter of this type is a form of starvation-for iodine, an ele- ment which is necessary to the propel' development and functioning of the thyroid and which is secured from the food or water. It is in certain areas where the iodine is reduced, or absent from the normal food, that simple goiter develops, and it is now being controlled in thousands of cases by the routine administration of iodine. Thyroid Stress at Puberty. It is evident from clinical experience that if the thyroid does not receive the necessary pabulum, it finds diffi- culty in accomplishing its customary work. On the other hand, this same difficulty is brought about if the out- side demands upon the gland are greater than its capacity to supply them. The latter takes place quite commonly in girls and young women, who frequently suffer from simple goi- ter in connection with a difficult puber- ty or, later on, with some ovarian dys- function. The thyroid is forced to en- large itself as a result of some hor- monic stimulus or need for greater service on its part, and in such cases, while there may be a lack of the neces- sary iodine, there is an associated diffi- culty in the ovaries which must be cared for. Mention frequently has been made 128 in previous chapters of the physiologic dependency of the endocrines upon one another, and the thyroid in particular is involved in these complex condi- tions, which depend upon the subtle call from some other organ which urges it to attempt to regulate or make up for some related deficiency. In such cases of simple goiter there are two essential therapeutic meas- ures : (1) Lessen the physiologic call upon the thyroid or regulate the ova- rian insufficiency if present. (2) Sup- plement the work of the thyroid by giving the necessary iodine and by ap- plying the fundamental principle of homostimulation, i.e., the administra- tion of thyroid. The Thyroid Function Test. It is particularly important to dif- ferentiate between simple goiter and the slight enlargement of the thyroid associated with an early form of hyper- thyroidism. The cause is usually quite dissimilar, and, of course, the treat- ment for the one would be a detriment to the other. Some years ago, I sug- gested a method of routine thyroid feeding as a thyroid function test (New York Medical Record, Aug. 3, 1918, xciv, p. 196). Still more recently (1923) the subject has been taken up by Pro- fessor Spirito at the University of Naples in his book entitled "Lo Stato della Tiroide in Gravidanza," and I can do no better than to translate from pages 144-145, Spirito's most concise and cordial appreciation of my test: " Dr. narrower proposes a method of research specially calculated to determine the state of pre-hyper- thyroidism. It is based on the assump- tion that the heart is primarily affected 129 in conditions of thyroid hyperfunction and that, if the thyroid is irritable, the administration of thyroid extract must result in an obvious rise of blood- pressure and increase in the pulse- rate. This continues for two or more days after the ingestion of thyroid preparations. If the thyroid is normal, it is but little affected and the reaction is slight and transitory. If the gland is in a condition of hypofunction, it will be practically unaffected by the stimulus of the substance ingested. " The method consists in the admin- istration of a dose of thyroid for three days; each of the following days, twice the amount of the preceding day should be given, beginning with half a grain on the first day at regular hours, e.g., at 8 A.M., 10 A.M., 12 M., and 2 P.M. The modifications of the pulse should be examined at regular intervals-on the day before the experiments, during the three days of the experiments, and on the two fol- lowing days. " This method is especially recom- mended by narrower, not so much in cases of frank hyperthyroidism, but in cases of latent hyperthyroidism or dysthyroidism. It has been criticized by Bram as calculated to increase the morbid symptoms of hyperthyroidism. In answer to this, narrower declared that his method had been suggested, not for states of obviously hyper- thyroid cases, but for the discovery of a condition of latent, or rather, potential hyperthyroidism, revealing a condition of functional instability of the thyroid body. " Parisot and Richard, studying the effects of injections of thyroid extract in 17 cases of Basedow's disease, in 130 32 normal subjects, and in 12 cases of hypothyroidism, observed that the dose of 1 grain of thyroid extract produced modifications in the pulse, in the blood-pressure, and in the oculomotor reflex. While, in normal subjects, the pulse does not deviate from the average, in hyperthyroid cases it produces an increase of 10 to 30 beats, and in hypothyroid cases there is either no response or only a slight increase. The oculocardiac re- flex is not changed in normal subjects, but in hyperthyroid cases it is accen- tuated, and in hypothyroid cases it is decreased. " Thus, in normal subjects, and in hypothyroid cases, the maximum blood- pressure is not modified, while the minimum blood-pressure rises by 10 to 15 mm. In hyperthyroid cases, on the contrary, the minimum blood-pressure is not modified, and the maximum rises from 20 to 40 mm. These researches, although carried out by men who were obviously unaware of the method pro- posed by Harrower, are a proof of the efficiency of his method, which is founded on a logical basis. The more an individual is saturated with the functional product of an organ, the more readily and the more intensely does he respond to the administration of the same substance." To the patient with simple goiter, iodine is not so much a drug as a food. It is a mineral substance which the body must have in accomplishing its necessary work. If there is no iodine, the thyroid cannot accomplish its work in its normal physiologic status, and even when it has become Iodine as an Essential Food. 131 enlarged and is perhaps better able to accomplish its work, it cannot do so so well as when iodine is easily available. It is fortunate that this discovery is very easily translated into clinical betterment, and as a result of some extensive work done in northern Ohio by Dr. David Marine and his associates at Cleveland, in Akron, another Ohio city, they have come to the conclusion that iodine therapy is both a prophylactic and a therapeutic measure. Marine recom- mends a varying dosage of a saturated solution of sodium iodide-30 gr. given in 3-gr. doses daily to each school pupil in the fifth, sixth, seventh, and eighth grades, and 60 gr. given in 6-gr. doses each school day for pupils in tha ninth, tenth, eleventh, and twelfth grades. This treatment is given twice annually-early in May and December. The reports in a num- ber of interesting articles regard- ing this mass study of the subject are altogether conclusive, but it is clear that in the treatment of simple goiter in girls, the results have not been so good if dependence has been placed alone upon the replacement of the evi- dently missing iodine for the following reasons: In the simple goiter which is found at puberty, evidently the thyroid finds itself unable to accomplish certain work. As a result of this, the ovarian function is irregular and brings about a still greater demand upon the thy- roid. It enlarges itself automatically, but rarely succeeds in accomplish- ing all that is demanded of it. Thyroid therapy is a distinct advantage that sometimes cures these cases altogether. Iodine therapy, as we have seen, is 132 extremely valuable. A combination of these is doubly valuable, but the most important addition in the treatment of simple goiter with dysovarism is ovarian substance. Two Endocrine Formulas. There are two formulas that have been developed as a result of very extended clinical experience which are recommended in the treatment of simple goiter. The first is a combina- tion of a suitable dose of thyroid extract, the iodide of iron, an iodine food (in a form which is particularly acceptable as a hematinic as well), and nucleinic acid, known as Iodized Thyroid Co. (Harrower). The latter, in addition to its leucocytogenetic influence, evidently exerts some ad- vantageous by-effect, for a combina- tion of these three substances is better than thyroid plus iodine. This is given in variable doses, depending upon the physiological needs. Usually a start is made with one sanitablet at meals and at bedtime, and later, per- haps after two or three weeks of treat- ment, the dose may be changed to two, three times a day. Such treatment is given either for several months, or for periods of six or eight weeks, once or twice a year. The other formula is Thyro-Ovarian Co. (Harrower) which, in addition to a necessary dose of thyroid and ovarian substances, also contains a dose of pituitary substance which, as has been outlined in Chapter VII, is equally advantageous in lessening the stress upon the thyroid due to ovarian insufficiency, because of the coopera- tive assistance of the pituitary and the thyroid upon one another. 133 XIII BETTER RESULTS IN MUCOUS COLITIS A Consideration of the Adrenals- Alimentary Muscular Asthenia-The All-Important Hepatic Aspect-Aggra- vating Intestinal Conditions-Para- thyroid in Alimentary Ulceration-A Routine Method of Treatment. THIS stubborn and far-too-common disease is sufficiently complex to be called by some a neurosis and by others an infection. I hope to show that it is also an endocrine problem or, at least, amenable in many instances to organotherapy. In fact, the compara- tively recent development in our knowl- edge of the internal secretions has put an entirely different aspect upon the prognosis of this intractable disorder. For years it has been presumed that the fundamental cause of mucous enterocolitis was a nervous one, and it is perfectly true that there is a well- defined nervous element in the major- ity of individuals who have this dis- ease. I am not convinced, however, that the nervous aspect is the principal etiological factor; rather do I believe that this feature is a result of the combination of conditions. A Consideration of the Adrenals. All admit that the patient with mucous colitis is toxic. The defective digestion and assimilation cause ali- mentary toxemia and many of the symptoms of mucous colitis indicate the seriousness of the alimentary poisoning. A common manifestation, especially in chronic cases of years' 134 standing, is adrenal insufficiency, not only manifested by asthenia, poor elimination of wastes, subnormal tem- perature, poor circulation, and the com- monly reduced systolic blood-pressure, but particularly by a lack of muscular tone in the alimentary wall,. which is a contributory factor to the' complex- ity of the syndrome. Every physician knows that mucous colitis is often as- sociated with alimentary stasis and intestinal ptosis. Every student of the X-ray findings in patients with mucous colitis knows that the tendency towards ptotic conditions, especially enlarge- ment or dilation of the lower bowel, is almost a rule. We know that all forms of toxemia overstimulate the adrenal glands with a result that for a time there is a con- dition of hyperadrenia and sympathetic irritability which may even stimulate a hyperthyroidism with its sympa- theticotonus, heart hurry, and " in- ternal nervousness." The treatment of this phase of such cases is to re- move the toxic condition which is overstimulating the adrenal mechan- ism, and in several cases I have found that the use of treatment such as is indicated in hyperthyroidism is of benefit in the sympatheticotonic fea- ture of patients with mucous colitis. The sympathetic sedative formula, Pancreas Co. (narrower), given one or two sanitablets three or four times a day, increases digestion, brings about a better tone in the alimentary wall, and lessens the heart hurry, the ner- vousness, and the undue irritability of the sympathetic system. However, the majority of these pa- tients in whom the adrenal glands have been overstimulated for months, and 135 sometimes for years, are not found in a state of hyperadrenia. The adrenal mechanism has become played-out and the patient more often is in the dia- metrically opposite state of hypo- adrenia. The remarkably insufficient circulation brings with it cold hands and feet, a poorly reacting skin, a tend- ency to venous stasis-especially in the large alimentary venous reservoirs -and the almost pathognomonic low blood-pressure. The chemical features of these cases include a reduction in the amount of the twenty-four hour urea, usually considerably reduced total solids index, and, in most cases, a high urinary acidity. There is also a reduction of the metabolism, a poor cellular activity, and, in many cases, a clear-cut condition of hypothyroidism. Alimentary Muscular Asthenia. The alimentary feature of these cases already referred to is summed up in one phrase-alimentary muscu- lar asthenia-and, while we admit that patients with mucous colitis period- ically have a most uncomfortable time with undue alimentary stimuli, cramps, tenesmus, and severe pain, this is but a temporary reaction to accumulated overstimulation due to the intestinal conditions. Organotherapy calculated to support the adrenals has been given to a good many patients with mucous colitis for the treatment of the neurasthenic and run-down features of their cases ; and it has been remarked many times that with the increased circulation and raised blood-pressure, there has come about a change in the alimentary fea- tures. In some instances a long-stand- ing mucous colitis has seemed to be 136 controlled more satisfactorily with this adjuvant treatment than with years of other measures. Certain it is that patients who have adrenal insufficiency with mucous colitis should receive treatment for the endocrine aspect of their problem. A tested means of encouraging the de- pleted adrenal-thyroid mechanism is this formula to which I have so fre- quently called attention-a combina- tion of a small dose of thyroid, total adrenal substance, and spermin from the interstitial cells of Leydig (with calcium glycerophosphate as an ex- cipient). Adreno-Spermin Co. (nar- rower) should be given to mucous co- litis patients as part of their treatment. The usual dose is one sanitablet at meals and at bedtime. In certain cases the dose may be increased to two, three times a day ; and many physicians ap- preciate the advantage of adding to the oral treatment, injections of Sol. Adreno-Spermin Co. (narrower), one mil every other day for the first month. Practically all cases of mucous colitis have hepato-biliary insufficiency. The whole alimentary cycle is sluggish and the production of bile is reduced. The frequency with which the condition called by the French " oligocholie " (a hypocholia or notably reduced bile pro- duction) is found in mucous colitis, has stimulated a good deal of research work, and Prof. H. Roger and his associates in Paris have developed a theory which is quite fascinating. They believe that the upper intestinal walls secrete a ferment called " mucinase," the chief function of which is to coagu- late mucus. This ferment is rendered The All-Important Hepatic Aspect. 137 Inactive by certain alcohol-soluble, heat-stable substances in the bile, and Professor Roger inferred that, since mucous colitis so often is associated with biliary insufficiency and can be produced experimentally by diverting the bile flow from the duodenum, the membrane formation so common in these cases was due essentially to an insufficiency of bile. Later, Italian workers, headed by Dr. Riva, actually isolated and identified mucinase in the feces of individuals with mucous co- litis. From an extensive clinical study, Nepper has concluded that mucous colitis is due to the hypocholic condi- tion mentioned above, and cannot exist without it ; and that the membrane formation results from the abnormal increase in the ferment mucinase, re- sulting from a relative and simultan- eous deficiency in the production of bile. This explains the statement made by Professor Roger: "For those who pass membrane, prescribe an extract of ox gall and you will frequently see a subsidence of the pain and a complete disappearance of the casts." This hypocholia is ideally treated withBile Salts Co. (Harrower)-a com- bination of equal parts of repurified bile salts and desiccated hepatic paren- chyma-for this is an excellent chola- gogue formula. Incidentally, the in- creased bile production, of itself, stimulates further bile production, for, after the bile has accomplished its duties in the digestive canal, it is absorbed and " worked over again " by the liver into more bile. Aggravating Intestinal Conditions. As the mucus normally produced in the upper part of the bowel for lubri- 138 eating purposes is coagulated as a re- sult of this lack of what we might call " antimucinase " in the bile, it is inevi- table that this poultice should absorb many of the alimentary poisons and become impregnated with the bacteria in the bowel. As a result of this, the alimentary wall is covered with a more or less irritating, poison-filled blanket. The " spells," which so many of these patients have, result from the undue irritation of the alimentary wall by this infected coating. As digestion is manifestly lessened, the general ali- mentary condition is foul. One of the principal results of this toxemia is the adrenal insufficiency mentioned previously. Bearing a more direct influence upon these conditions, the alimentary muscle is overstimula- ted, thus bringing about a temporary hypertonic and painful condition. Then, naturally, the alimentary muscle be- comes atonic and inelastic, indigestion and toxemia are increased, and a vicious circle forms that is difficult to break. Parathyroid in Alimentary Ulceration. Recent developments in the study of the blood-calcium and the effect that parathyroid therapy has upon condi- tions of ulceration have extended from the consideration of the original vari- cose ulcers of the leg to the alimentary ulceration, such as is found in sprue and mucous colitis. Unfortunately, many cases of mucous colitis have defi- nite areas of alimentary ulceration. The intestinal walls have not been able to withstand these irritating " plasters of iniquity " which, when passed out, usually are called " mucous casts." The intestinal wall itself is ulcerated and desquamated, and it is easy to see how 139 a bacteria-ridden and poisonous poul- tice upon such an ulcer would tend to perpetuate the ulcerative feature of this disorder. When the fundamental principle of the parathyroid control of ulceration came to the attention of certain phy- sicians practising in the Orient, they immediately saw in it possibilities for the treatment of sprue, which, as is well known, is a tropical alimentary ulceration often extending from the mouth to the anus. No single treat- ment has been so remarkably beneficial in the control of this alimentary ulcer- ation in sprue as parathyroid therapy, and very naturally another step in the broadening of the applicability of this remedy has brought it into action in the treatment of the ulcerated types of mucous colitis. Clinical experience is beginning to assure us that Parathyroid Co. (nar- rower) exerts a doubly beneficial effect in these cases ; for this formula- originally prepared for the treatment of patients with paralysis agitans-con- tains, in addition to an active para- thyroid preparation in suitable dosage, bile salts, spermin, and spleen. The biliary stimulation obviously is needed, provided the explanations given above are sound. The general musculotonic and dynamic influence of spermin is certainly beneficial in the played-out, run-down individuals who so commonly are troubled with this condition. The spleen is there because it has been shown to supplement the calcium-fixing powers of parathyroid and to increase its effects upon nutrition. Finally, the smallest but most potent ingredient, parathyroid, through its ulcer-curing influence, has caused a complete revo- 140 lution in our treatment of mucous co- litis. While it is too early to deter- mine in which types of mucous colitis Parathyroid Co. (Harrower) is most satisfactory, for it has been used only in a comparatively few of the more serious, ulcerated cases, it is very clear that this formula is a new weapon in our hands for the control of this un- usually intractable disorder. The writer submits a routine method which may stand many a physician in good stead in those chronic cases which have " been the rounds " with little or no help: First, cleanse the entire alimentary tract by very judicious and mild ca- tharsis. A gastro-enterologist sug- gests : " For a cathartic in most cases of mucous colitis there is nothing bet- ter than castor oil-half an ounce at bedtime." A very limited diet is given for a day or two. Cleansing enemata are employed. Sometimes normal saline solutions help to loosen the mucus very nicely. Where there is known ulceration high injections of oil (it may be well to try 4 oz. of cotton- seed oil containing 10 per cent, of ichthyol or isarol) should be retained overnight for two or three nights. In- testinal antiseptics are sometimes pre- ferred ; either salol, the sulpho-carbo- lates, iodine in a convenient form, or bismuth beta-naphthol. All these meas- ures are employed to reduce to a mini- mum the foulness of the alimentary canal, to unload it-especially its kinks and corners-and to reduce the num- ber and virulence of the bacteria. A non-toxic diet is then prescribed with the easily putrefiable proteins re- A Routine Method of Treatment. 141 duced to a minimum (no bran, cellu- lose, or mechanical irritants). Foods that are known to be irritating should be eliminated entirely from the diet. During all this it is advisable to give hot applications to the abdomen for thirty minutes after each meal, using a hot water bottle, electric pad, or fo- mentations. An essential part of the treatment is the administration of bile to encourage the hepato-biliary function as much as possible. Bile Salts Co. (narrower) may be given in the following step- ladder fashion: At first, prescribe one sanitablet three times a day between meals, for two or three days, then increase by adding an extra sanitablet to the last dose; in a little while give still another dose until at the end of a couple of weeks the patient is taking perhaps three or four sanitablets three times a day. The idea is to increase the dose until free bile is found in the stools, and the patient should be told to watch for the yellow-green bile floating upon the water in the toilet. When this appears, reduce the dose to the original amount and have the patient " start up the ladder " again, either at the same rate, increasing the dose every two or three days, or at longer intervals. Continue this pro- cedure for several months until bile production is more normal. In cases where the asthenic hypo- adrenal manifestations are noticed, there is nothing to prevent the asso- ciated administration of Adreno-Sper- min Co. (narrower), one sanitablet three or four times a day. This tonic remedy is directed at the results of the difficulty, that is to say, the depletion resulting from the alimentary toxemia; 142 and it is also an attempt to modify the atonic alimentary features present. Where ulceration is known to be present, or in peculiarly intractable and prolonged cases, as soon as the biliary activity has been reestablished, as suggested above, Parathyroid Co. (nar- rower) may be prescribed, one sani- tablet at meals and at bedtime, and continued for six or eight weeks. No case of mucous colitis has lasted less than a number of months. It is not an acute disease. Most cases which come for treatment have suffered more or less-usually more-for many years; consequently, any form of treatment that may be recommended should be persisted in for a number of months. Do not expect results in a short time. The biliary stimulation mentioned above takes weeks to bring about the maximum results. Parathyroid therapy is not known to influence ulceration in a short time. Adrenal support is a measure that is preferably given over a period of several months. Persistence and perseverance are just as necessary in the organotherapeutic as in the dietetic and alimentary treatment of mucous colitis. The organotherapy is an adjuvant measure. It cannot dis- solve-the mucous blanket. It does not unload the bowel. Naturally, it cannot have any effect upon the dietetic con- trol. The measures suggested here are supplementary and are recommended as a part of a well-ordered regimen. Judging from clinical reports, their administration has appeared to be the turning-point . in many intractable cases of chronic mucous enterocolitis. Persistence in Treatment Is Urged. 143 XIV ULCERATION, CALCIUM FIXATION, AND PARATHYROID THERAPY The Calcium Index and Leg Ulcers- Parathyroid in Paralysis Agitans- How the Parathyroids Function-Varied Ulcerative Conditions-Good Possibili- ties in Tuberculosis-An Active Prepa- ration-Some Strange Experiences. FOR the past fifteen years there has been an impj-ession that the para- thyroids control the calcium balance in the blood, but not until recently has this impression matured into demonstrated clinical facts. Labora- tory and clinical experiences alike have confirmed the relation which deranged calcium metabolism bears to chronic septic or ulcerative con- ditions and the potency of parathyroid therapy in modifying both the calcium imbalance and the associated ulcerous manifestations. These discoveries have revolutionized the whole treatment of ulceration of every description. Some unusually interesting work on the clinical relationship between chronic ulceration, septic disorders, calcium imbalance, and parathyroid therapy has been done by Dr. H. W. C. Vines, of Cambridge University. The Calcium Index and Leg Ulcers. Briefly, here is what has happened: Vines and his associates were studying the calcium metabolism; they hap- pened to note that the so-called " calcium index " of the blood was 144 uniformly low in a series of persons who had ulcers of the leg-those chronic, intractable areas of necrosis which for years had been resistant to all sorts of local and general treat- ment. The condition variously known as status calciprivicus or hypocalce- mia was quite usual. They sought a means whereby they could change this abnormally low blood-calcium index and, too, in a manner that could be quite accurately checked up in the laboratory. Knowing from the work of a number of earlier investigators, notably Dr. W. G. MacCallum, now of Johns Hopkins University, that the para- thyroid glands exert remarkable in- fluence upon calcium metabolism, they naturally tried to influence this by homostimulative organotherapy. That is to say, they hoped by the orai administration of parathyroid extract to encourage parathyroid function and thereby modify particularly that part of the chemistry of the body which the parathyroids are supposed to control. Their experiments brought to light the fact that there are two types of cal- cium deficiency, one where the active or ionized calcium is lessened without any marked alteration of the total amount, and, second, where the total calcium is diminished. In the acute and chronic septic states, the element is usually present within normal limits but in a form which cannot be utilized by the tissues, while in the relatively uncommon cases of spasmophilia and tetany, there seems to be an excessive excretion of the calcium, resulting in calcium starvation of the tissues. They found that when the calcium balance was reestablished the ulcers 145 began to heal. They treated scores of cases with really remarkable results and unqualifiedly have established a great advance in organotherapy. As a result of these experiences the study of the calcium balance has been given still greater prominence, and the laboratory investigations naturally were extended to other classes of cases in which the same underlying chemical pathology was expected, such as chronic otitis media, gastric and duodenal ulcers, and even tuberculosis. If some one should say to you: " Doctor, I have a new remedy which is good for chronic leg ulcers, and otitis media, and gastric ulcer, and tuberculosis," no doubt you, with the majority of physicians, would say that he was to be pitied, and especially so when it was learned that glandular therapy was recommended. And one could not be blamed for this attitude, for it does sound preposterous. I am quite sure that if Dr. Vines had dis- covered all that is now known before he said a word, and had reported all the later work at the same time that he reported his cures-the word is used advisedly-of the original cases with leg ulcers, he never could have aroused the interest of those who are now advancing these ideas. Parathyroid in Paralysis Agitans. For years, the value of parathyroid therapy has been known, and follow- ing the work of Dr. W. N. Berkeley, of New York, for the past eight years I have recommended it in paralysis agitans with an aggregate of results which certainly was encouraging. It is true that in paralysis agitans we have an organic difficulty which has 146 been years in the making, which is only modified in a certain percentage of the cases thus treated, and then only partially modified, for we have no cure for paralysis agitans in para- thyroid therapy, although this appar- ently is the best single method for its control. So for over seven years we have offered, with increasing appre- ciation, a formula called Parathyroid Co. (Harrower) which was developed especially for the treatment of paraly- sis agitans and the occasional cases of parathyroid insufficiency in children which are associated with tetany and allied manifestations. This formula contains an effective amount of an active, true parathyroid with spermin from the Leydig cells for its general cell-stimulating effect and bile salts for their hepato-biliary encourage- ment. More recently the excipient has been replaced by spleen substance, since it has been shown to cooperate very satisfactorily with parathyroid. The parathyroid substance is isolated with extraordinary care and a particu- lar effort is made to obviate contami- nation with thyroid substance, for it seems that these two preparations oppose one another in a clinical way or, perhaps, neutralize one another in certain cases. The big thing is to get a real parathyroid extract-one which contains nothing but the little para- thyroid glandules and no extraneous tissue, and particularly no lymphoid tissue or thyroid. How the Parathyroids Function. To revert to the underlying problem: It is evident that the parathyroids pro- duce a hormone or chemical principle responsible for initiating certain of 147 the metabolic activities of the body. Beside the pioneer work of MacCallum and Voegtlin, at Columbia University, New York; Koch, of Detroit; Noel Paton, of Glasgow; Morel, of Paris, and others have shown that these little glands evidently are concerned with the destruction of certain waste products, in the nature of protein split-products, like guanidin, which are unusually active and seem to have a predilection for the nervous system. Also this hormone makes it possible for the body to retain in suitable form, probably in the colloidal state, the calcium which a mass of experiments has shown to be so important in regulating the body's reactivity to various external impres- sions-especially infections. Vines and Grove have shown that the principal cause of the picture they have been studying, which undoubtedly must include hypoparathyroidism, is chronic sepsis, and whether the para- thyroids permit the sepsis, or whether their dysfunction results from it, is quite immaterial. The point is, we have learned that parathyroid homo- stimulation by the administration by mouth of active parathyroid prepara- tions will, in suitable cases, change the aspect of the blood-calcium and hasten healing in old ulcers. It was a most natural- thing for all who had experience with this new treatment of leg ulcers to presume that since they were associated with defi- cient blood-calcium, other ulcerous conditions at least deserved to be studied from this standpoint with a view to submitting them to experi- mental parathyroid feeding. And so Varied Ulcerative Conditions. 148 more recent experiences have included a large number of cases of every vari- ety of ulceration-chronic otitis media, ozena, sinusitis and catarrh, gastric and duodenal ulcers, intestinal ulceration as in sprue and mucous colitis, severe burns and bed-sores, corneal ulcers, and tuberculosis. Truly a most remarkably varied list of troubles treated by one remedy. Yet our present opinions are not now based upon speculation but upon an extended clinical experience. Practically every one of these cases in which the blood-calcium was studied had the typical calciprivic picture. And again, trials with parathyroid therapy in most instances have brought about a more normal calcium picture with coincidental benefit to the ulceration, just as with the original use of this method in leg ulcers. We all realize, of course, that an ulcer is more than a local, lowered resistance complicated by the bacteria that may be present. It is apparent also that an ulcer of the leg is somewhat different from an ulcer of the stomach or duodenum, because conditions in the actual ulcer can be controlled more easily on the leg than in the stomach. But despite the interference of the alimentary contents, these and other ulcers have been cured by parathyroid organotherapy, and this is a most remarkable advance in the therapy of a very discouraging medical problem. Good Possibilities in Tuberculosis. One more feature should be referred to-the relation that this particular matter bears to tuberculosis. Certain cases of tuberculosis are undoubtedly in the category that we have been considering. They are " lime starved," 149 and since they customarily lose more calcium than they should, the blood- calcium picture is almost identical with that referred to above as being pathognomonic of the condition under- lying leg ulcers. These cases are, there- fore, reasonably in another similar class which should not be investigated merely from the blood-calcium stand- point, but also from the possibilities of experimental parathyroid therapy. Tuberculosis presents a much more complex picture in which not only the mixed infection is a tremendous inter- ference to success, but the nutritional aspect is a discouraging one. How- ever, since the accepted treatment of tuberculosis is one which will include every feature likely to be of coopera- tive assistance to the patient, I cannot see why the foregoing recommenda- tions should not be of real promise. (Very considerable advances in this line have been made. They are re- ferred to in the next chapter.) To recapitulate: We have here a method of curing ulcers of the leg and chronic otitis media, as well as funda- mentally similar conditions, including both gastric and duodenal ulcers. Further, this method should have considerable prospect in the treatment of tuberculosis for it is based upon some sensible physiological and chemical foundations. The only way to find out if a remedy is any good is to test it-in " the crucible of the clinic." More of this kind of testing has been done with the applica- tion of this method in cases of leg ulcer than in tuberculosis. I do not say that the results can be as comparably good in the tuberculous conditions as in the others mentioned. But if I had 150 tuberculosis, one of the first things I should do would be to study this feature of my chemistry and to attempt to modify it in this manner. Parathyroid Co. (narrower) is the best preparation of this nature avail- able. At this writing it is the only pluriglandular formula of its kind, and the original application of the remark- able cooperative influence of spleen and parathyroid. It has rendered service in a great many cases of paralysis agitans, tetany, and leg ulcer. It has been beneficial in cases of gastric ulcer and chronic running ear. It has cured sprue as by magic. The time element has militated against getting reports in tuberculosis as yet, but there is no reason why physicians should not be aware of these possi- bilities and give their patients the benefit of them. The usual dose of Parathyroid Co. (Harrower) is one sanitablet at meals and at bedtime, representing a daily dose of one-fifth of a grain of the true parathyroid desiccation. Continue treatment till 100 sanitablets have been taken. If advisable, continue it. (It is not good policy to give this product for a few days even though it may be helpful within a short time.) In tuberculosis it must be given for at least three months, and it should be supplemented with injections on alternate days of Sol. Para-Spleen Co. (Harrower) (see pages 170 and 271). An Active Preparation. As the reports have come in the-1' have reminded me of the absurdities Some Strange Experiences. 151 of "Alice in Wonderland." Truly the results from this new method have been astounding. As with other forms of treatment, workers with para- thyroid have been led, first by one in- teresting experience and then another, into new fields in this almost virgin territory. To the right hand and to the left they have found opportunities they have been virtually forced to embrace. This accounts for the many conditions treated. While seemingly dis- similar-conjunctivitis at first thought does not seem to have much in common with sprue, or bedsores with consump- tion-one can discern an underlying relationship. Let me repeat a few of these reports: A physician read of the advances made with parathyroid treatment of ulcer of the leg, and as he, himself, was suffering from a duodenal ulcer, natu- rally he was more interested in the prospects of parathyroid by mouth than in the surgery offered him. He had severe pain in the epigastrium several hours after meals, which was relieved by food. The usual diagnostic measures and careful X-ray study confirmed the suspicion that his trouble was, indeed, a duodenal ulcer. Para- thyroid therapy was followed for less than two weeks and the discomfort and pain disappeared. Some months later the typical pain returned and Parathyroid Co. (nar- rower) was resumed for several weeks with control of the symptoms. Later the X-ray confirmed the fact that the ulcer was healed. Another similar report is, briefly, as follows: Mrs. K., after two years of treatment by various specialists for a resistant duodenal ulcer, was given 152 Parathyroid Co. (Harrower). The results are reported as " wonderful." No matter what the cause of the benefit, it came within a few weeks after commencing parathyroid therapy, and both physician and patient credit it to the application of this novel idea. A man, age 68, with an extensive ulceration of the leg that had been resistant to all treatment, was cured by Parathyroid Co. (Harrower) as by a miracle. Here is the report: " Everything in the usual line of treatment having failed /or twenty years, the man came to the hospital asking to have his leg amputated, even insisting that this be done. Finally, he consented to try Parathyroid Co. (Harrower), and in two weeks and a half he left the hospital with the leg nearly healed. . . . Parathyroid Co. at least saved this leg because the patient had become quite disgusted with medical treatment." Another arresting report from the same city: "A. M. K., age 50, a night clerk in a hotel, had a deep ulcer com- pletely covering the left leg from about four inches below the knee to the ankle. This large area was covered with a thick, foul-smelling exudate. The foot was very edematous and the whole leg seemed swollen. There was much pain. Various local and internal measures had been tried for three years with only occasional, slight im- provement which never lasted. Local treatment was continued (chlorazene followed by a parresine dressing) and Parathyroid Co. (Harrower) was given, one, q.i.d. In seven weeks the leg was completely healed, the edema had disappeared, and the man had gained 15 pounds during the treat- 153 ment." The doctor adds: " I feel that the progress has been remarkable con- sidering the large area involved and the long duration of the illness. Inci- dentally, the patient did not lose a single night's work during the treat- ment." Another unusual application of para- thyroid therapy is in the treatment of ulcerative conditions of the conjunc- tiva. The subjoined report opens up some interesting possibilities: " The following case was diagnosed as trachoma and the usual treatment with silver nitrate, copper sulphate, etc., was carried out for a number of years (at least nine). Finally, the case was rediagnosed as a badly treated case of follicular conjunctivitis. In view of the present interest in the use of parathyroid therapy in cases of ulceration, it was thought that perhaps parathyroid might be beneficial; so one-tenth of a grain of parathyroid extract was given twice a day. After five days the patient returned thor- oughly frightened and with the con- junctiva bleeding. He was reassured that this was a good sign and the bleeding stopped in less than twenty- four hours. Within the next ten days, the conjunctiva was clear for the first time in ten years, with the exception of the scars caused by the previous caustic treatment." The same physician experimented with a case of corneal ulcer due to infection with Aspergillus albus. For months, iodides by mouth and argyrol locally accomplished nothing. Para- thyroid Co. (narrower) was added to this treatment and within three weeks there was a complete recovery with only a slight corneal scar. As this 154 writer says, " The parathyroid evi- dently stimulated repair in the ulcer." Hundreds of reports are in my files, but we will have to be content with telling of a case in which parathyroid was used to assist healing following a very serious burn. The experience is doubly interesting since the physician who wrote it saw fit to do a little experimenting during the treatment: " Mrs. J. M., age 30, weight 150 pounds, was severely burned February 6, 1923. Two-thirds of the body was affected, some of it to the second degree and part of it to the third degree. The first-degree burns were ignored. Improved methods of combating shock, overcoming acidosis, and maintaining the tension were carried out for ten days. When the mummified tissue had sloughed off and the surface was fairly free from pus, the problem was how to get the large denuded surface covered with skin. Skin-grafting was out of the question because of the con- dition of the kidneys and the impossi- bility of using an anesthetic. She was given Parathyroid Co. (narrower), two sanitablets three times a day. Shortly it was noted that the skin began to grow so rapidly from the edges that it was believed that the entire area could be covered 'faster than by the use of skin grafts. Two physicians were called in to watch developments and they admitted that the quickest and safest way was to continue the organotherapy. The marginal advances of the growth of skin could be clearly seen, and the skepticism of my two associates was ended by what they saw with their own eyes. We experimented by dis- continuing the parathyroid and it was very clear that after three days. 155 without the treatment there was a decided standstill of the marginal skin growth, so the sanitablets were recommenced. On April 4, the patient was discharged as cured with four small places each about an inch in circumference where the skin was not yet thick enough to hold the blood in. Two weeks later, all the ulcerated areas apparently were cured and she was doing all her housework. However, she discontinued the para- thyroid tablets and during the hot summer months the tension in two of these very thinly covered areas caused the skin to break down; and two ulcers were formed, each about two inches in diameter. I was not aware of what had happened and another doctor attempted for five weeks to heal these ulcers without any result whatever. As soon as I heard of conditions I immediately gave her Parathyroid Co. (narrower) again, and in three weeks, with no other treatment than a paraffin dressing, the ulcers were entirely healed." Another feature of this same treat- ment has been considered in connec- tion with the treatment of sprue and the ulcerative types of mucous colitis (page 139). The successful application of this measure in nose and throat practice is discussed in Chapter XXII. 156 XV NUTRITIONAL CONTROL OF TUBERCULOSIS Functions of the Spleen-Bayle's Experi- ences with Tuberculosis-A Laboratory "Accident "-Increasing Blood-Calcium •-Lime Fixation in Tuberctclosis- " Cures " for Consumption-Parathy- roid-Spleen Therapy - Influence upon Blood Coagtilability-The Maintenance of the Colloids-Organotherapy in Tuberculosis. THE best way to bring this inter- esting development to the attention of the medical profession is by telling the story just as it happened. Here is a human-interest story with some con- clusions which, I believe, will open up new possibilities in the successful treatment of tuberculosis. In 1912, a fortunate combination of circumstances brought me into contact with the late Sir Lauder Brunton, one of the leading internists in London and, at that time, chief of the medical staff of St. Bartholomew's Hospital. Sir Lauder knew of my interest in the internal secretions and kindly invited me to visit him at his home on Strat- ford Place. Our conversation drifted toward the possibility of the spleen's being an organ of internal secretion. For many years the functions of the spleen have been discussed with more or less interest. At one time the spleen was considered to be the graveyard for Functions of the Spleen. 157 the red blood-cells. It is also supposed to have been one member of the lymphatic system with possibilities of being a leucocyte generator. Its action upon intestinal peristalsis has been noted by some physiologists as well as its influence upon the metabolism of iron. It exerts a valuable hematinic effect when given in the desiccated spleen parenchyma, and this product has been included in one or two of The narrower Laboratory formulas on this account. Still other investigators have demonstrated that the spleen has something to do with the development of immunity and, therefore, perhaps is concerned in the production of the opsonins, precipitins, agglutinins, etc. The upshot of my visit with Sir Lauder Brunton was that he expressed the wish to see a complete statement regarding the status of spleen therapy. This was sufficient stimulus for me to spend a good deal of time gathering together all the information I could find on the subject. As a result, my article entitled " The Therapeutic Action of Splenic Extract and Its Application in the Treatment of Tuber- culosis " was prepared; and it so pleased Sir Lauder that he sent it with a word of comment to the editor of The Lancet and it eventually appeared in that periodical (1913, i, p. 524). This article came to the attention of Dr. T. N. Kelynack, for many years editor of the British Journal of Tuber- culosis. He invited me to visit him and asked me to prepare a paper for his journal. The second paper was entitled " The Adjunct Treatment of Tuber- culosis with Certain Organic Extracts " and was published also in 1913. Perhaps ten years after this, I became 158 enthusiastically interested in the possi- bilities of modifying the blood-calcium by means of parathyroid therapy, as outlined in several articles and edi- torials in recent medical publications. I could not help referring to the work on the spleen that had been done years before and attempted to find some con- necting link between the parathyroids and the spleen, especially since several physicians were developing the use of parathyroid therapy as an adjunct in the treatment of pulmonary tuber- culosis, with most encouraging results. In the meantime, a good deal of research work has been done in the study of the blood-calcium in tuber- culosis and also on the influence that various organotherapeutic products may have upon blood-calcium in experi- mental work in the laboratory, as well as clinically, in practice. It is very evident that there is some cooperative factor associating the functions of these organs and that each apparently has a part in bringing about those conditions which assist in the fight of the organism against the " great white plague." Bayle's Experiences with Tuberculosis. It is the place here to recall some of the impressions received from the earlier use of spleen therapy in tuber- culosis. I have gained more interest in the subject from my correspondence with Dr. Charles Bayle, of Cannes, France, than from any other corre- spondent, although my files contain correspondence with literally scores of physicians on this subject. Bayle's theory was first brought before the pro- fession at the International Congress of Tuberculosis, in Rome, April, 1912. I quote from Bayle's original paper 159 as follows: "I feel authorized by my results to call splenic opotherapy a specific treatment for tuberculosis. It is specific from the therapeutic view- point, because it modifies the soil, rendering it less suitable as a medium for the growth of the bacillus of Koch. It is specific from the practical view- point, because it manifests all the function and rapidity of action of a specific medication. Employed in con- valescents, it prevents tuberculosis by increasing the mineral content of the tissue (en remineralisant le terrain). Employed in confirmed cases of tuber- culosis, it cures them." Previously to this, Bayle had made another communication in which he referred to 150 cases that had been treated by him in this manner, 146 of which " showed the unquestionable and rapid effects of the treatment." The writer continues: "Among those cases which I have been able to follow for a length of time sufficient to arrive at a conclusion, I note clinical cure in 75 per cent, of the cases (the author used the word guerison-cure), some of which had been in a very advanced stage and regarding which I had no hope to begin with." Not every one who has applied spleen therapy in tuber- culosis has secured such results; but at least the prospect is interesting. A Laboratory "Accident." We now come to one of the most interesting " accidents " in our expe- rience at The narrower Laboratory. Tor over a year, we had been making a nucleoprotein solution of the spleen and sending it to certain physicians in London and elsewhere, who apparently have been finding from it a certain 160 degree of therapeutic encouragement. It is possible that some publication regarding these experiences may ap- pear later. But, in the meantime, I want to call attention to an observa- tion that was made in our laboratory, a number of months ago, by our chief technician, Miss E. Ablahadian. It happened that two batches of different nucleoprotein solutions were being made, standardized, and studied simultaneously in different parts of the laboratory. Supplies of both these solutions, the one a spleen nucleo- protein solution, and the other a para- thyroid nucleoprotein solution, were taken down to our Animal Research Laboratory to be tested upon some rabbits. In testing the splenic solution for toxicity, protein content, etc., injections of the solution were made in rabbits and the blood was tested in several instances. At the same time, blood-calcium work was being carried out to improve, if possible, the method of blood-calcium determination at that time in use; and these rabbits' blood serums were tested with that in view. It was during this process that a sudden increase in calcium was noted in rab- bits that had just recently been injected with spleen nucleoprotein solutions. So sharp was the blood-calcium increase that it was considered advisable to place a series of rabbits under spleen treatment and observe what action would develop in the blood as a result. As the reports came in it appeared that, on comparing .the influence of these two particular preparations upon the blood-calcium, the spleen prepara- tion was found to be three or four times more active than was the parathyroid. As a result of this fortunate " acci- 161 dent," quite a considerable number of additional experimental injections were made and the attention of many friends has been called to this matter. It is believed that the information gathered together more than ten years ago, in my paper mentioned previously, may now be supplemented by informa- tion to the effect that spleen therapy exerts a subtle influence upon remin- eralization in a manner somewhat similar to that believed to be brought about by the parathyroids by what is now called " calcium fixation." Increasing Blood-Calcium. It is evident that injections of spleen nucleoprotein cause an outpouring or shower of ionic calcium in the blood- stream. This increase in blood-calcium is fairly rapid and reaches its greatest height in about twenty-four hours after the injection. In from twelve to four- teen hours more, the findings are, in terms of calcium, again practically nor- mal, but so far as we are aware, never become subnormal. It is very evident from our findings that any excess of lime in the blood is shortly eliminated by the kidneys, and that is our main idea in adding a small amount of para- thyroid substance to the splenic solu- tion, since the parathyroid preparation evidently acts as a mordant to hold the excess calcium in combination in the blood, thus preventing its rapid elimina- tion. We can readily see that the action of spleen substance and that of para- thyroid substance are, while similar in many ways, very different when one considers the calcium from the stand- point of its elimination. By combining the two preparations, we have produced a remarkable stimulant to the chemistry 162 of blood-calcium and a remedy whose activity already has been demonstrated as being a conserver of blood-calcium. The following tables will show how the calcium is markedly increased after the injection of spleen solutions intra- venously. In several instances as great a change as three milligrams of calcium per unit (100 mils) was observed after the injection of the spleen preparation, and in almost no instance have we observed a decrease in blood-calcium. It seems that this reaction is quite dependable. Normal Calcium Calcium Rabbit Blood- after 2 after 5 No. Calcium injections injections 9 15.3 16.0* 15.6* 10 16.5 20.0* 17.4* 11 15.0 18.5* 15.2* 12 16.0 17.0* 22.1* 13 15.0 16.0* 19.6* 14 16.0 15.5* 21.0* 4 14.40 15.42f - 6 15.9 15.801 - 7 16.9 16.20f - 4 14.78 -• 15.00f 5 14.41 - 14.93f 6 14.43 -. 18.20f Increases in the red blood-cell count frequently have been observed after the injection of spleen nucleoprotein. Contrary to the old belief that the spleen has a hemolytic action, it was found that the red-cells increased in some instances over one-half •million within a few days and, further, that the hemoglobin was proportionally in- creased, as would be expected when the red blood-cells were increased. * Figures estimated following _ spleen nucleo- protein injections, 1 mil (c.c.) daily. t Figures produced by injections of Para- Spleen solution, 1 mil daily. 163 The clotting time was shortened markedly in every case. This was noticed very readily when drawing blood from experimental animals. In some instances, the blood clotted so easily that it was withdrawn from the marginal ear vein with considerable difficulty, the wound having to be freshened frequently. Two rabbits were splenectomized and their blood tested at intervals for its calcium content. In both rabbits thus treated, the blood-calcium dropped almost fifty per cent. A control animal was cut open and sewed up without tampering with the spleen or any of the other abdominal viscera. In this rabbit, no change was noted in the blood-calcium. The two splenecto- mized rabbits were given intravenous injections of spleen solution, following which the blood-calcium index rapidly reached normal. Lime Fixation in Tuberculosis. We shall now turn to the other feature of this work which concerns particularly the influence of parathy- roid therapy in tuberculosis. In Decem- ber, 1923, I published an article in the American Journal of Clinical Medicine entitled " Parathyroid: A Calcium Mordant in Tuberculosis," in which I attempted to show how important the calcium metabolism is in tuberculosis, how common " lime starvation " is, how a certain subtle factor-the power to " fix " calcium-is defective, and how great would be the advantage of being able to use parathyroid therapy in tuberculosis as a " calcium mordant " in order to prevent " the leakage of lime," just as it was being done in the treatment of other ulcerative states, as 164 recorded in a number of articles, including those by Vines and Grove. Attention also was called to the fact that tuberculosis of the lungs was a form of ulceration. The following conclusions were drawn: (1) Hypocalcemia is the rule in tuberculosis. Parathyroid increases the blood-calcium. Therefore: Parathyroid therapy should be a reasonable addi- tion to our treatment of tuberculosis. (2) Tuberculosis really is a form of ulceration-of the lungs, bones, skin, throat. Parathyroid therapy apparently has cured ulcers elsewhere-of the leg, skin, intestine, middle ear. Therefore: Why not hope for similar results from parathyroid therapy in tuberculosis? A number of physicians have been using parathyroid extract by mouth in an experimental way in the treatment of tuberculosis and, while it is too early to pass definite judgment upon the curative value of this endocrine remedy, it is certain that it also exerts a nutritional influence which is of advantage. Hence my further de- duction-original, so far as I have been able to find-that a spleno-parathyroid combination should be of double therapeutic value, for there is no reason to believe that the dual influ- ence of these two remedies is not com- plementary, or cooperative. I do not believe that the cure for tuberculosis is ever going to be found, merely because the disease is so funda- mental and the infection with the tubercle bacillus forms but a small part of the syndrome. Tuberculosis is by no means a monovalent infection, at " Cures " for Consumption. 165 least not when the tuberculosis focus has come in contact with the outer air (so-called open tuberculosis); for, in that case, invariably there is pres- ent an associated mixed infection with a number of other micro-organisms, all of which exert their particular detri- mental effects upon the tuberculous or- ganism and really cause the " consump- tion " stage of the tuberculous disease. In one way, it may be said, tuber- culosis is not so much an infectious disease as a nutritional disorder; for where the nutrition of the subject is proper, a tubercle bacillus infection is speedily controlled and it cannot spread. Thus it is readily conceded that success in the control of tuberculosis involves many factors, and the benefits from a well-ordered regimen come not from any single part of it alone, but from the treatment as a whole. Hence, pluriglandular therapy must not be considered even as "a remedy for con- sumption." On the other hand, I do believe that every effort shouldbemade to increase the nutritional control of these individuals, and I am submitting the proposition that, since the para- thyroids and the spleen exert these particular nutritional influences that have just been referred to, efforts to emphasize the advisability of consider- ing the calcium variations and of modifying nutrition by means of organotherapy are not only fundamen- tally reasonable but also of consider- able prospective value. In keeping with the foregoing con- siderations a series of tuberculous patients was given Sol. Para-Spleen Co. (Harrower) by hypodermic injection Parathyroid-Spleen Therapy. 166 with some early and encouraging changes in the blood-calcium findings. These patients thus far have been observed for a comparatively short period; therefore, the clinical findings have not been changed so very mark- edly. One expects such cases to re- spond more slowly to treatment than in any other condition on account of the marked chronicity of the tuber- culous infection and the usual pro- longed toxemia preceding the tests. Further experiments must be carried out in tuberculosis to find, if possible, a strength of solution that can be used which will be comparable to the severity of the symptoms of the disease. Ordinary strengths of spleen extract, such as a four or five per cent, protein solution, probably are not sufficiently active to control Koch's infection. We have not set out to discover such a thing. If we can increase the strength and efficacy of the solution, well and good. That particular problem remains to be solved. In the meantime we have another means of encouraging the nutrition of the tuberculous, especially as regards the conservation of lime. Influence ztpon Blood Coagulability. We believe another of the possibilities of treatment with this pluriglandular solution lies in its capacity to inhibit a tendency to hemorrhage in pulmonary tuberculosis, as injections of solutions of spleen shorten the clotting time quite noticeably within a few hours. In passing it may be interesting to note that a surgical colleague, in looking over our charts, already has suggested the presurgical possibilities of hypo- dermic spleen therapy in patients who should not be allowed to lose a drop 167 more blood than necessary in serious surgical procedures. It is evident that spleen solutions, when injected into the human economy, cause an outflowing of calcium which is constant, marked, and readily pro- duced. Further, it is evident that this rapid increase of calcium will be fol- lowed shortly by a loss of that particu- lar substance due to elimination and lack of a supply. Since parathyroid is capable of fixing the blood-calcium and of preventing its undue elimination, a combination of parathyroid (the cal- cium mordant) and spleen (thecalcium mobilizer) should be an ideal one for use in all calciprivic states, including tuberculosis. Thus the advantages of pluriglandular therapy once more are emphasized, and this particular combination is quite superior to spleen alone on account of the conserving action of the parathy- roid ingredient upon the calcium- stimulating tendency of the accompany- ing spleen product. Combinations of the two already have shown themselves clinically to be more active in tuber- culosis cases than single-gland products. Also they are the most dependable, since in practically no instance has the combination of the two failed to bring about an increase in calcium and to maintain it at a satisfactory point, an accomplishment of obvious advantage in a disease in which lime starvation is so common. Spleen injections alone produce a rapid increase in calcium which disappears in a short time. It may be well to attempt to give an explanation of how this influence upon the body calcium is brought The Maintenance of the Colloids. 168 about. The theory underlying Bayle's idea is that the spleen contains a certain ferment or hormone which he calls a " colloidogen," because he believes that its action is connected with a hypo- thetical capacity of that organ to maintain, by means of this substance (presumed to be an internal secretion), the principal mineral elements of the blood in a colloidal state-the so-called " colloidogenic function of the spleen." The blood is believed to contain, the mineral elements in two forms: (1) those in the colloidal state suited for cellular appropriation and thus less readily eliminated by the kidneys, and (2) the mineral cellular wastes which are dissolved in the plasma and destined to be eliminated. If the elements which are supposed to be present as colloids in some way lose their colloidal form, they are promptly eliminated by the emunctories and a condition of de- mineralization obtains. The capacity to maintain these mineral salts in a col- loidal state evidently is a protective function of considerable importance and it may indeed be that the spleen is re- sponsible for its maintenance. It is cer- tainly true that spleen therapy lessens the abnormal elimination of calcium in the urine and increases the calcium con- tent in the blood quite rapidly; while the years have confirmed Bayle's convic- tion that opotherapie splenique exerts a beneficial nutrition-stimulating effect. Organotherapy in Tuberculosis. The narrower Laboratory now sub- mits two products which are offered as adjuvant measures in the treatment of tuberculosis. One of them is Para- thyroid Co. (narrower), a combination of an active true parathyroid product, 169 plus bile salts and spermin, to which, has been added a generous dose of the desiccated nucleoprotein of the spleen. The recent modification of this formula adds to its value as a nutrition-promot- ing remedy in tuberculosis and by no means interferes with its use in Park- inson's disease or in the numerous ulcerative conditions for which it has been so frequently recommended; in fact, its general value has been con- siderably enhanced by this addition. The other product is a solution of the nucleoproteins of the parathyroid and the spleen in suitable combination, known as Sol. Para-Spleen Co. (nar- rower) , each ampule containing a four per cent, sterile saline solution of these active principles. So far as I know, there is no similar product available. It is suggested that Parathyroid Co. (Harrower) be given, one sanitablet at meals and at bedtime, while hypodermic injections of Sol. Para-Spleen Co. (Har- rower) be given on alternate days, the average dose being one milliliter (c.c.), although it is best for the initial dose to be 1/4 or 1/3 of the contents of an ampule. Gradual increases should be made during the first two weeks until the full daily dose is given. It is best to give this combined treatment simul- taneously. Occasionally the daily dose of the oral remedy may be increased, although it is better to give an average dose over a longer period than the same quantity in large doses for a shorter time. Equally, the hypodermic injec- tions may be given daily for a few weeks, but it is better to prolong the treatment, using, say, thirty doses in eight or ten weeks rather than to at- tempt to " crowd " the treatment. 170 XVI REDUCING HIGH BLOOD- PRESSURE Endocrine Imbalance in the Etiology-■ Adrenal Forms of Hypertension-The Control of Hyperadrenia-Pancreas an Anti-Adrenal Remedy-The Thyroid Fundamentally Involved-The Cause of Cellular Infiltration-Thyroid Therapy Often Advisable-Ovarian Considera- tions-Variations in Blood-Pressure- Endocrine Balance Is Vital-A Change of Life in the Male-Pltiriglandular Therapy Indicated - Supplementary Measures. THAT the endocrine glands are re- lated to certain functional disturb- ances of the arterial tension is now well known. While it is still true that the problem of the control of hyper- tension is a complex one, involving several factors which cannot be con- sidered here, the fog of years is lifting, and clinical experience is showing us the real facts. It is just as obvious that the two distinct types of increased blood- pressure (functional and organic) offer two very different therapeutic prob- lems. Individuals with a functional hypertension are suffering from more or less temporary physiological de- rangements resulting, among other things, from conditions which irritate or unduly stimulate the so-called "pressor mechanism"; while in the other class, mechanical or anatomical factors are involved and invariably there is some real pathologic condition. 171 It should be clear that an individual with arteriosclerosis, renal impermea- bility, cardiac hypertrophy, or other structural changes, is not in the same ■category with an individual whose thy- roid is inactive or whose adrenal sys- tem is overdriven. The prospects in the treatment of such organic cases are not nearly so good. Endocrine Imbalance in the Etiology. Since the advent of the simple sphygmomanometer, medical men have been discussing hypertension with avidity, and when we look over the various writings we are much inter- ested to note that several years ago some of the men with deep insight and special ability in diagnosis were hint- ing that there must be an endocrine feature in many cases of hypertension. We read remarks like this : " It is very evident that many cases of hyperten- sion could, or do, have other symptoms pointing to endocrine imbalance." " Many cases of arterial hypertension can be found who have remote toxic conditions that are bringing about the hypertension through stimulation of certain of the endocrine organs." To-day many of us are thoroughly convinced that so-called " essential hypertension" is by no means idio- pathic, but is a true expression of such essentially endocrine conditions as adrenal irritability or hypothyroidism. Dr. H. T. Cox, in the Eclectic Medical Journal for June, 1923, states that " the internal glands need attention in hypertension cases where there is no evidence of renal, cardiac, or arterio- sclerotic change." He further traces the condition to some disorder " usu- ally toxic in character, which is affect- 172 ing the production of the internal secretions, such as adrenal irritability or ovarian changes at the menopause." Recently a prominent Dutch intern- ist said that we have no grounds for the assumption that high blood-pres- sure always is secondary to heart, kid- ney, or vascular disease. It has no more significance than the sclerosis of a nor- mally soft organ. He continues : " Be- cause we can measure the blood-pres- sure, we have paid too much attention to it and hidden our ignorance behind the term ' essential hypertension.' The rise in blood-pressure is merely one element of a morbid series which has to be regarded as a whole." I propose to discuss this matter briefly from the standpoint of the gen- eral practitioner and especially from the aspects of the endocrine causes and the organotherapeutic treatment. I will, therefore, divide the subject into three parts. I. Functional hypertension may he due to a temporary overstimulation of the adrenal glands. Despite an occasional statement to the contrary, the consensus of opinion is that the adrenal glands exert a very definite control over the muscular tone of the vascular mechanism, and conse- quently of the arterial pressure. Wiesel was the first to call attention to the relation of hyperplastic adrenal glands to arterial hypertension, main- taining that this increased tension was caused by an excess of adrenin in the blood. A host of writers have since accepted this view and many ex- periences, both clinical and experi- mental, have so substantiated this Adrenal Forms of Hypertension. 173 belief that most clinicians now ac- cept it. Professor Sajous, of Philadelphia, places the blame for arteriosclerosis on hyperadrenia. He not only explains hy- pertension itself by adrenal irritation, but also is confident that two main find- ings in arteriosclerosis-angina pec- toris and cerebral, hemorrhage-are due to the chromaffines. Dr. I. Bram, of the same city, calls attention to the fact that postmortem findings have shown a hypertrophy of the adrenals in cases definitely known to be hyper- tensive or arteriosclerotic before death. Wiesel reported a similar hypertrophy in all the twenty-two cases of hyper- tension and arteriosclerosis which he brought to autopsy. At least a dozen investigators have attempted to show, by biological tests, an excess of adrenin in the blood-stream in hypertonia, but until a more accurate method is to be had, nothing of great value can be re- ported from experimental work in that sphere. Mason makes the very defi- nite statement that " hyperactivity of the adrenals manifests itself clinically by cardiovascular syndromes charac- terized by hypertension associated with a hypertrophy of the heart." He also says that both the systolic and diastolic pressures are increased, and mentions the hypertrophy of the left ventricle so commonly found in hypertension. This hypertrophy is due partly to direct adrenal action and partly to a neces- sary increase in the musculature. Prof. Swale Vincent, of London, considers that often adrenal symptoms may be ex- pected in hyperpiesis (essential hyper- tension) and refers to the experiment in which Roger and Gouget produced arteriosclerosis by means of lead, and 174 upon postmortem examination found an adrenal hypertrophy. Dr. Lorand, of Carlsbad, throws his evidence into the balance in favor of the adrenal cause of hypertension and cites as factors which cause adrenal hyper- secretion, those mentioned before, such as tobacco, alcohol, lead, mercury, syphilis, etc. In other words, instead of saying that these irritants are the cause of arteriosclerosis, we should say that they bring about arteriosclerosis through adrenal irritation. According to Dr. L. Klein, of Detroit (Tlterap. Notes, May, 1921), the hor- mone of the adrenal medulla, adrenin, controls the contraction of the blood- vessels. A corollary of this proposition is that the presence of high blood- pressure may indicate adrenal hyper- secretion. In the study of a case of hypertension without cardiovascular or renal foundation, the logical procedure is to determine which glands, if any, have become sufficiently abnormal to derange the endocrine chain and thus cause hypersecretion of the adrenals. The glands that are most frequently at fault are the thyroid, pituitary, and the gonads. " Occasionally the etiological factor is an uncomplicated hyper- adrenia." The Control of Hyperadrenia. To modify successfully an excessive functional activity of the adrenals, first remove all infectious foci or sources of toxemia, thus lessening the irritat- ing character of the blood as it passes through the adrenals. Secondly, if others of the endocrine glands, because of some abnormal re- lationship, are causing an irritation of the adrenal system,' such dyscrinism 175 should be carefully studied and modi- fied when it is possible. Finally, since it has been definitely determined that the pancreas and the adrenals are antagonists, any hyper- adrenia would involve a lessened pancreatic function, or, at least, should encourage us to increase pancreatic function so that the antihormone produced in the Langerhansian cells might be Increased in the expectation of overruling at least a part of the excessive adrenal activity. It is pre- sumed by many investigators that dia- betes is due to a deficient internal se- cretion of the pancreas, which von Noorden has called " the brake to the sugar mechanism." Individuals with pancreatic insufficiency often have an associated hyperadrenia with an un- usually sensitive sympathetic system, glycosuria, and a functional high blood- pressure. Obviously, the treatment of these cases, in addition to the indi- cated regulation of diet and hygiene, is the encouragement of the pancreas gland, which can be brought about very satisfactorily by the use of certain pancreas preparations, especially Pan- Secretin Co. (Harrower). (See Chap- ter XVIII.) Pancreas an Anti-Adrenal Remedy. Pancreas substance-the total gland, including the internal secretory cells in the tail-is an anti-adrenal remedy, and there are a number of references in the literature, especially the Italian, indicating that the pancreas treatment of functional hypertension has been successful in certain cases, and it may be enhanced materially by associating it with cooperative endocrine products. Great emphasis must be laid upon 176 the necessity of controlling factors which continually irritate the adrenals. It is absurd to expect that physiologic antagonism to hyperadrenia will suf- fice. Every factor liable to irritate the adrenal glands, including all the mat- ters mentioned above, should be regu- lated simultaneously and pancreas therapy is only a cooperative factor. The Thyroid Fundamentally Involved. II. The thyroid gland is largely responsible for metabolism, and conse- quently, when it is functionally ineffi- cient there may ensue an accumulation of wastes which serve in a mechanical way to raise the blood-pressure. Some years ago Prof. L. F. Barker, of Baltimore (Ohio State Med. Jour., Oct., 1920, xvi, p. 709), stated that high blood-pressure appears to depend chiefly upon a narrowing of the lumina of the arterioles in the precapillary areas, and that it is first functional and caused by hypertonus of the ar- terial musculature, but later may as- sume a partly organic character as a result of changes in the arteries them- selves. He believes that different types of chronic hypertension probably rep- resent different changes in the develop- ment of the same fundamental process which may advance with variable rapidity and with varied associated involvement of the cardiovascular, renal, cerebral, and other structures in different cases. The Cause of Cellular Infiltration. There is an especial interest in this matter when one realizes that hypo- thyroidism uniformly causes a cellular infiltration that is a result of deficient cell chemistry. The accumulated wastes 177 cause a swelling of the cells, based upon the principle of osmosis, for these solids draw into the cell an increased amount of fluid in order to dissolve them, and the cells become puffed up with their own waste products-ex- actly as in myxedema. Presumably this occurs as much in the so-called precapillary areas as in other parts of the body. So aside from disturbances in the detoxicative mechanism, due to thyroid insufficiency, there is this mechanical cause of high tension. This seems to explain why thyroid extract is sometimes so beneficial in certain cases of functional high blood-pressure. The consequent enhancement of cellular chemistry, the removal of the accumu- lated effete materials, and the lessen- ing of this mechanical opposition to circulation in the arterioles is, I be- lieve, an important factor connecting the thyroid with conditions of high blood-pressure. In addition to my own ideas of the hypothyroid basis of hypertension, I might cite several other authors whose opinions are very similar. While Scott does not emphasize the idea of infiltra- tion, he does depend on thyroid to de- crease hypertension in the aged. He mentions cases which he has treated very successfully in this manner and gives us as an interesting little side- light a quotation from Sir Victor Horsley : " Senility is due, at any rate in part, to thyroid degeneration, while myxedema may be described as prema- ture senility." We might mention here that postmortem examinations in cases of myxedema very often demonstrate advanced arteriosclerosis, frequently attended with intense calcification. We have at hand a quotation from Dr. 178 Randel Short stating, " I have found thyroid extract quite as effectual as iodide of potassium in healing tertiary syphilitic ulcers." In other words, the action of iodides upon lesions of ter- tiary syphilis is really due to an increased thyroid secretion in the blood stream. The same reasoning can be applied to the treatment of hyper- tension by means of iodides : i.e., the advantages following iodide therapy are not due to iodine ingestion but rather to increased thyroid secretion. Thyroid Therapy Often Advisable. There are many references in the literature to the therapeutic advantages of thyroid therapy in certain forms of essential high blood-pressure, and as Klein puts it, " If the diagnosis is doubtful, a few days of thyroid treat- ment will quickly elicit the desired information." He reports having re- cently seen three patients, all of whom had a systolic blood-pressure ranging from 180 to 210 mm., who were made perfectly comfortable and whose blood- pressures were reduced below 160 in a short time with no other medication than one-sixth of a grain of thyroid extract three times a day. I want to call special attention to the frequency with which this form of high blood-pressure occurs in patients who are obese. It seems clear to me that these patients are not oxidizing with sufficient rapidity the products of de- structive metabolism, and, therefore, because of the deficient stimuli from the thyroid and associated glands, cer- tain protein wastes accumulate which overburden the emunctories and there- by directly raise arterial tension, not merely from the cause just mentioned 179 but from their irritating influence upon the adrenal mechanism. Thus the thyroid aspect of func- tional high blood-pressure is extremely important since the administration of thyroid in suitable cases, besides bring- ing about a better chemistry in the manner just suggested, is also an indi- rect means of antagonizing adrenal irritability and, consequently, is a doubly valuable cooperative measure when pancreas is given. III. The sex glands, or gonads, and especially the ovaries, exert some subtle influence upon factors which, when un- controlled, cause changes in the blood- pressure. This seems to be particularly true in women at the menopause. The charac- ter of the tension, and especially of its response to the regulation of disturbed endocrine function at this period, has caused pleasing changes in many cases of abnormal systolic tension which confirm its essentially functional char- acter as well as its responsiveness to suitable organotherapy. The expected normal decline of gonad function in both sexes evidently is compensated for by readjustment in other endocrine organs. When these readjustments are not made as thoroughly or as quickly as they should be, symptoms of the imbalance soon make their appearance and we find an involvement of the pressor mechanism. Undoubtedly there is an intimate relation between the adrenals and the gonads. Carey Culbertson, of Chicago (Surg. Gynec. and Obst., Dec., 1916, xxiii, p. 667), K. I. Sanes, of Pittsburgh (Am. Jour. Obst., Jan., 1916, xxix, p. 7), and Ovarian Considerations. 180 others, have stated in no uncertain terms that the instability of the pressor mechanism at the menopause is con- nected definitely with ovarian insuf- ficiency, and ovarian therapy has been efficacious in modifying the excessive systolic pressure in these cases. Cum- mings, of Los Angeles (Calif. State Jour. Med., 1919, xvii, p. 373), also is convinced that increased blood-pres- sure, hot flushes, and other circulatory and nervous manifestations at the menopause, are definitely endocrine in origin. In addition to the bromides, he recommends various endocrine ex- tracts for their beneficial influence upon functional hypertension. Variations in Blood-Pressure. One of the chief characteristics of so-called " essential hypertension " of the menopause is variation in tension. The condition is often transitory, and many of us have observed while taking blood-pressures in menopausal cases that it is difficult to find two duplicate readings even during one sitting. Therefore, I recommend that in all cases of hypertension it is best to take the blood-pressure reading when the pa- tient first arrives, wait five or ten min- utes and take it again, and also take it a third time before dismissing the pa- tient. This process has the double ad- vantage of eliminating extra pressure due to the excitement of coming to the doctor's office, and of disclosing the fact that we are dealing with an essentially adrenal hypertension, especially if there is a great variation in the three readings. In adrenal hypertension, attendant symptoms point to adrenal factors such as hyperglycemia, glycosuria, and tre- mor. Glycemia is very frequently seen 181 in the menopausal period and often is found to be of the adrenal type. This form of glycemia often disappears after the readjustment of the endocrines, as the climacteric years pass. The great- est percentage of female diabetics who present hypertonic symptoms are found to be in the menopause. Both Maranon and Culbertson have called attention to a very interesting characteristic of climacteric hyperten- sion-the fairly constant finding of a lower diastolic pressure than we should expect to find in high systolic pressure cases. This disproportion in the two tensions is found even in menopausics who have no markedly increased sys- tolic pressure, which, to my mind, is another indication of the great instabil- ity of adrenal hypertension during the menopause. This instability of blood- pressure is, of course, the one means of differentiating between adrenal hy- pertension and that due to arterioscle- rosis or to cardiorenal conditions. The " essential hypertension " of the change of life is due to a decrease in the hypotensive ovarian hormone and an increase in the hypertensive secretion of the adrenals. Therefore, this process is bound to be a rather " wobbling " one. As the ovaries gradually disappear from the field of sexual activity, the adrenals come forward and perhaps at times may overstep themselves. In an editorial note in Clinical Medi- cine (Dec., 1920) the following state- ments appeared : " Endocrine balance is vital ; when it is disturbed the organ- ism is ailing. Does one member of the endocrine chain lag or for any reason fail to function, then another, in the Endocrine Balance Is Vital. 182 absence of a normal restraint exercised by an opposing gland, renews its efforts with provocative increase of secretion. A striking example of this is given by Bandler (N. Y. Med. Jour., June 5, 1920, cxi, p. 972). He shows us that the thyroid gland during pregnancy is under a strain in consequence of the extra work it has to do. The same is true during lactation, and occasionally symptoms arise that are referable to an unopposed adrenal action, such as high blood-pressure, flushes, palpitation, nervousness, and so on. The preven- tion or control of these symptoms is accomplished by thyroid therapy, and Bandler reports excellent results from the administration of small doses of thyroid gland." From my own observations and by reading the reports of others, I am led to believe that the male, in a way, passes through a form of menopause or gonadopause, and that secondary to testicular atrophy we meet hyper- adrenal syndromes. It is difficult to demonstrate true adrenal hypertension in the male at the age of forty-five or fifty. Men are forced to meet conditions in life to which few women are sub- jected. Hard muscular work, stress and strain of carrying on a business in the face of rapidly changing price systems and brisk competition, the overuse of tobacco, many times sexual excesses in past years, too much liquor-all have tended to obscure a clear endocrine picture. Dr. P. Zenope, now of Constanti- nople, formerly of the Pasteur Insti- tute, Paris, also leads us to believe that much of the arterial hypertension met A Change of Life in the Male. 183 to-day is due to the influence of the adrenal glands. He mentions various toxins which are known to produce hyperactivity of the adrenals. Among these are alcohol, tobacco, lead, syphilis, tuberculosis, malaria, etc. This is men- tioned as additional proof of the gen- eral belief among sincere investigators that hyperadrenia is our greatest single finding in " essential hypertension." Zenope has systematically studied ap- proximately one hundred individuals and was greatly surprised to find a definite relation existing between the ovaries or testes and the adrenals. His investigations tend to prove that the arterial tension is in,inverse ratio to the sexual potency in man and the quantity of the flow in women. In other words, a sexually hyperactive man has a lower blood-pressure than the sex- ually weak man. Likewise, there is a lower blood-pressure in a woman who flows abundantly than in one who flows but a day or two. As a final statement, we quote di- rectly from this author : " It is then but a step farther to believe that a similar synergy is equally possible be- tween the gonads and the adrenal glands. We believe that the internal secretions of the ovaries and the testes act upon the adrenals as a brake." Pluriglandular Therapy Indicated. Each of these three organothera- peutic measures previously mentioned -pancreas, thyroid, and ovary-is especially helpful in the type of cases mentioned. Many of these cases over- lap, and it is not an overstatement to say that often all three of these factors are simultaneously present. At all events, it is very common to find hypo- 184 thyroidism at the menopause (it is said that ninety per cent, of all cases of myxedema occur in women ; and ninety-five per cent, of these occur in women in the decade between forty and fifty). The hypothyroidism and hypo- ovarism which one expects to find under such circumstances routinely are accompanied with adrenal irritability and, consequently, the treatment of functional high blood-pressure at the change of life is best accomplished by the addition to the routine detoxicating and regulating measures, of a pluri- glandular therapy involving the ovaries and the pancreas, and by reinforcing these with small doses of thyroid. Very few writers now defend uni- glandular treatment for hypertension. The majority are falling in line with my pluriglandular ideas and are using my two blood-pressure-reducing formu- las with eminent success. The French and Spanish writers have for years adopted a pluriglandular treatment for these cases, and, judging from their routine findings of lower blood-pressure following this form of treatment, we are confident that the majority of the English-speaking physicians will soon decide in favor of pluriglandular rather than uniglandular therapy in the treatment of the so-called " essential hypertension." For many years I have been at work upon this particular problem, and not merely have I been successful in reduc- ing functionally high blood-pressures, ranging from 180 to as high as 300 mm., but many of my colleagues have seen fit to follow my suggestions, and the reports which have come to me prove that this is a rational and advan- tageous measure. Provided the in- 185 creased tension is functional, it may be reduced very encouragingly by follow- ing this method of treatment. Thyro-Pancreas Co. with Ovary (nar- rower) contains two grains of desiccated total pancreas gland (not pancreatin), two grains of total ovarian substance, and one-twelfth of a grain of U.S.P. thyroid. One such dose is given at each meal and at bedtime, or four times a day, for a minimum period of two months and in some instances consid- erably longer, especially in women with other evidences of dyscrinism. In the treatment of functional high blood-pressure in men, a similar prep- aration is almost as efficacious. It is Thyro-Pancreas Co. with Spermin (narrower), No. 29 on our list. The formula is identical with the one men- tioned above, save that the ovarian ele- ment is replaced with spermin from the interstitial cells of Leydig. The dosage also is the same. Both of these pluriglandular formu- las have been tested many thousands of times. The aggregate of results has been good, and, while this treatment has been used in many cases in which there was really no functional endocrine basis for the high blood-pressure, still the average has sufficed to convince us of the possibilities of this measure. These formulas are well worthy of con- sideration, since high blood-pressure, whether functional or organic, is a dangerous matter. I have yet to find any reports of detrimental by-effects. Certainly such measures are more rational than the nitrates or other vasodilating drugs, for organotherapy accomplishes something of a real fundamental, physiological charac- ter. 186 Simultaneous Supplementary Measures. It should be emphasized in closing that our consideration of this subject and the treatment of these cases from the endocrine standpoint always should be a part of a well-regulated regimen. Although certain investigators prefer to regulate their treatment so that they can acquire definite information as to the responsiveness of the patient to their remedy, I am very much opposed to this in a clinical way for this reason: I consider that the patient's interests come before my own ; that while it would be interesting to know certain reactions of the patient to a certain line of treatment, and to acquire as much diagnostic information in this way as possible, it is wrong to deny the patient the benefit of whatever may be funda- mentally advisable until we are satis- fied that a certain measure is good or not. If the patient is in need of elimi- native or dietetic care, these should be given. If there is an endocrine dys- function of several ductless glands, they should be treated together, and every measure calculated to render service to the individual should be instituted-simultaneously if possible. The whole subject of the treatment of functional high blood-pressure has been revolutionized by the development of organotherapy, and particularly pluriglandular therapy. Many corre- spondents of mine have written enthus- iastic statements in regard to the splendid reductions in blood-pressure that have followed this method of treat- ment, and for this reason Thyro-Pan- creas Co. with Ovary (Harrower) (or with Spermin, as the case may be) is confidently recommended. 187 XVII MAMMARY THERAPY IN MENORRHAGIA Uterine Relaxation-Excessive Ovarian Activity-Antagonistic Mammary Ther- apy-A Utero-Tonic Measure-Exces- sive Menses in Girls - Suggestions about Dosage-Clinical Experiences. Menorrhagia, or flooding, is a condition which, may be encoun- tered at any age from puberty until the menopause. The term, in its re- stricted sense, is used to designate an excessive menstrual flow coming on at the normal time. Winter's definition is : " Excessive or prolonged bleed- ings from the uterus, which follow, more or less, the regular four-weekly rhythm of menstruation and which are associated with the local and con- stitutional symptoms of menstruation, are called menorrhagias ; whereas bleedings which are of an irregular intermenstrual character are called metrorrhagias." In its broader sense, the term menor- rhagia refers to any form of uterine oozing whether due to functional or to organic causes. Naturally, we are particularly interested in functional menorrhagia, and, from the standpoint of differentiation, organic causes should be ruled out. In his book on gynecology, Leuf dis- cusses menorrhagia thus : " A good name to include all kinds of uterine bleeding would be hysterrhagia, which, though etymologically no better than metrorrhagia, has the advantage of not 188 being, by long custom, limited in its significance. The bleedings have many causes, among which may be men- tioned general plethora, polypi, cancer, fibroids, retained placental tissue, fungous endometrium, subinvolution, uterine displacements, chronic ovaritis, and . others less common. The cause should be discovered and, if possible, removed." In discussing the organic causes of menorrhagia, Rittenhouse says : " The cause of bleeding from the uterus usually is a relaxed condition of the uterine muscles and mucosa, the latter being covered with granulations that bleed upon the slightest provocation. This condition of relaxation may result from various causes, one of the most common being subinvolution fol- lowing either parturition or abortion. It also may be owing to a fibroid, a polypus, to misplacement, or cancer. Sometimes anemia seems to be the only cause, so far as can be discovered. Certain women appear to have a nat- ural and unaccountable tendency to menstruate too profusely or too fre- quently." Of course, none of these organic causes can be treated solely from an endocrine standpoint, but we should treat patients and not conditions. Many such cases have an endocrine feature. One may be dealing with an apparently organic condition, for which ordinary treatment does not produce the desired results. In such a case, diligent search should be made for the presumed dyscrinism and the patient given the benefit of the doubt, by the institution of the indicated treatment. Uterine Relaxation. 189 Excessive Ovarian Activity. One of the common causes of func- tional menorrhagia is ovarian hyper- activity. Long ago, menstruation was supposed to be the result of uterine engorgement. This fact is still acknowl- edged, but it is also known that it is the ovarian cycle which initiates the flow. We might say that as long as there is just sufficient ovarian hormone to meet the body's needs, menstrua- tion is normal as to time and amount. If, however, the sex organs become hyperactive, increased menstruation is one of the obvious results. Dr. W. P. Best says : " Hyperfunction of the ovaries does doubtless have a direct bearing upon the endometrium, pro- ducing excessive hyperemia. If we are dealing with an abnormal endome- trium, especially of the adenoid type, or if the uterus has lost its elasticity, its contractile power diminished, then the usual normal ovarian stimulation may produce excessive results." In the work, " Endocrinology and Metabolism," in the chapter on " The Rhythm of Gonadal Function " (Vol. II, Sec. 6, p. 593), Dr. H. M. Evans makes this interesting statement regarding ovarian hyperactivity : "Before men- tioning the instances of true ovarian disorder which cause disturbances of the menstrual rhythm we may com- ment briefly upon ovarian hyperfunc- tion. The indications of overactivity on the part of the ovary are not at present satisfactorily understood. It is easy to understand that excessive activity of the corpus luteum would conceivably increase the amount of the pregravid endometrial changes and hence the amount of menstrual 190 necrosis and bleeding. Hence some menorrhagias may be referred to this cause, though it is commonly believed that in such conditions increased con- tractile power of the myometrium Would prevent excessive bleeding." The subject of hemorrhage at the age of puberty or in younger patients is very ably taken up by Dr. W. Blair Bell in his book, " The Sex Complex." He says: "An excessive ovarian secre- tion leads to an increase in sexual ac- tivity both locally and generally. The local effects may be seen in more pro- fuse and protracted menstruation. . . . This condition occurs chiefly in girls about and just after puberty, in whom the correlations of the internal secre- tions in regard to the altered condi- tions have not been finally adjusted." He then advises surgery and antago- nistic organotherapy. Both extremes of thyroid activity produce the same end-results. Menor- rhagia is found in cases suffering from hypothyroidism as well as in the hyper- thyroid type. I suggest that the hypo- thyroid menorrhagia is the result of infiltration, which causes a large, boggy uterus ; while the hyperthyroid menor- rhagia is due to real sex gland stimu- lation. It is such conflicting conditions as this that emphasize the importance of studying the cause from every possi- ble standpoint. Authors have dis- agreed, because, while some have found menorrhagia in cretins, others have noted an entire lack of the menstrual functions. These findings can very easily be correlated if one stops to con- sider the question thoroughly, for the thyroid gland is one of the sex gland stimulants, and hypothyroidism would of necessity leave the ovaries without 191 one of their strongest activators. In Gibbons' book, " Sterility in Wom- en," particular attention is called to the fact that menorrhagia is a fre- quent finding in female patients who have suffered the loss of the thyroid. Antagonistic Mammary Therapy. Since it is well established that the ovaries and mammary glands are antagonistic, many investigators have used mammary therapy in the treat- ment of the functional types of menor- rhagia. This treatment will be found effective for the relief of menorrhagia due to hyperovarism and hyperthy- roidism, but it will not be likely to benefit the hypothyroid type. • Fortu- nately, these cases are so compara- tively easy of recognition that thyroid therapy will suggest itself. Von Zelinski, in an article on the treatment of menorrhagia in the American Journal of Clinical Medicine, pays due respect to Professor Hoehne, of Stoeckel's clinic at Kiel, who empha- sizes the basis for scientific mammary therapy, although we are convinced that the idea was first introduced in 1896 by Dr. Robert Bell, of Glasgow. He further states that Hallion and Battuaud frequently refer to the antag- onism existing between the ovaries and the mammary glands. Von Zelinski •continues : " A number of writers, Hoehne in particular, have called at- tention to the possibility of diminishing excessive menstrual flow and curtail- ing its unusual duration by means of mammary extract. It is also asserted to be useful in lengthening abnormally short intervals between the catamenia, restoring the normal rhythm of men- 192 struation in frequency, amount, and duration. Luncz, especially, credits this method of treatment with remarkable efficacy and emphasizes its absolute harmlessness." A Utero-Tonic Measure. Pituitary extract directly stimulates involuntary muscle regardless of the enervation, and for this reason it has long been used in obstetrics, and some physicians have found it valuable in the treatment of menorrhagia. No less an authority than Sajous has said : " Pituitary is useful, in fact, in all forms of hemorrhage of the genital sys- tem." Probably the best-known and most frequently used remedy for such cases, however, is ergot. A combina- tion of these three substances, then, should be productive of remarkable re- sults. The formula known as Mamma- Pituitary Co. (Harrower), containing mammary parenchyma, total pituitary, and Bonjean's ergotin, is useful in the control of uterine bleeding, whether of postpartum, climacteric, or fibroid origin, and even in the oozing so com- mon in cancer cases. The ergotin sensitizes the uterus so that the effect of the associated remedies is directed more definitely to this organ. The claim that this formula has proved of benefit in the treatment of uterine fibroids is not so preposterous as might at first appear, although one may contend justly that fibroids are an organic condition. I have previously made this statement ("Practical Or- ganotherapy," III Ed., p. 216) : " More than twenty years ago, Robert Bell dis- covered that mammary extract exerted an influence upon uterine fibromata which caused a reduction or cure of 193 the menorrhagia and a recession in their size. Feodoroff, of Petrograd, wrote many reports on the subject and enthusiastically advocates this treat- ment. As a matter of fact, reports enumerating more than a hundred cases in all might be collected from the literature extolling mammary ex- tract as a curative remedy for this condition. ... I prefer not to urge mammary preparations as a means of remedying fibroids, but rather to recommend their use in the functional conditions such as show themselves in menorrhagia, etc., but I will not deny that there are possibilities that if this treatment, preferably perhaps the Mamma-Pituitary Co. (Harrower), is used to control the hemorrhagic fea- ture of the fibroid syndrome, besides the expected benefit to the menorrhagia there may be a very pleasing reduc- tion in the size of the uterine tumor. " Briggs, of Sacramento (Calif. State Jour. Med., Sept., 1917), reports his experiences, which were quite encour- aging, and believes that the mammary hormone probably antagonizes the uterine stromal hormone, thereby modifying or preventing an excessive hyperemia and thus controlling menor- rhagia and the local nutrition of the uterine tissue (fibroid). The effective dosage depends on the degree of hyper- ovarism. I learn from a physician in Mexico that the above formula has been used by him for six months in a woman with an ' inoperable fibroid,' with hemorrhages, malnutrition, and a heart which precluded surgery. He writes : ' The excessive flow has been entirely controlled, the patient is bet- ter in every way, and the fibroid is reduced fully one-half.' " 194 Another mammary combination, Mamma-Ovary Co. (Harrower), is used in those menstrual difficulties which are of a functional ovarian character and in which there is a tendency toward an excessive flow. This class of cases can hardly be placed in the same category with true menorrhagia, since usually the flow is not particu- larly serious. In these cases, which ordinarily occur in girls and quite young women (in contradistinction to the real menorrhagia of older women, especially at the menopause), the flow lasts six, seven, or more days and may recur at shorter intervals than is nor- mal. There is not so much a condition of ovarian irritability or excess in such cases as a dysovarism which is accompanied with pelvic congestion and which results in the minor form of menorrhagia just mentioned. Be- cause there is a decided dysfunction of the ovaries, the mammary substance is combined with a thyro-ovarian com- bination; and, despite the known rela- tions of these glands, the body seems to be able to use the differing stimuli simultaneously. Excessive Menses in Girls. Suggestions about Dosage. The method of administering either Mamma-Ovary Co. (Harrower) for excessive menstruation especially in girls and young women, or Mamma- Pituitary Co. (Harrower) for the more serious, later forms of menorrhagia, is quite similar. It should be remem- bered that a step-ladder, or cyclic, method is recommended in treating ovarian dysfunction. It is advised to push the dosage prior to the flow 195 and to omit it during and for a while after menstruation. In contradistinc- tion to this, when giving any formula for menorrhagia, the heaviest dosage should he given just before and during the entire time of the flow. I suggest that the month be divided into three periods of ten days. During the period which starts two or three days before the flow and lasts through it, the highest dose is given, that is, two sani- tablets t.i.d. For the next ten days the tablets may be discontinued alto- gether, and during the remaining ten days the patient should take one sanitablet t.i.d. Clinical Experiences. " I want to report the good results secured in the case of my daughter, who has been suffering from menor- rhagia. The first week in February I secured two packages of Mamma- Pituitary Co. (Harrower) and began to administer them. At that time she had been menstruating for three weeks. After she had taken the tablets for a few days, the flow began to decrease and at the end of a week it had entirely stopped. Her next period was quite normal, lasting only a few days. Her general health has been greatly improved and it seems to me that these tablets did the work very quickly." " I gave the patient in question one package of Mamma-Pituitary Co. (Har- rower) and the results were miracu- lous-all her nervous and gastric symptoms, as well as the menorrhagia, completely cleared up and she says that she has not felt so well in years." " Mrs. B. was troubled with flooding at the menopause. Most of the ovarian tissue had been removed, 196 she had been curetted, and her uterus had been packed three times, with only slight and temporary relief. After three months' treatment with Mamma- Pituitary Co. (Harrower) she is perfectly well." " Regarding the woman who was treated for severe and long-standing metrorrhagia with your Mamma- Pituitary Co., will say that after taking the tablets for four months she was completely cured. No other associated treatment was used." "A neighbor of mine, suffering from menorrhagia, had been the rounds of gynecologists without successful results and came to me as a last resort. As I knew about Mamma-Pituitary Co. (Harrower) I was the lucky one! I gave her only two hundred tablets and she has been well ever since." " Mrs. K. suffered from a very severe menorrhagia. Her periods were almost continuous with oozing between times. As a result of the use of your Mamma- Pituitary Co. she looks better and weighs more than she has for several years and she has complete relief from the flooding. Her menses are now regular and normal. She sends her gratitude and I, my thanks." "Mrs. C., age 40, with two children, was so sick every month that she had to go to bed and it was necessary to put blocks a foot high under the foot of the bed. She lost so much blood during her periods that it took her the rest of the month to gain strength enough to get around. After the administration of Mamma-Pituitary Co. (Harrower), the next menstrua- tion was normal in every respect, and she has been well ever since. She is teach- ing school and has not lost a day." 197 XVIII LANGERHANSIAN THERAPY IN DIABETES Pancreas Tail Therapy-Homostimu- lating Islet Function-Notes on the Etiology-The Pancreas Anti-Hormone -Pathology in Diabetes-Endocrine Therapy Possible-Progress Delayedby Criticism-Results from Oral Adminis- tration-Pan-Secretin Co. (Narrower) -Action Evidently Catalytic-The Sug- gested Procedure-Comparisons with Insulin-So-Called "Genuine Diabetes." AT the International Congress of . Medicine in 1913, of which I was a member, I made a point of discussing diabetes and the possibility of benefiting the underlying factor by Langerhansian therapy, with such men as von Noorden, Cammidge, Gley, Schaefer, Heinrich Strauss, and W. R. Crofton, of Dublin, who had been using organotherapy in diabetes for three or four years. All admitted the growing importance of the endocrine character of the disease, encouraged my aspirations, and assured me that a fault in the Langerhansian islets was at the bottom of the trouble, at least in certain types of diabetes. Professor Strauss invited me to visit him in Berlin, which I did a few months later, and there I was brought in touch with the work along this same line then being done by Dr. G. Zuelzer at the Hasenheide Hospital. Pancreas Tail Therapy. I then prepared an article entitled " The Langerhansian Hormone and the 198 Hormone Treatment of Diabetes " (N. Y. Med. Record, June 14, 1914), in which, was outlined what I had learned and in the course of which I remarked: " The evidence is by no means unanimous, nor are the results con- stant; but it is proved beyond all ques- tion that such a condition as the ' Langerhansian insufficiency ' men- tioned by Thoinot exists in many cases of diabetes, and that a possible means of controlling this may be found in extracts of these islands. However, this is but one factor in the control of this complex disease. It seems that pancreas, or preferably Langerhansianpreparations, should be added as a part of the routine treatment of all cases of diabetes. . . This essentially basic form of organo- therapy is still as fundamental to-day, and the advent of insulin with its spectacular influence upon carbohy- drate metabolism has caused some physicians to overlook the fact that insulin is not active through the pan- creas, but that it exerts a drug-like effect irrespective of the functional capacity of the pancreas, or even whether the patient is diabetic, and in a manner comparable to the influence of adrenalin in asthmatic paroxysms, or pituitary solution in the delays of labor. I am prompted to make these com- parisons because it is evident that the action of insulin has little or nothing to do with the pancreas, else Banting could not have kept his depancreatized dogs alive for weeks by injecting his insulin extract. On the other hand, the problem I was interested in more than ten years ago is the same to-day-the object of organotherapy is the same- the aim in pancreatic diabetes is to encourage or support or reestablish the 199 waning islet function, and to help the pancreas to get into useful hormone production again. Homostimtilating Islet Function. Fifteen years ago it was presumed that if the pancreas produced an internal secretion and this function was impaired, the essential principle of homostimulation should be made to apply, just as it is applied successfully in other forms of endocrine insufficien- cy, which to-day are treated with a con- fidence born of many successes, by the oral administration of extracts of the corresponding animal tissues. Before we consider the developments in the oral homostimulative organo- therapy of Langerhansian insufficiency, let me reiterate a telling statement I once heard made by Dr. Elliott P. Jos- lin, of Boston: "Insulin causes an altogether artificial carbohydrate toler- ance. The patient is, as it were, placed up on stilts. His balance is always artificial-precarious. His treatment must be careful-continuous. The physician should never forget this. It is a matter of life and death to the diabetic "-or words to that effect.* Diabetes is essentially a sequel to protracted indigestion or pancreatic stress. Its incidence, carefully studied and tabulated by numerous writers, Notes on the Etiology. * I have read many remarkably terse state- ments in Joslin's writings, but none were so forceful as that quoted above, which was made before the Tri-State Medical Society at Des Moines, la., October, 1923. Incidentally, Dr. Joslin gave weight to his warning by recount- ing an experience with a patient of his own who, apparently progressing splendidly, for the lack of a lunch omitted in the hurry to catch a train, died a few hours after. 200 shows that some races, known for cer- tain gastronomic tendencies, provide a much larger number of cases of diabetes than others. Chronic digestive disorders, and es- pecially alimentary foci of infection of long standing (gall-stones, cholecystitis, enteritis, colitis, and chronic appendi- citis), seem to predispose to this disease. An etiological relation with the sympathetic-endocrine mechanism is presumed by the frequency with which this disease is initiated, on the one* hand in connection with serious pro- longed stress or worry, or on the other hand, following a sudden accident or shock. The overburdened business man is far more liable to develop diabetes than the hard-working farmer. The fact that the adrenal and pan- creatic endocrine mechanisms balance one another, favors this idea. Severe adrenal irritation, which, as Prof. W. B. Cannon, of Harvard University, has shown, may be emotional or toxic in origin, brings about a hormonic de- pression of the islet function. Again, pancreas hypofunction frequently per- mits an undue assertion of the adrenal activities with evidences of hyper- tension and sympatheticotonus, for a period, to be followed later by adrenal depletion and its related Addisonian symptomatology. In this connection it may be recalled that von Noorden aptly has called the pancreas " the brake to the adrenal mechanism," and the famous French physiologist, Prof. E. Gley, insists that the pancreatic islet principle is not really a hormone, since its function is not to " arouse " or " set in motion," but rather it is more The Pancreas Anti-Hormone. 201 properly an " anti-hormone," since its endocrine influence is opposed to the stimulating hormone influences of the adrenals, thyroid, and the pituitary. Since the time of von Mering and Minkowski (1889) it has been increas- ingly evident that the pancreas is at the bottom of the difficulty in a large share of the usual cases classed as diabetes. The experimental removal of this organ invariably brings about hyperglycemia and later, death, with the typical laboratory findings- polyuria, glycosuria, and often the ketone substances, acetone, diacetic and oxybutyric acids in the urine, just as we expect to find them in the serious stages of diabetes mellitus. The principal changes in the organism •are found in the previously mentioned Langerhansian islets and, while there may be a marked insular degeneration, possibly the result of a severe pan- creatitis, the visible pathology may be negligible. In other words, the symptom-complex which we call pan- creatic diabetes may have no macro- scopic pathology. However, the func- tional changes are decided, and with the imbalance of the endocrine relations there is deranged metabolism (espe- cially of the carbohydrates)* reduced immunity, defective nutrition, and cer- tain sympathetic disorders. Pathology in Diabetes. Endocrine Therapy Possible. A voluminous literature of experi- mental and clinical reports shows quite conclusively, not only that pancreatic hypofunction is the expected finding in the majority of cases of diabetes, but also that it is possible to treat this 202 hypocrinism with varying degrees of success, by a suitable organotherapy. For years, work has been proceeding on the application of the essential principles of organotherapy in diabetes. My own aim has been to develop an active concentrated extract of the tail of the pancreas, protected from autolysis, as free as possible from the acinous or ferment-producing cells. This differs from pancreas extracts just as do corpus luteum and ovarian substance, or posterior pituitary and the total gland. Since Langerhansian insufficiency was the underlying difficulty we had to modify, my attempt was to prepare an extract as rich as possible in the islet or endocrine tissue in order to be the better able to apply Langerhansian therapy. The isolation of the active principle of the islets of Langerhans called " glucopyron " by Murlin, of Rochester (N. Y.) University in 1916, and by Banting and Best in Toronto in 1922 (" insulin"), has caused a regen- eration of interest in the whole subject. A great deal of criticism and doubt has interfered with progress in this particular field. First, the pancreas was a well-known digestive gland, and the announcement of its probable endocrine influences (by the noted Claude Bernard over fifty years ago) naturally was questioned quite severely. Later, the experiments with piqure glycosuria with certain coincidental information, such as the neural aspects of diabetes, obscured the issue and added to the doubt. Every attempt to develop an organotherapy, on the fundamental principles of this science, has been ridiculed, and the expression of the Progress Delayed by Criticism. 203 idea that pancreas therapy logically should be helpful in pancreas insuffi- ciency has been derided equally with the use of ovarian substance, mammary substance, or even adrenal substance. The usual plea is that " all these sub- stances are destroyed in the stomach," and while other stumbling-blocks have been overcome, it still seems to be difficult for some to believe that pancreas therapy, like other similar forms of glandular administration, indeed may be efficacious when given per os. This position seemingly is strengthened by the fact that insulin, already renowned for its amazing influence upon the blood-sugar (equally of normal rabbits or diabetic patients in extremis) must be given two or three times a day subcutaneously, for " it is quite inert when given by mouth." Results from Oral Administration. This facility with which insulin, is destroyed by digestion has caused some to declare that all pancreas products are similarly rendered inert. The fact that injections of insulin are remark- ably prompt in their action and that even large single doses of Langerhansian extract have had no immediate effects, has seemed to substantiate this posi- tion, and when solutions were made of the oral remedy and found to " contain no insulin " the case against oral ad- ministration seemed complete. Never- theless, clinical betterment comes about from the oral use of desiccated concen- trations of this kind in therapeutics (rather than in laboratory experi- ments). I do not believe this results from the actual material administered, or from its influence as a substitute for that which may be missing, but more 204 particularly from its specific stimula- tion of the depleted islet endocrine cells to a better service. The administration of suitable amounts of islet extract gradually brings about changes in diabetes mellitus, which correspond very closely in type to those which follow the pro- tracted use of other endocrine remedies. Since the successful control of the manifestations of pancreatic diabetes undoubtedly depends first and foremost upon the degree of pancreatic dysfunc- tion, if a given case of glycosuria is not essentially pancreatic in origin, but is in one of several categories variously termed " renal diabetes," " hepatic diabetes," " neurogenous diabetes," etc., one cannot expect a method cal- culated to stimulate the pancreas to be of very much effect. Another vital factor concerns the pancreas extracts used. Extracts made with the expectation of retaining as much as possible of the endocrine value, and ignoring the ferment value (such as is protected and standardized in the production of pancreatin), should be more useful. Since the islets of Langerhans are largely concentrated in the tail of the pancreas and are larger and apparently more active in young animals, The narrower Labora- tory has done pioneer work in develop- ing therefrom the manufacture of a pancreas endocrine concentration. In its production the greater proportion of the pancreas is discarded (for later use in preparing pancreatin), and from the small posterior portion (or tail) a powder is made which is combined with an acid extract of the duodenal mucosa, under the name Pan-Secretin Co. (Harrower). 205 This preparation is given in pan- creatic diabetes in the hope of encour- aging the general pancreatic service to the body, by opposing the digestive insufficiency so commonly present in early diabetes, and increasing endocrine capacity of the islet cells on the principle of homostimulation. The clinical experiences following the use of various experimental batches during more than three years, as well as in the treatment of literally thou- sands of cases of diabetes with the finished formula, Pan-Secretin Co. (Harrower), indicate definitely that this product is by no means inert when given by mouth! It must be remembered that the chief aim in endocrine therapy is to en- courage the glands of the patient, and their response varies in different types of individuals, at different stages of a disorder, and even in different periods of the day. Hormone absorption and the resulting endocrine regulation, whether of incretions produced in the body or products administered as remedies, is a clinical manifestation, and its value must develop upon clinical trial. Pan-Secretin Co. (narrower). As a matter of fact, Pan-Secretin Co. (Harrower) contains a catalytic prin- ciple, which is activated after absorp- tion, just as secretin was shown by Hustin to be activated, and just as various endocrine products adminis- tered to the patient by mouth render a service evidently that of a chemical catalyst or activator. In view of the misunderstandings outlined above, and the attitude of Action Evidently Catalytic. 206 disbelief in all forms of oral pancreas therapy in diabetes which has been fostered by those interested in insulin, it is necessary to outline an ideal method for administering Pan-Secretin Co. (Harrower). Since some of those who do not believe in this preparation insist that the benefit which so frequently has followed its administration is due to the dietetic regulation, the detoxi- cation, or the general treatment of the patient, or even to a psychic effect, clinical tests must be arranged so as to obviate this. This does not mean that Pan-Secretin Co. (Harrower) should be given only to patients who receive no other treatment, but rather that every effort should be made to accomplish as much as possible before it is adminis- tered-if the benefit claimed to follow its use is to be dissociated from benefit derived from other measures. My formula is not a remedy for ultimate conditions like diabetic coma, and should not be expected to cause such rapid results as those which follow injections of insulin. The Suggested Procedure. Establish as best one can a condition of ideal sugar tolerance. Reduce toxemia by thorough elimination. Re- course to the Allen method for a day or two (fasting and dietetic control) reduces the stress upon the pancreas, ordinarily lessens the hyperglycemia and glycosuria, and naturally is a distinct advantage to the patient. Accomplish as much as possible in this way before giving this remedy. After careful examination, estimating if possible both the urinary and blood sugar at several different times, put the patient for several days upon what 207 seems to be a suitable diet in view of the clinical findings. The ideal treat- ment should include the regulation of the diet and the maintenance of a uniform dietetic control for two weeks before Pan-Secretin Co. (narrower) is given.* Then, when the laboratory find- ings are fairly constant, the following procedure is recommended: During three or four days administer one sanitablet of Pan-Secretin Co. (narrower) just before meals and at bedtime (i.e., four a day). If the per- centage of sugar in the urine has been five per cent, or greater, gradually in- crease the dosage one sanitablet a day every fourth day, until as high as three sanitablets at a time are taken, four times a day (i.e., twelve a day). The urinary sugar should be estimated fre- quently. When it drops below five per cent.-as it will in almost every case of pancreatic diabetes-reduce the dosage just as it was augmented. In many cases the sugar will not rise on the gradual withdrawal of the organo- therapy. During this withdrawal period the dietetic latitude may be extended, increases in the urinary sugar being followed by the gradual increasing of the dosage again, mean- while maintaining the broadened diet. If this turns out satisfactorily, again reduce as advised above; if the dietetic latitude evidently has been * Note.-These suggestions are made to enable the doubter to prove that this method is indeed active. Delay in starting to use Pan-Secretin Co. (Harrower) is advised only if there is doubt that this formula has any effect upon the pan- creas and its service. When that doubt is dis- pelled, naturally the physician will begin the use of this pancreatic support as early as pos- sible, since regulation of the toxemia and less- ening of pancreatic strain can be carried out in conjunction with this measure. 208 indiscreet, advise a return to a more strict regime. On the other hand (and this will be seen in quite the larger share of the usual cases, especially in adults), when obvious control is gained by the treat- ment-evidenced by the patient's reports and checked in the laboratory •-reduce the dosage in the same gradual manner to four sanitablets a day and continue at this level for several months. In simpler cases, as where the minimum urinary sugar is below five per cent., start with four sani- tablets daily. Increase the dosage by one tablet a day every week until a maximum of six or eight tablets a day is reached, when, on suitable reports from the laboratory, the dosage may be reduced with more or less rapidity depending upon the clinical and labora- tory findings. There is no fair basis of comparison between Pan-Secretin Co. (narrower) and insulin. The latter is a solution containing an active principle which stimulates sugar-burning only when given subcutaneously. On the other hand, the islet product in Pan-Secretin Co. (Harrower) is given by mouth, and its effect is not direct, but upon the pancreas functions and through them upon metabolism. One can compare these two pancreas preparations with several other endocrine substances: Adrenalin, the well-known and remark- ably active adrenal (medullary) prin- ciple, is quite another thing from adrenal substance and its administra- tion and indications are quite dissimilar. Again, pituitrin (or infundibulin), comparatively speaking, is just as dif- Comparisons with Insulin. 209 ferent from total pituitary substance and it is used in a very different manner. The difference, then, between these two remedies is not merely in form and method of administration, but in their clinical usage and therapeutic possi- bilities, despite the fact that both are used to obtain similar ends-the con- trol of the conditions present in diabetes mellitus. Insulin is effective whenever given-to diabetics and non-diabetics. On the other hand, Pan-Secretin Co. (Harrower) is intended to be used in pancreatic insufficiency and is not active when given to normal persons or to those who have non-pancreatic diabetes. A correspondent in Liverpool put this very concisely when recently he wrote : " I quite agree with all that is said with regard to the value of pancreas given by the mouth in many cases. The value of the hypodermic use of insulin seems, however, to be very definitely indicated in those serious cases whose diabetic limitations and rapidly failing metabolism do not allow of sufficient time for the effect of oral administration to produce the necessary improvement, and allow, of the increase in dietary values which are essential to the recovery of the more acute type of diabetic case. It does not seem to me that the use of insulin is at all liable to usurp the place of such endocrine preparations as Pan-Secretin Co., but it may prove a most valuable accessory means of rapidly improving a patient's power of carbohydrate metabolism, and thereby enhance the value of continued oral administration." About So-Called " Genuine Diabetes." Perhaps some interesting corre- spondence may be included here as an 210 attempt to explain a misconception about a source of error in diagnosis. A correspondent in Chicago writes: " In discussion with my associates, the question arose as to whether Dr. Harrower's statements were largely evolved theoretically from his concep- tion of endocrine developments, or whether they were based on definite clinical work. Of course, all realize that numerous patients with glycosuria will improve under any form of treat- ment, or with no treatment. I am not speaking now of severe diabetes, but of the transient, pancreatic disturbances seen in every physician's practice. My object in writing you was to try to learn whether in the use of Pan-Secretin you had checked over your cases closely enough to know the approximate percentage of genuine diabetics that were helped, as compared with these transient glycosurias." The following is taken from my answer: "It is practically impossible to take a series of cases with glycosuria and hyperglycemia and say that a certain percentage have true diabetes and the remainder do not. The advent of insulin has not simplified this either, because insulin will reduce blood-sugar in normal individuals, in patients with non-diabetic glycosuria, and, of course, in true diabetes. " The idea behind Pan-Secretin Co. (Harrower) is to encourage the general pancreatic function which we believe to be deficient. It is my personal opinion that the two principal causes of diabetes are: an infection by con- tiguity from the bowel to the pancreas, with a resulting chronic or subacute pancreatitis; and, perhaps, more common and more important therefore. 211 chronic digestive difficulties, or pan- creatic stress. " We certainly try to rule out the * transient glycosurias ' by dietetic regulation. The ideal method of using Pan-Secretin Co. is to have the patient under control for some weeks, or per- haps months, before it is given. In the cases receiving my formula, other methods have been used over long periods, and this preliminary differ- entiation has been made. "We have not claimed that Pan- Secretin Co. (narrower) has an influ- ence upon blood-sugar, but that it has an influence upon pancreatic activity, which, in turn, certainly has some definite influence upon the blood-sugar, the nutrition, and the general welfare of the patient. " I have on my desk a letter from a physician in New York who himself is a diabetic. He says: ' I have about used up the supplies of Pan-Secretin Co. which you were good enough to send me and shall be delighted to go on with the treatment, as I really feel that the product is helping me. I feel much better than I did two or three weeks ago and am growing stronger. I am checking up my blood-sugar and. it is lower now than it has been for nearly two years, and, as I have not changed my diet, something must have done it.' " This doctor certainly is not in the class which you have in mind-that is, those who are not genuine diabetics but who have ' transient glycosuria.' As a matter of fact, this doctor previ- ously had written me as follows: " 'As I have stated in one of my previous letters, I am an absolutely standardized case, having had my carbohydrate tolerance established after 212 a period of two years' work with Dr. F. M. Allen. It was found that 20 grams of C.H. was my daily tolerance with about 60 grams protein, or a total caloric intake of about 1800. At the time I was on this diet my weight dropped from 211 to 136 pounds, and I was, of course, more or less confined to the house. At present, since May, 1923, I have been gradually increasing my dose of insulin, so now I am taking 11 units of the new U-20 three times a day, one half-hour before meals. This, as you know, has been a godsend to me, has put me on my feet; I now weigh 154 pounds, and am getting along mighty well. However, in my last letter to you I referred to the big " but " in this proposition, which is this: Insulin does not, as far as I can see,'reduce dosage in any way, but the trend seems to be a gradual increase in dosage. Whether this is due to the gradual increase in weight, I cannot say, but I am rather under the im- pression that with increasing weight, insulin must be increased. ... If, however, by the use of Pan-Secretin Co., the activity of the pancreas can be increased without damage or depres- sion and consequently the dose of insulin can be decreased, then cer- tainly we have a very valuable agent in the treatment of diabetes.' " We have a remedy which un- doubtedly influences the pancreatic service to the body. It is made from an extract of the duodenal mucosa and the posterior one-seventh (by weight) of the pancreas (about one-fourth by length). I was the first to suggest such a combination, and that pancreas therapy in diabetes might be enhanced if we discard the larger part of the 213 pancreas; and I did not say it because of the influence of trypsin upon the pancreatic endocrine principle, but because on purely arithmetical grounds there would be a larger percentage of the endocrine product in the tail of the pancreas, since approximately ninety per cent, of the islets are found in that area." Clinical Results Obtained. Hundreds of physicians have used Pan-Secretin Co. (narrower) with what they have confidently believed to be clinical proof that: It is not inert when given by mouth. It increases carbohydrate tolerance. It stimulates pancreatic activity, and It enhances weight and nutrition. It reduces hyperglycemia (but does not cause hypoglycemia, nor reduce blood-sugar if the pancreatic activity is normal). It reduces glycosuria, and therefore It lessens polyuria and frequent micturition. Finally, it cannot be emphasized too strongly that these benefits are not artificial or pharmacological, but the result of fundamental hormonic, homo- stimulative, or catalytic influences upon pancreatic function; hence, results from such a procedure are likely to be remedial and less ephemeral. The extent and character of these benefits are best appreciated by an examination of the clinical reports published else- where. 214 XIX ENDOCRINE MEASURES IN PROS- TATIC DYSFUNCTION Macht's Prostate Feeding Experiments ■-Other Endocrine Relations-Compen- satory Prostatic Hypertrophy-Gonad Comparisons in Both Sexes-A Pros- tatic Form of Neurasthenia-Case Reports from the Literature-My Pluri- glandular Formula-A Physician's Personal Experience. SOME of the earliest evidence that the prostate is a gland of internal secretion was advanced by two French observers, MM. Serrallach and Pares, in 1907. These investigators removed the prostate from dogs and found that a cessation of spermatogenesis ensued, as well as gradual testicular atrophy. They then prepared glycerine extracts from fresh prostate glands, injected them into these animals, and found that the foregoing symptoms were alleviated. Other investigators have criticized these results, stating that it is almost impossible to remove the canine prostate completely. Macht's Prostate Feeding Experiments. The most convincing and most brilliant work in demonstrating the internal secretion of the prostate was done by Dr. David Macht, of Johns Hopkins University. He recalled that Gudernatsch had produced a remark- ably rapid metamorphosis in tadpoles by feeding them with thyroid. Since tadpoles lent themselves so readily to these experiments, Macht chose tad- 215 poles from five different types of amphibia, divided them into groups, and each group which was fed upon prostatic preparations was kept side by side with similar tadpoles used as controls. These were treated exactly as the experimental tadpoles, with the one exception that they did not receive prostatic substance. Various experiments were made with prostatic substance from the ram, bull, steer, and the prostate of man, obtained in the operating room. The result of these experiments was manifested within two weeks and in some cases changes were noticed within a few days. While growth changes were not so pronounced as in thyroid feeding experiments, they were never- theless definite and marked. Feeding prostatic substance to these animals could be continued indefinitely, whereas it will be remembered that in thyroid feeding, periods of rest must be given or the experimental animal will die. It is interesting to note that Macht observed a weaker action from the prostatic substance taken from the steer than from the bull, and this is to be expected inasmuch as the steer is a castrated animal. The results from feeding human prostatic substance were almost identical with those following the use of rams' prostates. Having completed the experiments on amphibians, higher animals were given varying amounts of the prostatic preparations. Rabbits, kittens, pup- pies, and rats were fed with weighed quantities of desiccated prostatic sub- stance and the increase in growth was observed as before by using control animals. While these experiments on the higher animals were not so spectacular. 216 nevertheless they definitely demon- strated the growth-stimulating action of the internal secretion of the prostate. Later Macht, working with Matsu- moto in 1920, studied the action of pros- tatic extracts on isolated genito-uri- nary organs. The following organs were excised : uterus and fallopian tubes, bladder and urethra, and vas deferens and seminal vesicle. Aqueous saline ex- tracts of prostates taken from rams, dogs, bulls, steers, and men were used. From the tabulated results it can be seen that all the genito-urinary organs are stimulated by prostatic extracts. Other Endocrine Relations. Several authors have expressed the opinion that it is as possible for a menopause to take place in men as in women, and they consider that many of the neurasthenic symptoms observed in men about the age of forty-five often can be compared to the climacteric findings in women. In this connection Barnham says: "Man has his critical age of sex cell deterioration as well as woman. The age chart swings between forty-five and fifty-five. Here enters upon the scene that organ of external and internal secretion, the prostate, the most important accessory sex gland in the male. . . . Furthermore, the microscope reveals cyclic changes in those cells comparable to the men- strual phenomena of the uterus. . . . The regression of the prostate is the central episode of the male climacteric." While men may not experience the hot flushes that women undergo during this period, they often suffer from constipa- tion, headache, malaise, loss of appetite, loss of strength, lack of sexual power, insomnia, and all the other symptoms 217 that make up the so-called neurasthenic syndrome. Since ovarian substance is of value in the menopause, why might it not be advantageous to use prostatic sub- stance in men presumed to be deficient in the internal secretion of the prostate? Clinical application shows that this query may be answered in the affirmative. Compensatory Prostatic Hypertrophy. We must remember that because of the definite relation between the testes and the prostate, it is probable that many times the prostate hypertrophies after the removal of the testes, evidently as a temporary compensatory reaction due to lack of the gonad internal secretion. This is no more fundamentally different than for the thyroid to enlarge itself when there is an ovarian insufficiency, or for the pituitary to hypertrophy in its attempt to make up for a lack which it feels able to supply. At all events, it was in 1918 that I suggested to my friend, Dr. Victor G. Vecki, of San Francisco, that if the foregoing premise was sound, Leydig cell stimulation should be a reasonable treatment in cases of simple (non-surgical) prostatic hypertrophy, especially when gonad function was known to be waning. The formula now known as Leydig Cell Co. (Harrower) was first used by Dr. Vecki and he still uses it after eight years, as do many hundreds of physicians who since have learned of this phi- losophy or deduction which I based purely upon general principles. In the interim, several articles have been pub- lished embodying similar ideas, and whether the idea of compensatory prostatic hypertrophy is right or wrong, the treatment suggested has been clinically efficacious time and again. 218 Gonad Comparisons in Both Sexes. In an article read before a meeting of the Medical Society of Paris, in 1922, Professor Guelpa stated that enlarge- ment of the prostate shows a predilec- tion for men in certain types of intellectual, work whose sexual activity has been arrested; and that in tribes Whose customs allow polygamy and little mental strain there are but few cases of enlarged prostate observed. This writer voices the opinion that has been stated elsewhere that the uterus and the prostate are similar in many ways; and that early breaking off of sexual activity is liable to cause enlargement of the prostate gland. In this connection it is interesting to note that Guelpa considers fibroids of the uterus to be most common in nul- liparous women; and, since we are to consider the prostate a male uterus, diseases of that gland would appear more often in inactive glands. Rohleder (1921) states that, in gen- eral, medical m?n and laboratory re- search workers have not considered that the prostate contains an internal secre- tion, but it is generally known that there is a humoral relation between the prostate and the testes. Some facts that lend themselves to the proof of this theory are, for instance, observed in experiments in which prostatic atrophy follows castration. This atrophy, how- ever, is usually preceded by an effort at hypertrophy, thus indicating a reciprocal or mutual compensatory relationship be- tween the testes and the prostate. With a waning gonad function, there is an attempt on the part of the prostate to compensate for this loss; hence it hypertrophies. But with castration the 219 connection is completely broken, and the initial prostatic enlargement is soon fol- lowed by recession. However, prostatic atrophy does not occur in castrated dogs if solutions or extracts of the testes are injected (Walker). He states that in the first and second periods of prostatic hy- pertrophy administration of testicular substance by mouth will give beneficial results in many cases. Sex gland transplantation is suggested for. men suffering from prostatic enlargement. A Prostatic Form, of Neurasthenia. The late Dr. G. Frank Lydston, of Chicago, in his book, " Impotence, Sterility, and Sex Gland Implantation," has given us some very important facts relating to sexual neurasthenia and prostatic dysfunction. Lydston's ex- tended clinical experience led him to the conclusion that neurasthenia in the male many times is secondary to prostatic disturbances, including in- flammation of the prostatic urethra and hyperesthesia of the verumontanum. He states that it is a definite fact that the prostate secretes a hormone " the perversion of which conjoined with the absorption of infection toxins often has much to do with the etiology of sexual neurasthenia, disturbed digestion, ir- regular bowel action, headaches, de- pression, lassitude, melancholy, brood- ing, hypochondriasis, introspection, and unstable emotions." To carry further the suggested anal- ogy between the prostate and seminal vesicle on the one hand, and the uterus and tubes on the other, he brings to mind the fact that infected tubes and uteri with the surrounding pelvic infil- tration produce pressure and therefore neurasthenic symptoms ; likewise, in 220 the case of inflamed seminal vesicles (periprostatic infiltration) in the same way disturbances can be produced ■which may develop into general nervous symptoms. The chronic, long-drawn- out course of both conditions is well known. Vincent makes some encourag- ing statements in regard to prostatic organotherapy to the effect that he has several reports which apparently demonstrate that advantages are to be had from the administration of pros- tatic substance in suitable cases. Dr. Arnold Lorand, of Carlsbad, in speak- ing of the experiments of Camus and Gley, who found that seminal fluid pro- duces more active spermatozoa when a small amount of prostatic extract is given, states : " Thus it is very prob- able that by adding prostatic extracts to those of the testes, the vitality of such extracts may be enhanced." Mason, in his book, " Endocrine Glands," re- fers to the advantageous use of pros- tatic extracts in neurasthenia of sex- ual origin, and makes a definite state- ment that it is mainly in " neuras- thenia that dry prostatic extracts give appreciable results." Case Reports from the Literature. It may be well to report a few clin- ical cases. The first case has been men- tioned before in my book, " Practical Organotherapy," p. 213. This man, age eighty-one years, came to me in the hope that I might in some way relieve him, for he had undergone long periods of treatment from various standpoints with no relief. Examination and history proved that he had a very much en- larged prostate as well as the resultant urinary difficulty and an extremely ob- stinate constipation. He was very old. 221 his health was much impaired, his heart was not functioning properly and we felt that surgery would without a doubt cause his demise. I told him to use Prostate Co. (Harrower), although I assured him there was not much prospect of a recovery. He reported later in the following words : " I am much better. The difficulty with urina- tion is gone and, with two or three short exceptions, I have had no trouble with dysuria and frequent micturition." His report showed that there was a decided reduction in both the size and the tenderness of the prostate. In the American Journal of Clinical Medicine for March, 1920, Dr. Malford Thewlis reports a case of prostatic hypertrophy (senile). This man, age seventy years, also complained of urin- ary trouble, especially at night. He was experiencing considerable pain and dif- ficulty before and during micturition ; in fact, the prostatic obstruction was so great that it became necessary to catheterize him with a metal catheter. Prostatic examination and urinalysis revealed the fact that he was suffering from prostatic hypertrophy and chronic interstitial nephritis. A dietetic regime was instituted, general tonic treatment was employed, and prostatic extract was given by mouth every three hours. Thewlis reports that his patient was relieved on the second day and that soon further catheterization became unnecessary. The improvement was marked from the very first and within a week the patient had practically re- turned to a state of normal senility. He further remarks that he has observed the same beneficial results from the oral use of prostatic extract in a num- ber of other cases, and that this method 222 not only relieves the prostatic condi- tion, but also removes many of the dis- tressing symptoms of a neurasthenic nature attendant upon this condition. In the treatment of prostatic condi- tions, the German writer, Rohleder, has employed a pluriglandular prepara- tion containing testiculai' extract, pros- tatic substance, and an extract from the seminal vesicles. In addition to these substances, his first pluriglandu- lar preparation contained yohimbin, but as the yohimbin did not in any way assist the other preparations in gain- ing beneficial results, it was discon- tinued. Rohleder reports two cases that are worthy of our attention : The first Was a man of seventy-five years who had been " a prostatic " for about fifteen years and who for the last eleven years had endured chronic cystitis, nephritis, and, of course, uri- nary retention. He had been forced to catheterize himself three times a day, had tried sitz-baths, had avoided alco- hol and other irritating substances, and had had bladder irrigations with silver nitrate (1:1000). Due to his age and general condition, prostatectomy was contraindicated. Rohleder placed this man on the pluriglandular formula mentioned above and required him to take it regularly three times a day for two weeks. While a complete cure was not realized, the painful micturition and many of the other distressing symptoms were relieved. He also cites a case of a man, seventy years old, who for four months had suf- fered from an enlarged prostate with cystitis, cloudy urine, dysuria, and residual urine. He also was given pluriglandular therapy. After twenty days there was very little difficulty in 223 urination ; there was no residual urine, and no further cloudiness. After two more weeks of treatment there was still more improvement. It was observed, however, that when treatment was sus- pended all the symptoms returned. Rohleder draws several conclusions that are worthy of thought : First, yohimbin is not necessary in pluri- glandular preparations for the treat- ment of prostatic difficulties ; secondly, pluriglandular formulas bring about the best effects when used in the early stages of prostatic hypertrophy, i.e., when there is as yet no residual urine but a difficulty in urination ; and lastly, the results from organotherapy, while they may not be permanent, are bene- ficial and often relieve conditions in inoperable cases. He does not hold out much hope for the late, so-called " third stage" of prostatic hypertrophy. Martinez has tried out this same treatment in several cases, all of whom were relieved. The first case reported, age seventy-seven years, had been the rounds in the attempt to find a cure. He finally called Martinez to his home on account of complete retention of the urine. By catheterization, four liters of urine were removed. Examination re- vealed no other stricture than urethral compression due to pressure from the hypertrophied prostate, which was very sensitive. Catheterization was repeated the next day and again on the third day. Then organotherapy was begun and almost immediate relief followed. At the end of a month he freely passed large amounts of urine. To-day, two years after, he is in very good health but still continues the endocrine treat- ment. The second case was seventy-six 224 years of age. The details of his trouble were very similar to those of the first case, except that the urine was found to contain much pus. The same treat- ment was given and in this case the same beneficial results were obtained, though it required two months to get complete relief. Other cases are reported by this author, of patients at, or nearing, the seventy-five-year period-all presenting the same symptoms-each of whom, after receiving pluriglandular treat- ment, realized either a cure or a defi- nite degree of relief from the major symptoms. My Pluriglandular Formula. After considering the possibilities, both experimental and clinical, of pros- tatic substance, we have prepared a formula to meet the demand for pros- tatic slipport. It is called Prostate Co. (Harrower), each sanitablet of which contains equal parts of desic- cated prostatic substance, and inter- stitial cells of Leydig from the testes (spermin extract), together with an effective dose of nucleinic acid. The nucleinic acid is added to the formula because of its leucocyto-stimulant effect and its well-known value in overcom- ing the low resistance of individuals who have suffered from infection. The spermin extract is added for its syner- gistic homostimulative effect upon the gonads and because there is an evident relation between the testes and the prostate, as well as for its well-known tonic effect. Incidentally, as has been mentioned by various investigators, it has often been observed that the pros- tate enlarges following castration or any condition which causes functional 225 gonad hypoactivity. The beneficial action of ordinary testicular extract alone in many cases also suggests the logical value of the more active sper- min extract in this formula. The usual dosage of Prostate Co. (Harrower) is one sanitablet before meals and at bedtime. In severe or advanced cases, double this dose for occasional periods of from two to four weeks. There is no detrimental reac- tion to such treatment and, while re- sultsmaybe quite prompt in appearing, often a month or more may elapse before definite progress is noted. Such treatment, especially in elderly men, must be continued for many months. A Physician's Personal Experience. I have had many pleasant compli- ments regarding good experiences with this formula-usually in cases that had been previously treated, some- times for years. I will refrain from quoting them and will content myself by passing along the following from a grateful colleague : " Dear Dr. narrower : " You cannot appreciate what this treatment means to a man who needs it. ... I have had all the ' hell.' a man deserves due to an enlarged prostate. I have been through the mill. I know ! "After years of fooling with all sorts of treatment, the God of Luck was kind to me and put me in touch with you and your wonderful formu- la. I admire you for your work, your energy, and your nerve ; but most of all for your Prostate Co.! " Yours sincerely, 226 XX HYPEREMESIS GRAVIDARUM AS AN ANAPHYLAXIS Protein Sensitization a Cause-Produc- ing an Artificial Immunity-Used at First as a Last Resort-Confirmation Has Come-An Experimental Observa- tion-Good Clinical Reports. MOST forms of organotherapy are administered in order to produce an effect upon a given endocrine organ. The principle of homostimula- tion usually is at the foundation of most phases of this therapy. For in- stance, we give thyroid because it exerts a specific effect upon the organ corresponding to that from which the extract is prepared. But the idea sub- mitted here is entirely different-we are attempting to increase the immun- ity of the body to a certain class of toxic bodies. Protein Sensitization a Cause. The discomforts of early pregnancy which too often develop from simple nausea into occasional vomiting, and still later into hyperemesis gravi- darum, are now 'believed to be due to 'protein sensitization. The new organ is delivering into the blood, with which it is so generously nourished, certain cellular wastes which are equally " new " to the rest of the body. Many individuals rapidly accommodate them- selves to these protein products, and the discomfort believed to be due to their influence on the organism fortu- nately is short-lived. 227 Certain women, however, seem not to be able to accustom themselves to these substances, and like those who are sensitive to other proteins in foods, such as strawberries, shell-fish, eggs, etc. ; or to air-borne proteins such as produce hay-fever and horse and flower " asthmas," they react in vari- ous degrees to the influence of these subtle substances. It has been an in- teresting study to note how frequently women who develop severe vomiting during pregnancy show in their his- tories a tendency to other anaphylactic manifestations. The fact that this form of placental toxemia commonly is limited in degree and especially in time, lends emphasis to the probability that ordinarily the body accustoms itself to these foreign substances, and in due time they are allowed to circulate in quantities which previously would have been dangerous. Producing an Artificial Immunity. Granted, for the moment, that this theory has a reasonable basis, why should it not be possible to bring about an artificial immunity to such present or prospective placental protein intoxi- cation ? And why might this not be accomplished in the same way that other forms of protein sensitization are controlled, i.e., by administering the same proteins in gradually increased amounts, thus bringing about an arti- ficially increased tolerance to the of- fending substances ? Originally this was made a basis for clinical trial in a few cases, who, con- fronted with an " inevitable " abor- tion, were willing to postpone surgery long enough to " try one more thing." A fresh human placenta was shredded, 228 the greater part of the peculiar connec- tive tissue " whorls " was thus combed out, and the pulp was desiccated in vacuo and put up in gelatine capsules. An arbitrary dose was given, which was repeated and increased. The patient knew nothing of the character of the treatment. She swallowed it, and fought hard to keep it down. Some- times retention was aided by judi- ciously arranging the doses to fit in with usual " free periods " (of rest and sleep), and occasionally by the simul- taneous use of sedatives, often in an enema. The results were astonishing. Sev- eral of the cases were admittedly in extremis and the new treatment was tolerated by the medical attendants who could not very well deny an urg- ing husband " one more try." Not every case responded in the same degree or manner. Some responded quicker and more thoroughly than others. Occa- sionally the woman's troubles seemed to be aggravated and the treatment failed. I mention this to emphasize the distinctly non-drug character of this remedy and also the fact (since tested by many observers) that the reactivity to the administration of this placental extract evidently depends much upon the responsiveness of the patient, which always is an unknown quantity to begin with. Several really bad cases were cured entirely. Within a week or ten days- occasionally in as short a time as three or four days-the patient was better. The vomiting was relieved both in de- gree and frequency, and later subsided into a nausea or near-vomiting, which within a short time was overcome. Case after case was cured. Occasion- 229 ally a patient would appear to be over her difficulty when it would recur. Invariably in such cases a renewal of the treatment brought control, which later was permanent by prolonging the use of the organotherapy. This seemed additional evidence against the sug- gested coincidental character of the benefit. Used at First as a Last Resort. Let it be said at once that all the first cases thus treated were severe ones. As with other forms of organo- therapy in new hands, the opportunity was not given in early or simple cases. Those who permitted its use often did so grudgingly and even scoffingly. Per- haps it was a colleague who had brought the attending physician's at- tention to this method, and so far as I have been informed by such doctors, the treatment was accepted with doubt and forebodings. Anyway, two-thirds of the cases thus treated were benefited, and the diffi- culty controlled in varying periods. The development of the remedy and its gradual acceptance by the profes- sion have made possible a better pro- portion of good results, and it is now the rule to have recourse to this treat- ment at a much earlier and less com- plicated stage of the difficulty. Even now, we meet an occasional flat failure, which, however, is more than offset by the scores of really spectacular results. So far as I am aware, this method was original with me. At least, I was the first to make it clinically possible in the United States and Great Britain. Since that time several interesting, Confirmation Has Come. 230 confirmatory items have appeared in the literature. Dr. S. W. Handler, of New York, in his book, " The Endo- crines," agrees with me in this theory. He says, on page 319 : " The nausea and vomiting represents a reaction on the part of the system to the introduc- tion of the placental secretion. If a stable adjustment results quickly, the nausea disappears quickly. In this re- adjustment, undoubtedly (in the cases which vomit decidedly1), we are con- cerned with a toxic influence produced by the placental extract or with an exaggerated reaction on the part of the posterior lobe, with resulting hypersensitiveness of the gastro-intes- tinal tract." Dr. Eugene Cary reports having used this method with splendid results. He says : " I have collected thirteen cases of vomiting of pregnancy, which have occurred at different periods during gestation. One or two of these develop- ing later in pregnancy, as they did, might have developed into the perni- cious type had they been allowed to con- tinue. Of these thirteen cases, two were lost sight of. Of the remainder, seven ceased vomiting within a day or two and the nausea soon disappeared. Two improved and remained fairly free from nausea, although the administra- tion of the extract had to be continued over a longer period of time. In the remaining two cases, the results were not satisfactory ; one was neurotic." An interesting observation made by Dr. A. T. P. Garnett appeared in the American Journal of Obstetrics for August, 1917. He reasoned that hyper- emesis is a toxemia, but instead of An Experimental Observation. 231 establishing an artificial immunity, he attempted to give the patient an im- munity already prepared in the body of another. Accordingly, two cases were given a blood transfusion. Both donors had just been delivered. The first transfusion amounted to 250 c.c., and in both cases improvement was rapid. One case, however, required the second transfusion, but the results were none the less gratifying. To revert to the fundamentals of this method : The idea is to have the patient ingest enough of the placental proteins to augment the body's resis- tance to them-and to those produced within the patient. It does not involve any unknown fundamental of immunology and, " from a purely theoretical standpoint, should be en- tirely feasible," as one technical worker has expressed it. This anti-anaphylaxis is brought about in the body itself-the remedy is useless, save only as it initiates a beneficial reaction on the part of the body cells. Consequently, it takes time, and is quite different from the results expected from drugs. It has absolutely no direct or sedative action ; hence the need for applying it early. Each dose of Placenta Co. (nar- rower) consists of approximately 25 grains of the parenchyma of fresh bovine placenta deprived of blood and as much connective tissue as possible, plus a minute dose of thyroid extract. This is put up in a five-grain sani- tablet. The usual dose is five a day, when convenient, with charged water or sedatives, or timed so as to be re- tained as fully as possible. Such treatment must be given for at least five consecutive days, and in cases that 232 bid fair to respond to this treatment, the formula should be continued for at least three weeks, or for a full week after the vomiting has ceased. Good Clinical Reports. The best proof of the value of a remedy of this type is clinical results. Many thousands of women have been successfully treated by my formula, some of them two or more times. Here are a few reports from my files : " I had a remarkable case of vomit* Ing of pregnancy, which came to me at the hospital for an operation as her doctor had been unsuccessful in get- ting results. Instead of operating I treated the lady with your Placenta Co. and got a fine response. The other doctors were amazed at the results." " The patient suffering from hyper- emesis gravidarum who took Placenta Co. (Harrower) simply did splendidly. Her trouble entirely ceased after tak- ing the preparation for only five days and there was no subsequent trouble." " I am pleased to advise that I have had uniformly good results from the use of your Placenta Co. in three cases of hyperemesis gravidarum, all symp- toms disappearing within a week after treatment was instituted, and not re- turning in a single instance." " I am glad to report that the Placenta Co. (Harrower) gave me bet- ter results in the case of vomiting of pregnancy than anything else I have ever tried. The mother carried her baby to term with less nausea, and came to term in better condition than with her other three children." 233 XXI THE HORMONES IN IMPOTENCE, ASEXUALISM, AND STERILITY Brown-Sequard's Pioneer Work-Impo- tence in the Male-The Vital Pituitary Influence - Comprehensive Pluriglan- dular Therapy-Asexualism and Steril- ity in Women-Differential Diagnosis. THE sex glands, or gonads, are also really important incretory organs forming an integral part of the endo- crine system. They depend upon sev- eral of these organs for needed hor- mone stimuli and, in turn, cooperate with them in maintaining the " hor- mone balance." Proper gonad functioning is indeed of decisive importance to the body as a whole, and when one finds evidence that the sex glands are deficient- " hypogonadism," as it is called-the difficulty always extends to others of the closely related endocrine chain ; consequently, the pluriglandular aspect of such conditions is of far greater importance than a consideration of the gonads alone. It is proposed here to call especial attention to the subject from the pluri- glandular standpoint and to show the advantages of pluriglandular therapy in functional hypogonadism. Brown-Sequard's Pioneer Work. In. 1888 the renowned Brown-Sequard demonstrated in his laboratory in Paris, on himself as the subject, the remarkable results following the use of a product made from a dog's testes. 234 His reports, the first of which was made to the Paris Academy of Medi- cine and published in his own Archives de Physiologic, 1889 (vol. xxvi, p. 651, also p. 739), were really the beginning of scientific testicular organotherapy, although there are references to the cruder and empirical application of this idea in the uncanonical books of the Bible and the writings of physi- cians and philosophers thousands of years ago. This fundamental principle of or- ganotherapy, first consistently proved by Brown-Sequard, and since dupli- cated times innumerable, is as rational and physiologically sound as any other method of glandular therapy. It has always seemed strange to me how will- ing some physicians are to use ova- rian therapy when indicated and how reticent they are about the use of " orchic substance." Briefly, this form of treatment offers two important therapeutic possibili- ties : (1) It increases dynamos-mus- cular, nervous, and sexual ; and (2) it homostimulates the gonads just as other endocrine extracts homostimu- late the organs corresponding to those from which they were made. It is in- teresting to recall that Brown-Sequard found a marked increase in his mental and physical vigor-he was a man in the seventies-and in his own words, " considerable laboratory work hardly produced any fatigue, and to the astonishment of my two assistants I was able to work for several hours in a standing position." The dynamom- eter has established this accurately and Mosso's ergograph shows definite dynamic Increases following this or- ganotherapeutic procedure. 235 Not long after the establishment of The Narrower Laboratory, we were in- vited to collaborate in the experimental development of several pluriglandular formulas for the treatment of impo- tence and asexualism. Several inter- ested specialists asked us to cooperate with them and eventually a pluri- glandular formula was developed which since has been used with success in many hundreds of cases. This formula is called Gonad Co. (Narrower) and is a combination of several products of closely interacting endocrine glands. In impotence, a large neurasthenic element is often present for obvious reasons, and in addition to an asthenia of gonad function there is a " run- down " condition identical in character to the adrenal insufficiency, which has been discussed fully in other articles. In other words, the majority of these cases require adrenal support (see Chapter II) and should have it. Hence, adrenal siibstance is one of the ingredi- ents of this formula. Another impor- tant reason for this is the fact that the adrenal cortex (adrenal substance con- tains about 85 per cent, of adrenal cor- tex ) is recognized as playing an impor- tant part in gonad development, and several references in the literature in- dicate that the cortical principle is an activator not merely of sex gland development but of its function as well. For very similar reasons thyroid ex- tract is a part of the formula. First of all, in asthenia, hypothyroidism, even though it may be of a minor type, is customary. There is also plenty of evidence to show that the thyroid is a responsible factor in initiating and maintaining normal gonad activity, Impotence in the Male. 236 else why should the cretin, with its athyria, have no noticeable sexual development ? We now come to a really important phase of this subject. The pituitary body, especially the anterior or glan- dular portion, is fully as important a factor in the development and mainte- nance of gonad function as any other endocrine element. This has been proved and re-proved from several standpoints. For instance, hypopitui- tarism, or the dystrophia adiposo- genitalis, always includes a disturb- ance of gonad function-hence its de- scriptive name. This aspect of these cases probably is as important as any other, for infantilism may be purely of pituitary origin. Again, an acquired pituitary dystrophy may nullify the physiological efficacy of the already es- tablished gonad function and not merely destroy the hormon'e-producing capacity of the sex glands, but actually cause an atrophy of all the repro- ductive organs in both sexes. Now, in hypopituitarism, pituitary therapy may modify not merely the pituitary aspects of the case, but the gonads themselves are stimulated, and this method of treatment is customa- rily recommended for both these pur- poses. Why not then consider the possibility of a pituitary aspect of asexualism, even though the patient may not have well-defined dyspituitar- ism ? As a matter of fact, there are a number of references in the litera- ture to the efficiency of anterior pitui- tary stibstance as a sex stimulant, and impotence in both sexes has been bene- fited by its use alone. The Vital Pituitary Influence. 237 it has seemed that the prostate gland is involved in many cases of functional impotence and that prostatic therapy has been beneficial, especially in those forms of impotence that are related to a demonstrable disturbance in pros- tatic form and activity. Finally and most important, the essential gonad principle known as spermin, which is made from the inter- stitial cells of Leydig, is added for its general dynamic influence as well as for its specific homostimulative influence upon the interstitial cells of Leydig in the patient. Pluriglandular therapy of this quite comprehensive type is directed at all the real or prospective causes of a functional hypogonadism. Not merely are the Leydig cells stimulated di- rectly, but the effort is made to modify those allied factors which may be fun- damentally the caicse of the hypogonad- ism, notably in the anterior lobe of the pituitary and the prostate, while the association of the general toning and cell-stimulating influence from suitable doses of adrenal and thyroid makes a combination hard to beat in the treatment of functional impotence. However, this treatment, while suc- cessful in many instances, fails almost as often, and I cannot refrain from lending decided emphasis to the neces- sity for careful selection of cases suit- able for this method of treatment. If local treatment is necessary and is not given, surely organotherapy will not accomplish the desired end. If there is a structural difficulty, as for example an organic destruction of tissue, organotherapy cannot be ex- ComprehensivePhtriglandular Therapy 238 pected to be of much value under such circumstances. Again, a psychic cause obviously cannot be modified in the least regard by such therapy no matter how well directed. Hence in cases of impotence it is very necessary to rule out associated factors not of an endo- crine character, and therefore not amen- able to pluriglandular therapy. And too much emphasis cannot be laid upon this aspect of the treatment of these cases. The cases of impotence that respond to organotherapy are the functional cases that have followed a severe in- fection as influenza and severe in- toxications, either wilful (drug ad- dicts) or accidental, and the large class in which a developmental factor of un- known origin has interfered with com- plete functional development of these organs. Unfortunately, perhaps, there is quite a large class which includes the senile and the roue, who do not deserve to recover their lost powers, for they have been misused, in whom organotherapy has been used with just the same kind of good results as we expect from homostimulative organo- therapy of any other endocrine organ that has been functionally overworked and played-out, as, for example, in adrenal support. Most of the cases in which Gonad Co. (Harrower) has been used have been treated previously without sat- isfactory results, and the reestab- lishment of those factors which are dependent upon normal sex function- general, chemical, and reproductive -are just as possible in cases of impo- tence due to hypocrinism, as the re- establishment of a deficient menstrua- tion following suitable organotherapy, or the control of other dystrophies 239 which may be due to glandular insuf- ficiency. The prospects are better than heretofore merely because we have ac- quired a broader view-point, and are now willing to treat not merely the victims of the circumstances-the gonads themselves-but the associated factors which may be just as responsi- ble for the difficulty. Treatment of this type should be con- sidered as empirical. It is not always possible to determine in advance whether a given case is purely func- tional or whether there may not be some organic or extraneous circum- stance that will militate against suc- cess. One thing is certain, that the broadening of organotherapy by mak- ing the right combination of the asso- ciated glandular substances is nowhere more obvious than in the treatment of impotence with this formula. Asexualism and Sterility in Women. Sterility and. asexualism in women are very much more common than some may believe. The former usually is borne for years in silence and the latter often seems too delicate a matter to be taken up with a physician. This subject is none the less of considerable clinical importance and naturally is a complex problem. For the moment we are concerned chiefly with one aspect only-the endocrine aspect-and the remarks previously made apply with the same force in either sex. The adrenal glands exert the same influence upon general muscular tone in the male as in the female ; and the adrenal cortex is just as responsible for ovarian development as for testicu- lar. The influence of the thyroid is identical in both sexes, and all that 240 has been said about the pituitary aspect of impotence applies with equal force to both asexualism and sterility. It is even believed, from clinical experience, that spermin is an excellent ovarian stimulant, largely, it is presumed, be- cause of its known affinity for the re- productive cells and because of the fact that it stimulates muscular tone and that subtle something known as " dynamos," irrespective of sex. Pluriglandular therapy, then, is the most rational method of treating func- tional sterility as well as asexualism. The combination of thyroid, pituitary, and ovarian substances, as represented by Thy r o-Ovarian Co. (narrower), not merely has served to regulate the ab- normal menses and to modify the neu- rotic and psychic manifestations so common in these individuals, but ac- tually has cured sterility in many cases. Considerable clinical work was carried out to develop a formula similar in character to Gonad Co. (narrower) for those cases among women of a more se- vere character that might not respond to the usual Thyro-Ovarian combination. A modification of this latter formula was made by adding a generous dose of anterior pituitary substance and of spermin, and the resulting formula, known as Gonad-Ovarian Co. (nar- rower) was first used in a number of serious cases, as, for example, a case of ovarian insufficiency in whom the menses had been absent for six years, a woman who had been barren for thir- teen years, and a very unusual case of infantilism in whom a psychosis com- plicated matters. All three of these seriously difficult cases responded sat- isfactorily to this formula, and since those experimental days many hun- 241 dreds of cases of disordered endocrine function involving especially the sex and reproductive capacity have been treated in this manner with a suffi- ciently large average of success to be of great encouragement both to myself and to scores of physicians who have seen fit to write me in enthusiastic terms. Differential Diagnosis Important. As in the treatment of impotence in the male, extraordinary care must be given to the preliminary diagnostic work in the treatment of asexualism, and especially sterility, in the female. A careful analysis of all the conditions present must be made first, for organo- therapy is not effective if a woman has had a specific infection of the fallopian tubes and their lumina have been occluded, for here the sterility is purely mechanical. Again, if the woman is luetic and consequently is subject to frequent miscarriages, nat- urally the syphilis must be remedied before normal conditions can be re- established, which will allow a preg- nancy to run to full term. A mechan- ical factor in the endometrium, which may prevent the nesting of the impreg- nated ovum and its development, is on a par with the mechanical occlusion of the tubes already mentioned. Under such circumstances organotherapy is destined to failure. Again, an infection of the vaginal tract which causes an abnormally acid secretion must be remedied before an associated hypo- ovarism, or dyscrinism involving the ovaries and other associated glands, is treated, for in such cases, while organo- therapy may be indicated and, indeed, may be efficacious, this factor interferes. It has been discovered many times, 242 clinically, that ovarian therapy stimu- lates the ovaries to a better menstrual function, and it is believed that with this capacity of facilitating a more normal menstrual service to the organ- ism, the other functions of the ovaries are simultaneously encouraged. I have repeatedly seen cases of ovarian insuf- ficiency, in which amenorrhea was the rule, recover also from two other usually associated manifestations- asexualism, or a lessened or lost sex capacity, and sterility. This brings us to a point of diagnostic value : If a woman has a normal menstruation and a normal sex reaction and is still sterile, the chances are that the ob- stacle is an anatomical one, and not likely to be amenable to organotherapy. If, on the other hand, there is other evidence (besides the sterility) of ovarian insufficiency as manifested by amenorrhea and asexualism, the chances for clinical results are better, because it is likely under such circum- stances that the ovarian endocrine complex, as a whole, is deficient ; in other words, that there is pluriglandu- lar insufficiency, involving, with the ovaries, those glands which help to maintain their functions. In spite of the inherent difficulties in considering and treating this class of cases, and especially the many oppor- tunities for failure resulting from the ignoring of overlooked factors of the character already mentioned with em- phasis, I have seen, personally, enough individuals with light in their eyes and enthusiasm in their tone to be con- verted for all time to the real possibili- ties of this method, and to the impor- tance of the relations of the endocrine glands and their control on one another. 243 Method of Administration. Gonad Co. (Harrower) or Gonad- Ovarian Co. (Harrower) (see pp. 279 and 280) are given for several months, for, naturally, such conditions invari- ably are of long standing and the treat- ment is in the nature of an educative factor, and such measures as this take time. The former is used one sani- tablet four times a day for at least three months, coupled, of course, with such general hygiene and elimination as one would naturally advise, depend- ing upon the circumstances. In many cases it has been found helpful to give simultaneous injections (every other day) of Sol. Gonad Co. (Harrower). The second formula, Gonad-Ovarian Co. (Harrower), is best given in a cyclic manner, in the expectation of exerting the utmost influence upon the ovaries at their height of functional activity. Consequently, at the onset of menstruation the preparation may be omitted for ten days, then give one three times a day during the next ten days, and double this dose for the ten days prior to the expected flow. This is then repeated for at least three or four periods. In individuals in whom there is no menstruation nor molimen, the same graduated method may be followed ; and as soon as there is the slightest evidence of discomfort in the nature of a molimen, or ever so small a flow, the remedy is omitted for the short period and pushed, i.e., the dose is doubled for a week or ten days prior to the expected periodic manifestation. The use of this formula also may be supplemented by hypodermics of Sol. Thyro-Ovarian Co. (Harrower), usually on alternate days. 244 XXII ORGANOTHERAPY IN E. N. & T. WORK Essential Principles Involved-Focal Infection and the Adrenals-Coinci- dental Ovarian Dysfunction - Thyroid Therapy in Tinnitus-Parathyroid in Otitis Media-Ozena as a Form of Ulceration-Sedation in Sympathetico- tonus - Anemia and Hemoglobin Therapy. HOW many times have I heard, " I'm a nose and throat man, so naturally have very little interest in the internal secretions." And how many times has a specialist raised his brows in surprise when I have told him of some of the possibilities of or- ganotherapy in otorhinolaryngology! It really seems as if the attitude of those practising this specialty has been due to the same misunderstanding of a number of other physicians who have said that organotherapy should not be of special interest to them, i.e., the fact that the internal secretions are sup- posed to be connected with a certain list of definite, structural diseases, such as myxedema, Addison's disease, acromegaly, and hyperthyroidism- which they saw only rarely. Essential Principles Involved. As a matter of fact, the fundamental principle underlying many of the re- cent developments with endocrinology applies equally in otorhinolaryngology. This principle is broad and, I believe, incontrovertible. It is this : Since the 245 endocrines are subject to the influences, of toxemia, emotional stress, malnutri tion, etc., such factors must modify their function in a large percentage of the ordinary cases in general practice. We do not have to look for cases of " ductless glandular disease " to find endocrine problems. Many of our daily cases have a functional endocrine phase. I propose to outline here a number of suggestions which will make organo- therapy a prospectively interesting pro- cedure to every ear, nose, and throat specialist, and I can assure my readers in advance that the prospects along these lines are just as encouraging and remarkable as those from its application in other branches of medicine. Focal Infection and the Adrenals. Perhaps the most important single clinical entity which brings patients to the otorhinolaryngologist for study, is focal infection. Infected tonsils, sinuses, and mucous membranes are extremely important factors in bringing about not merely functional endocrine disorder but definite endocrine disease. For instance, it is believed that one of the most usual underlying causes of hyperthyroidism is tonsillitis and kin- dred infective difficulties. No case of hyperthyroidism has been properly studied until the nose and throat spe- cialist has passed his judgment and rendered the assistance that it is so often possible for him to render. It is an axiom that where there is a chronic focal infection, there must be a corresponding reaction on the part of the body to the poisons absorbed from it. Those who have studied the influence of toxemia upon the adrenal 246 mechanism know how frequently one can find adrenal insufficiency following an experience with an old, chronic running ear, a frontal or maxillary sinusitis, or even tonsillitis. The ab- sorbed poisons stimulate the adrenal mechanism. By the long overstimula- tion the adrenals are depleted, and a clinical endocrine picture is brought about which is extremely common-it is the all-too-common asthenic, run- down state. The patient is tired all the time, the circulation is poor, the blood-pressure is low, the elimination is reduced, and the patient is " all in." While necessary treatments are being given to control the focus of infection, why not support the depleted endo- crines with suitable organotherapy? The subject has received full con- sideration in Chapter II, and it should suffice to state that a great many ear, nose, and throat specialists have found considerable satisfaction from the ad- ministration of Adreno-Spermin Co. (Harrower) to cases of this type. It not merely has a salutary general influence upon the symptoms enumerated above, but it seems to bring about a better reaction to local treatment. The dose is one sanitablet at meals and bedtime, or, in acute cases, two, three times a day. Coincidental Ovarian Dysfunction. Many a specialist has noted an exac- erbation of chronic infective conditions at or near the menstrual period. On the other hand, many gynecologists know how focal infections of this kind can interfere with the ovarian activities and their influence upon the general health. The thyroid, pituitary, and adrenals are influenced detrimentally by the products of focal infection. They 247 are also very definite factors in the initiation, maintenance, and regulation of the monthly ovarian service. Thus it is easy to understand how common, functional, ovarian irregularities, such as amenorrhea, dysmenorrhea, men- strual neuroses, and climacteric dis- orders, can be connected with nose and throat disorders. Aside from these di- rect endocrine aspects, the indirect ef- fects through the sympathetic system are undoubted. While treatment of the endocrine features of such cases is not likely of itself to benefit the nose and throat factor, when such treatment is added to proper attention to the local diffi- culty, the aggregate of results is found to be much better. In other words, given a case with a sinus infection, a chronic tonsillitis, or some nasal ir- regularity, and treatment directed at a coincidental ovarian irregularity will enhance the progress and treatment far more than if this feature were left alone. Many physicians in general practice, who also do nose and throat work, have found how broad are the benefits from the use of Thyro-Ovarian Co. (nar- rower) as an ovarian regulator. They have also found that when an ovarian imbalance has been modified by such treatment, the response of the patient to other necessary procedures very often is much more satisfactory. If there is dysovarism with asthenia, Adreno-0 varian Co. (narrower) is used : and when either of these ova- rian regulating formulas is given, it is advisable to follow the step-ladder method of dosage as follows : For ten days prior to the expected menstruation and until the flow is established, give two sanitablets three times a day. For 248 ten days beginning with the onset of menstruation, omit the treatment en- tirely. During the middle of the men- strual month, give one sanitablet three times a day, before meals. Repeat this cyclic method for at least three men- strual experiences, at the same time giving such attention to the local nose and throat disorders as may seem best. (See also Chapter VII.) Quite a number of interesting papers are creeping into the literature con- necting the fundamental manifestation of thyroid insufficiency-cellular infil- tration-with tinnitus aurium. It may be recalled that the thyroid is essential in maintaining the cellular chemistry. When the thyroid is defective, there ensues a reduction of the cellular ac- tivities, not merely from the stand- point of what is known as the basal metabolic rate, but from every poison- destroying, waste-burning aspect. The wastes in these cells draw from the surrounding serum a sufficient amount of additional fluid to make the specific gravity in the cell equal to that of the surrounding fluid. This puffs out the cell or, as it is called, infiltrates it. This condition occurs in all parts of the body, including the mechanism of the ear. A number of reports indicate not merely that thyroid insufficiency of a well-marked degree has been found to accompany many cases of tinnitus aurium, but better still, that thyroid therapy has been clinically valuable in the control of this condition. The following paragraphs from the year book, " Practical Medicine," series for 1922, volume on " Ear, Nose, and Throat," p. 242, are very interesting : Thyroid Therapy in Tinnitus. 249 " The success of the treatment of tinnitus aurium by glandular thera- peutics depends on the condition being a symptom resulting from gland ex- haustion or due to a deficient activity of the adreno-thyroid apparatus. The extract of a gland organ will exert an exciting influence in the same organ so that a sluggish gland can be prodded into activity to a degree quite beyond belief, and result in a glandular read- justment. The thyroid gland undoubt- edly is largely responsible for the distressing symptom of tinnitus au- rium. This can be explained by a thy- roid deficiency causing a generalized infiltration in which cellular growth and oxidation are interfered with throughout the body. When this infil- tration affects the auditory apparatus we get the characteristic symptoms of tinnitus aurium without any definite ear lesions. Sajous describes this by the low blood-pressure present as well as by the poverty in the oxidase, its oxidizing principle, causing impairment of hearing and tinnitus. According to Gake, adrenal insufficiency is a potent cause by producing either anemia and mental fatigue or congestion of the labyrinth. " In a series of sixty cases in which tinnitus aurium existed without any disease of the ear, thyroid extract was the routine gland substance admin- istered. From one-fourth to one-half grain three times daily was given, and the patient was watched carefully for symptoms of over-dosing. Some patients reported improvement on the third day and others after a week. "About 70 r>er cent, of the patients responded to thyroid. Some of these were free from ear noises in two 250 months, others improved greatly and continued calling at the clinic regulaily with the hopefulness of being relieved entirely. In 10 per cent, of this series of cases thyroid either had no effect at all or else the patients were improved but slightly. In such cases, adrenal sub- stance, total gland, two grains three times daily, was given. This produced marked amelioration of symptoms, but not so quickly or completely as thyroid. " From 10 to 20 per cent, of these cases did not respond to glandular treatment. These were the very old chronic cases in which the patients have been coming to the clinic for the past ten years. One man, age sixty, obtained relief at first with orchitic substance, but this was only tempo- rary, and further treatment with inter- nal glands proved futile. This can be accounted for by a degenerative process of the ductless glands due to old age and resulting in an autointoxication." One of the most remarkable recent developments in organotherapy is the manner in which parathyroid therapy has come to the front as a means of controlling ulcerative conditions. It is only a short time since Vines and Grove, of Cambridge, first showed that patients with chronic varicose ulcers of the leg often have a coincident reduc- tion in the blood-calcium (hypocal- cemia) which could be modified by giving parathyroid extract by mouth. Remarkably enough, with this change in the blood-calcium, came complete cure in a very large percentage of these ulcers, some of which had lasted for fifteen or twenty years. It soon developed that this ulcer-curing capac- Parathyroid in Otitis Media. 251 ity of parathyroid was very much more broadly applicable. Physicians are now using this treatment in gastric and duodenal ulcers, in the ulcerative con- dition known as sprue, to hasten the healing of burns, and even in mucous colitis. (See Chapter XIV.) It was not long before this appar- ently fundamental idea was applied to some of the ulcerative conditions found in nose and throat practice, and it can be said without equivocation that para- thyroid therapy is the most remarkable single remedy for the modification of the underlying capacity of the body to heal a chronic ulcerative condition. Parathyroid has been given with notable benefit in chronic otitis media, in chronic sinus infections (of both the frontal and maxillary sinus), and in postnasal infections which have not been responsive to ordinary measures. Calcium salts play an important role in the body's defense against infection, which is explained, at least partly, by their ability to bring about a marked increase in the number of poly- morphonuclear leucocytes. The re- sponse of chronic suppurative or ulcer- ative processes to parathyroid therapy is probably due, not only to a readjust- ment of the calcium balance of the blood, but also to a marked increase in these polymorphonuclears. Because of this fact, chronic and somewhat quiescent septic foci may become sud- denly and temporarily acute, indicated by an increase in the purulent dis- charge, after the ingestion of parathy- roid preparations. This phenomenon points to the specificity of the remedy and implies an increase in the defen- sive response rather than an increase in the virulence of the infection. 252 I have run across cases of " chronic running ear," of over ten years' stand- ing, that have benefited as by a miracle following a month's treatment with parathyroid. A similar case of much longer duration is reported in the fol- lowing letter from a colleague : "A case of otitis media of twenty-one years' standing came to me for treat- ment. After using Parathyroid Co. (Harrower) for a short time we no- ticed a change for the better, and in about two weeks I added Calcium- Phosphorus Co. (Harrower), according to your suggestion. I am proud to say that his ear is now free from pus." Another most interesting case was with a returned missionary from Japan who had been suffering from sprue which had resisted treatment for over a year. After two weeks of parathyroid therapy, the ulceration of the mouth had been controlled ; and within a few more weeks she was delighted to find that a frontal sinusitis of long stand- ing was not giving any further trouble, and on transillumination it was found to be apparently healed. Many other nose and throat infections are respond- ing to Parathyroid Co. (Harrower) and one of the most recent reports con- cerns a woman with a chronic running ulcer in the nose which had resisted years of treatment. Her pillow " was covered with pus and blood every morning." This formula was given for a month, one, t.i.d., the discharge dried up, and the ulceration healed up completely. Ozena as a Form of Ulceration. Another unusual prospect from organotherapy is in the treatment of ozena with Parathyroid Co. (Har- 253 rower). It is not, in any sense of the word, a specific ; but a number of par- ticularly intractable and malodorous cases are much improved from follow- ing the treatment for six or eight weeks. Whether the benefit is perma- nent, is not yet known. The only ex- planation of the philosophy underlying thisdevelopmentis that ozena is a form of ulceration which, like other ulcera- tions, responds to parathyroid therapy. It is an incontrovertible clinical fact that oral parathyroid therapy exerts a remarkable, though subtle, influence upon the healing of ulceration. This capacity needs to be encouraged many times in connection with the work of the nose and throat specialist and, therefore, I predict that parathyroid therapy will be one of the most val- uable adjuvant measures in the hands of the otorhinolaryngologist. The usual dosage is one sanitablet of Parathyroid Co. (Harrower) at each meal, three times a day ; and such treatment should be continued for at least a month or six weeks. Elsewhere attention has been called to the frequency with which hyper- thyroidism is built upon a chronic tonsillar or sinus infection (Chap. IX). The principal clinical manifestation of hyperthyroidism is a remarkable de- gree of sympathetic irritability mani- fested not merely in heart hurry, tre- mor, and an exaggerated degree of nervousness, but in the fundamental irritability of the sympathetic nervous system which is called " sympatheti- cotonus." It may be said that it is possible, by means of an organotherapy originally suggested by Dr. Andrd Sedation in Symyatheticotonus. 254 Crotti, of Columbus, Ohio, to bring about a degree of sympathetic sedation which is distinctly advantageous. Pan- creas Co. (Harrower) is the remedy. It is given one sanitablet at or between meals and at bedtime (in severe cases, two, three times a day), in conjunction with the measures calculated to re- move the source of the substances which are irritating the thyroid. This is a purely symptomatic measure and a means of sympathetic sedation con- siderably superior to that expected from drug therapy though less im- mediately effective. Anemia and Hemoglobin Therapy. One other form of organotherapy- may be mentioned in closing. Many cases coming to the otorhinolaryngolo- gist are anemic and suffering from malnutrition. Possibly the long-stand- ing difficulty which brings them for special treatment coincidently has brought about the anemia. As adjunct measures of considerable merit, two organotherapeutic formulas may be mentioned : Hemoglobin Co. (nar- rower)-a combination of repurified hemoglobin, spleen substance, and nucleinic acid (the latter of particu- lar value in stimulating white blood- cell production and activity, and Sper- min-Hemoglobin Co. (narrower)-a similar formula containing the Adreno- Spermin combination, more definitely useful in asthenic anemia, and in cases where the blood findings are associated with low blood-pressure and hypo- adrenia. Either of these preparations may be used with distinct advantage to round out a treatment, and the usual dose is one or two sanitablets three or four times a day. 255 XXIII PLURIGLANDULAR FORMULAS A Ready-Reference List THE reason for the establishment of The narrower Laboratory was a firm belief that organotherapy is a vital phase of medicine, and that there were opportunities to broaden it and make it more practical by considering the relationships of the endocrine glands. This meant that pluriglandu- lar therapy was more likely to be help- ful than the use of single gland prod- ucts. Despite considerable opposition based upon " the unscientific charac- ter " of such premises, clinical results have established the truth of this, and that we are serving the profession ac- ceptably. This laboratory has pio- neered in the development of valuable endocrine ideas which have revolution- ized the therapeutic procedure of thou- sands of medical men and women. The following pluriglandular for- mulas, indicated collectively by the word-mark "Polycrines" {poly, many; crinos, I separate), facilitate the appli- cation of the essential principles of organotherapy to several large groups of conditions. The ingredients are of maximum potency, and the equal of any obtain- able, being made altogether regardless of price considerations. The amounts indicated in the formulas represent the ultimate desiccations minus connective tissue, fat, and water. It is necessary to lay particular emphasis on this for two reasons : First, numerous imita- 265 tions are now on the market whose principal claim is that they are cheaper; and second, several high-class manufacturers dose their endocrine products upon a basis of the fresh gland substance represented, which tends to mislead the prescriber since desiccations are dry, and those that are official are dosed in the various phar- macopoeias on a basis of dry substance. The combinations and the various dosages of their several ingredients have been carefully worked out in an extended clinical way over a period of many years, and it is with a confidence born of innumerable excellent results that they are recommended to the pro- fession. These original formulas at first were put in gelatin capsules, but the hygro- scopic nature of both the capsule itself and the desiccated glandular substances made a change necessary. The sani- tablets, which replace the capsules, are superior to the capsules in protecting the glandular remedies. Sanitablets are friable, compressed tablets, individually wrapped and sealed with paraffin. This is quite the greatest recent advance in pharma- ceutical technique, since this method of packing prevents contamination and deterioration, obviates substitution, and favors convenience both in dispensing (they come in units of twenty doses, five to the package) and use by the patient, for a few sanitablets can be torn off and carried in the pocket or purse and remain hermetically sealed until taken. (Incidentally the Harrower formulas are the first, and at present the only, glandular products to be pro- tected in this excellent manner.) 257 No. 1. ADRENO-SPERMIN CO. (Harrower.*) Asthenia: Hypotension ; Neur- asthenia; Run-down Conditions. Formula: Adrenal total gr. 'A, Thyroid gr. 1/12, Spermin Extract (from gonads) gr. 2 with Calcium Glycerophosphate q.s. Prescribe: R Adreno-Spermin Co. (narrower). No. C. (one hundred!). Sig. 1, q.i.d. just before meals and at bedtime. (In acute cases every 3 hours.) Effects: Supports depleted adrenal function, thus reducing neuromuscular asthenia due to hypoadrenia. Enhances sympathetic tone, stimulates oxidation, and increases " dynamos." An organo- therapeutic tonic and reconstructant. Indications: Chronic asthenic con- ditions with deficient oxidation (low urinary elimination) such as accom- pany chronic toxemia and follow acute infectious diseases, especially influenza, pneumonia, etc. The " fatigue syn- drome " (run-down states) with low blood-pressure, cardiocirculatory in- sufficiency (cold extremities), and sub- normal temperatures. Many neuroses, as neurasthenia, psychasthenia, etc. Remarks: Give early in acute conditions as a prophylactic against the " let-down," which invariably is an adrenal syndrome. Begin with 1 every 3 hours, later 1, t.i.d. In chronic asthenias the blood-pressure is an excellent guide to dosage and length of * For mutual protection, it is desirable to specify "Harrower" as indicated throughout. There are many cheaper imitations. t It is most satisfactory to prescribe an original package of one hundred sanitablets, chiefly because brief periods of treatment are usually unsatisfactory. One package is approx- imately one month's treatment. 258 administration. A B.P. (systolic) of 110 mm. calls for 1, t.i.d.; of 100 mm., 1 q.i.d.; and 90 mm. or less, 1, 5 or 6 times a day. No. 1a. SOL. ADRENO-SPERMIN CO. (Harrower.) Same formula as above, but in ampules containing one milliliter of a standardized 4 per cent, nucleoprotein solution for hypodermic injection. The usual dosage is one injection every other day and the package of 15 am- pules is an average month's treat- ment. The sanitablets should be given simultaneously. No. 2. ANTERO-PITUITARY CO. (Harrower.) Defective Children : Maldevelop- ment; Epilepsy; Cretinism. Formula: Pituitary (anterior lobe) gr. 2, Thymus gr. 1, Thyroid gr. 1/12 with Calcium Phosphorus Co. (see No. 11) q.s. ad. gr. v. Prescribe: R Antero-Pituitary Co. (Narrower). No. C. Sig. 1, twice a day at meals, for 4 out of every 5 weeks. Continue for several months. (In children over 8 years, and later in the treatment, 1, t.i.d.) Effects: A growth stimulant and endocrine regulator in defective develop- ment in children and youth. Found to be beneficial in petit mal and epilepsy. Indications: Children with obvious endocrine deficiencies-thyroid, pitui- tary, etc. Retarded mentality ("back- ward children " with or without stigmata), deficient growth,mongolism, dwarfism, etc. Epilepsy, petit mal, chorea, and indefinite disorders often 259 associated with, or due to, dyscrinism. Broadens value of thyroid in cretinism. Remarks: Results have been remark- able and unexpected, while, of course, this formula has been used in definite, cerebral cases with no benefit whatever. This cannot be determined in advance, so it is often a " last straw " well worth trying. Give an understanding that results are possible but not necessarily probable, and that it is useless to give it for less than four to six months. No. 3. PLACENTO-MAMMARY CO. (Harrower.) Galactagogue: Uterine Involutant; Postpartum Stimulant. Formula: Desiccated Placenta gr. 2, Mammary Substance gr. 1%, Pituitary (total) gr. % with Calcium Phosphorus Co., q.s. ad. gr. v. Prescribe: B Placento-Mammary Co. (narrower). No. C. Sig. 2 sanitablets at meals 3 times a day for the first 2 weeks, thereafter one 3 times a day. Effects: Mammary stimulant, gal- actagogue; postpartum regulator and encourages uterine involution. Bene- ficial influence upon infant's nutrition. Indications: Deficient or poor milk secretion, agalactia, hypogalactia. In- fantile malnutrition. Prophylactic in mothers with poor previous nursing experiences. Remarks: Push dosage for the first period, reduce until after three weeks or a month it may be omitted. In some cases it has been given throughout entire nursing period, since its omission caused hypogalactia within a few days. This formula has seemingly inhibited menstruation during nursing months, with advantage to mother and child. 260 No. 4. THYRO-OVARIAN CO. (Narrower.) Dysovarism: Amenorrhea; Dys- menorrhea; S TERILIT Y; N EUR- asthenia; Menopause. Formula: Ovarian Substance with Corpus Luteum gr. 2^, Thyroid gr. 1/12, Pituitary (total) gr. % with Cal- cium Phosphorus Co., q.s. ad. gr. v. Prescribe: R Thyro-Ovarian Co. (Narrower). No. C. Sig. 1, t.i.d., a.c. for 10 days, double dose for 10 days be- fore menses, omit at onset of menses for 10 days. Repeat. (In total amenor- rhea: 1, t.i.d. for 10 days, 2 t.i.d. for 2 weeks; omit a week; repeat.) Effects: Ovaro-uterine regulator through ovarian endocrine function and that of associated synergistic glands. Indications: Amenorrhea (scanty, absent or difficult menses); dysmenor- rhea; sterility; sexual apathy; numerous neuroses and psychoses con- nected with menstruation. Climacteric disorders and circulatory imbalance. Remarks: This is one- of the most efficient endocrine formulas, for often the whole trouble is not so much ovarian in origin as thyroid or pituitary, as physiology and clinical experience repeatedly shows that this formula is helpful when corpus luteum or ovarian substance alone has failed. No. 4a. SOL. THYRO-OVARIAN CO. (Narrower.) Same formula but in ampules con- taining 1 mil of a standardized 4 per cent, nucleoprotein solution for hypo- dermic injection. To supplement the oral use of the same formula in more 261 aggravated cases of dysovarism and long-standing amenorrhea, sterility, psychoses, etc. Given every other day. No. 5. HEPATO-SPLENIC CO. (Harrower.) Intestinal Stasis : Hepato-Biliary Insufficiency ; Alimentary Tox- emia; Malnutrition. Formula: Hepatic Parenchyma and Desiccated Spleen aa gr. 2, Spermin Extract gr. 1, Adrenal Substance gr. %, and Thyroid gr. 1/20. Prescribe: R Hepato-Splenic Co. (Harrower). No. C. Sig. 1 after each meal and at bedtime. Effects: Alimentary stimulant and regulator through liver and spleen mechanism and general endocrine system. Encourages secretory and detoxicative powers of liver. Not a cathartic. Indications: Hepato-biliary insuffi- ciency and sluggishness, resulting in intestinal stasis and toxemia. Hepatic cirrhosis. Malnutrition of long stand- ing, toxic origin, in cachexia, tuber- culosis, malaria, etc. Remarks: This formula seems to go deeper than one expects of an ordinary hepatic stimulant. Its effects are slower. It offers a support or physio- logical encouragement which is more satisfactory than is expected from " liver medicines." No. 6. PANCREAS CO. (Harrower.) Sympathetic Irritability : Heart Hurry and Cardiac Weakness; Hyperthyroidism. 262 Formula: Adrenal and Pituitary (total) aa gr. y2, Ovarian Substance gr. 1, Pancreas (total) gr. 3. Prescribe: R Pancreas Co. (Har- rower). No. C. Sig. 1, q.i.d., before meals. (In acute cases, in severe hyperthyroidism, increase dose to 6 or 8 a day for a time.) Effects: A cardiac muscular support and sedative. Functional antagonist to sympathetic irritability due to exces- sive thyroid secretion. Ovarian con- tent added since dysovarism is quite common in such cases. (No objection to using same formula in men.) Indications: Irritable, irregular, rapid, and weak pulse, especially of endocrine origin. Nervousness and irritability of hyperthyroidism. Post- influenzal and toxic asthenias with a susceptible thyroid. Where No. 1 is needed but hyperthyroidism is present. Remarks: Sympathetic sedative remedy in hyperthyroidism, but with no influence upon its causes. Must be used with measures which antagonize or remove (1) sources of toxemia (teeth, tonsils, sinuses, colon, gall-bladder, or pelvis), (2) dyscrinism, especially dysovarism or persistent thymus, or (3) psychic conditions which stimulate the thyroid and adrenals. A means of preparing a case of toxic goiter for surgery, and a remedy in toxemias where radical measures are contraindicated. Nos. 8-9. THYROID CO. (gr. (Harrower.) Hypothyroidism: Myxedema; Cretinism. Formula: Each sanitablet contains 5 grains of Calcium Phosphorus Co. 263 (see formula No. 11) with *4 or % grain of desiccated and standardized Thyroid Extract. Prescribe: R Thyroid Co. (nar- rower), gr. (or y2, as desired). No. C. Sig. 1 sanitablet t.i.d. Effects: Supplementary organo- therapy in functional or organic thyroid insufficiency. Remineraliza- tion. (See No. 11.) Indications: Hypothyroidism- myxedema, with lesser forms of thyroid insufficiency, manifested by infiltration (of skin, mucous membranes, and tissues), suboxidation, obesity, derma- toses, or ovarian dystrophies. Cretinism, mental backwardness, etc. In many nutritional disorders with metabolic insufficiency and defective elimination. Remarks: Thyroid extract is given to increase cell chemistry, for any degree of hypothyroidism always entails reduced metabolism and consequent excessive production of acid wastes which automatically reduce the alkaline reserve. This explains the acidosis and cellular poisoning so common in hypo- thyroidism, and supplements thyroid stimulation by restoring depleted alka- line salts. Hence the excipient may be as therapeutically useful as the thyroid. No. 10. THYROID TEST CAPSULES. (Harrower.) Thyroid Test: Differential Diag- nosis of Goiter; Estimation of Thyroid Secretion. Formula: Each small box (3 in each package) contains 12 graduated cap- sules of thyroid extract, 4 each of small, medium, and large, representing 1, and 2 grains of Thyroid, respectively. 264 Prescribe: R One Thyroid Test (Har- rower), with chart. Sig. Follow printed instructions carefully. Effects: A graduated thyroid func- tion stimulant, bringing about a reac- tion which may be recorded on a pulse chart which serves for comparison between different cases, or the same case under different circumstances. A means of measuring thyroid function. Indications: In all forms of simple goiter and where thyroid enlargement is not due to well-established hyper- thyroidism. A means of discovering latent thyroid sensitiveness without goiter. Differential diagnostic measure between goiter due to thyroid secretory incapacity or overstimulation. Valuable in study of metabolic dyscrasias where thyroid element may be present, and where thyroid stimulation properly may be added to other treatment if needed. Remarks: A simple and extremely convenient measure, as instructions are outlined on accompanying chart. Places thyroid medication upon a rational basis instead of its haphazard administration until patient complains of overstimulation. Useful in goiter and in study of disturbed cell chemistry, in ovarian disorders, in nutritional disturbances, and in cases where to uncover thyroid irritability or apathy would offer a new angle for treatment. No. 11. CALCIUM PHOSPHORUS CO. (Harrower.) Demineralization : Hyperacidity (Acidosis) ; Toxemias. Formula: Magnesium Phosphate 2, Calcium Phosphate (dibasic), and 265 Glycerophosphate aa 8, Potassium Bicarbonate 32, and Sodium Bicar- bonate q.s. to 100. Tablets of 1 gram. Prescribe: B Calc. Phosphorus Co. (Harrower). No. C. Sig. 3 tablets, crushed, with much water, twice a day, 1 hour before food. Effects: Neutralizes systemic acid wastes. Beplaces alkaline mineral re- serve, depleted by poor oxidation and abnormal production of acid, or " alkali-robbing " products. Indications: Useful in chronic toxemic conditions, especially those commonly associated with endocrine insufficiencies. Indicated in many chronic disorders with gland feeding. Remarks : This formula (plus sodium chloride) contains mineral salts in approximate proportions present in blood, and is the standard excipient in The Harrower Laboratory. Often advisable to push dosage for first few weeks with pluriglandular therapy. At least 6 grams a day should be given during initial 3 weeks. No. 12. AMYLO-TRYPSIN CO. (Harrower.) Indigestion : Flatulence ; Gastric Dilatation. Formula: Amylopsin gr. Pan- creatin gr. 2%, Papain gr. ^.Berberine Sulphate gr. 1/12, and a mixture of Cinnamon, Nutmeg, and Ginger, q.s. Prescribe : B Amylo-Trypsin Co. (Harrower). No. C. Sig. 2 sanitablets, 2 hours after eating. Effects: The first three ingredients further proteid and starch digestion. Berberine is an efficient mucosal tonic; 266 well-known plant carminatives as excipient. A polyenzyme, tonic, diges- tant formula. Indications: Gastro-intestinal indi- gestion with achlorhydria, flatulence, and fermentation. Wherever alimen- tary enzyme medication is called for. Remarks: Ferments are highly active. No pepsin is present, but papain ("vegetable pepsin" active in either acid or alkaline media) is used. No. 13. HEMOGLOBIN CO. (Harrower.) Anemia: Chlorosis; Malnutrition. Formula: Hemoglobin (repurified) gr. 4, Desiccated Spleen Parenchyma gr. 1, Acid Nucleinic (Nuclein) gr. %. Prescribe: B Hemoglobin Co. (Har- rower). No. C. Sig. 1, before meals and on retiring. (Increased doses may be given when marked hematinic ef- fects are needed; 3, 4 times a day for a week or more.) Effects: Purveys acceptable and easily absorbable iron. Non-constipat- ing. Stimulates hematopoiesis. En- courages leucocyte production and phagocytosis. Indications: Where iron ordinarily is indicated. Anemia, primary and secondary. Malnutrition due to blood conditions; following a considerable loss of blood. Cachexia, cancer, and chronic blood-destroying conditions, including pernicious anemia. Remarks: An unusually .excellent combination which has caused many remarkable changes in the Hgb. index and blood-picture. Quite the best form of iron for oral administration. 267 No. 15. SECRETIN CO. (Harrower.) Indigestion: Pancreatic and Bil- iary Insufficiency; Intestinal Toxemia. Formula: Secretin Extract (Duo- denal) gr. 3, Bile Salts gr. 1%, Adrenal Substance gr. % with Calcium Phos- phorus Co. q.s. ad gr. vss. Prescribe: R Secretin Co. (Har- rower). Sig. 2, between meals, t.i.d. May be well to push dosage to 3 or even 4 sanitablets per dose for 10 days in intractable cases. Ordinarily 1, t.i.d. Effects: Secretin stimulates pancre- atic, biliary, and intestinal glandular secretion, forming part of finished enzymic products. Bile salts encourages increased biliary production. Adrenal is tonic to unstriped muscle. Indications: Chronic indigestion with toxemia, stasis, constipation and their results. Hepato-alimentary in- sufficiency with fetid, clay-like stools. Pancreatic insufficiency. Hypochlor- hydria. Remarks: Unlike enzyme products commonly used in various forms of indigestion, secretin is a normal, rational, and physiological stimulant. In digestive disorders of tabes, preg- nancy, and cancer, this formula often is very valuable. No. 18. IODIZED THYROID CO. (narrower.) Goiteb: Thyroid Enlargement; Hypo- thyroidism. Formula: Thyroid, Ferrous Iodide, Acid Nucleinic (Nuclein) aa gr. % with Calcium Phosphorus Co. q.s. 268 Prescribe: R Iodized Thyroid Co. (Harrower). No. C. Sig. 1, t.i.d. between meals with water. (Occasionally it may be best to give 4 to 6 sanitablets a day.) Effects: Replaces deficient thyroid hormone, stimulates its secretory activity. Iodine is a thyroid stimulant (food) and nucleinic acid encourages leucocytosis. Indications: Simple goiter or thyroid enlargement without thyroidism; anemia and malnutrition, especially in girls at puberty with slight thyroid enlargement; hypothyroidism. Remarks: Where thyroid enlarge- ment is due to an attempt to meet certain special demands for thyroid stimuli, the hypertrophy is com- pensatory. In girls at puberty and women during various ovarian changes, thyroid enlargement often appears which is benefited by treatment with this formula. The value of thyroid is increased by an active hematinic form of iodine plus the leucocyte and resis- tance-stimulating effect of nuclein. No. 22. BILE SALTS CO. (Harrower.) Biliary Insufficiency: Mucous Colitis ; Constipation ; Intestinal Indigestion. Formula: Six-grain sanitablets of repurified Bile Salts and Hepatic Sub- stance desiccated, equal parts. Prescribe: B Bile Salts Co. (Har- rower). Sig. 1, q.i.d. between meals for 3 days, dozible dose for 3 days, treble dose for 3 days, continue until free bile appears with stool, then reduce to 3 a day for some weeks. (Repeat this routine monthly, especially in stubborn cases.) 269 Effects: Hepato-biliary stimulant, increasing flow of bile and hepatic activity, including its detoxicative func- tions. Indications: Functional liver insuf- ficiency, intestinal stasis, sluggish bile flow, gall-stones, duodenal indigestion, and chronic nutritional disorders such as tuberculosis. Mucous colitis. Chronic hepatic disease with cirrhosis or hypertrophy. Remarks: This combination is superior to either of its ingredients. Proper dosage is " enough." If consti- pation is marked and patient is taking cathartics, continue them. Suggest graduated dosage and when free bile is seen, omit cathartics, continuing high dosage of Bile Salts Co. for 2 or 3 days and gradually reduce it, until just 2 or 3 are taken at night. No. 23. PANCREATIN-BILE CO. (Harrower.) Intestinal Indigestion : Biliary Insufficiency. Formula: Each sanitablet contains 2 grains each of Pancreatin, Bile Salts, and Hepatic Substance. Prescribe: R Pancreatin-Bile Co. (Harrower). No. C. Sig. 2 sanitablets an hour or more after each meal. (Later this may be given in smaller doses or after the two main meals.) Effects: Digestant, hepato-biliary regulator, and general alimentary secretory stimulant. Indications: Intestinal indigestion with hepato-biliary torpor, alimentary toxemia, and stasis. Essentially as suggested for No. 22. 270 No. 24. PARATHYROID CO. (Harrower.) Ulceration: Paralysis Agitans; Tetany; Hypocalcemia; Tuber- culosis. Formula: Desiccated Parathyroid (true) gr. 1/20, Spleen Substance gr. 2; Sperniin Extract gr. 1 (from Leydig cells), and Bile Salts gr. with Cal- cium Phosphorus Co. q.s. Prescribe: R Parathyroid Co. (nar- rower). No. C. Sig. 1 sanitablet 4 times a day before meals and at bedtime. Effects: Stimulates calcium metab- olism, lime fixation, and detoxicative influence of parathyroids; increases nutrition, especially healing in all forms of ulceration. Ionizes colloidal calcium in a very short time. Indications: Parathyroid insuffi- ciency, including certain neuromuscu- lar disorders as paralysis agitans, tetany, and perhaps chorea; chronic septic or ulcerative conditions, such as varicose ulcers, gastric and duodenal ulcers, bed-sores, chronic running ears, sinusitis, stomatitis, sprue, ulcerative colitis, tuberculosis, etc. Remarks: Parathyroid therapy, originally recommended in paralysis agitans, has been applied in recent years in many cases of ulceration of every description. It is a specific in ulcers with low blood-calcium. This formula is superior to parathyroid alone. No. 24a. SOL. PARA-SPLEEN CO. (narrower.) A standardized 4 per cent, solution of nucleoproteids from spleen and 271 parathyroids. Used to increase efficacy of foregoing oral formula, especially in tuberculosis. Dose: 1 mil every second day for at least 2 months. No. 26. ADRENO - HYPOPHYSIS CO. (Harrower.) Asthma: Bbonchial Asthma. Formula: Adrenal (total) gr. Pituitary (anterior lobe) gr. 2, Calcium Lactate and Calcium Phosphate aa q.s. Prescribe: R Adreno-Hypophysis Co. (Harrower). No. C. Sig. 1 q.i.d. before meals and at bedtime. (Occa- sionally a larger dose may be given, 1 every 3 hours or 2, t.i.d.) Effects: Antagonizes asthenia and hypoadrenia; exerts an indeterminate but beneficial effect on many cases of bronchial asthma. Indications: Asthma and bronchial asthma in children and adults, where an underlying endocrine element may be present. Remarks: Dosage suggested causes no unpleasant reactions. Does not replace antispasmodic remedies, which may have to be used also. This remedy apparently influences the underlying cause of certain types of asthma. No. 29. THYRO-PANCREAS CO. w. SPERMIN (Harrower). No. 39. THYRO-PANCREAS CO. w. OVARY (Harrower). Functional High Blood-Pressure. Formula: Pancreas Gland (total) gr. 2, Thyroid gr. 1/12, Spermin Extract gr. 2 (or Ovarian Substance, respec- tively) with Calcium Phosphorus Co.q.s. 272 Prescribe: R Thyro-Pancreas Co. w. Spermin (or Ovary as desired) (Har- rower). No. C. Sig. 1, q.i.d. at meals and at bedtime. Effects: Antagonist to adrenal irrita- bility and functional irritation of blood-pressure regulating mechanism, stimulates oxidation and regulates gonad function. In the male, spermin stimulates cell activity, while in the female, ovarian substance regulates dysovarism, especially near menopause. Indications: High blood-pressure. Remarks: Numerous clinical tests checked by careful sphygmomanometry showed control on high blood-pressure where it is evident that sole cause is not renal, cardiac, or vascular (arterio- sclerosis). In organic hypertension, a functional element may be responsible for a small part of increase, with conse- quent prospects of slight betterment. No. 38. MAMMA-OVARY CO. (Harrower.) Dysovarism: Menorrhagia; Pro- longed Menses. Formula: Mammary Substance gr. 2%, Ovary (total) gr. 1, Thyroid gr. %, Calcium Phosphorus Co., q.s. ad. gr. v. Prescribe: R Mamma-Ovary Co. (Harrower). No. C. Sig. 1, t.i.d., a.c., double 3 days before and during menses, omit for 1 week. Repeat. Effects: Ovarian regulator, antago- nist to excessive ovarian endocrine function; pelvic decongestant. Indications: Moderate menorrhagia with or without dysmenorrhea; diffi- cult menstrual onset; too frequent or prolonged menses, especially in girls; 273 dysovarism with ovarian irritability and abnormal pelvic congestion. Remarks: For best results give just before and during flow. In disturbed ovarian functioning, alternate with Thyro-Ovarian Co. or replace it in ovaro-uterine conditions which lean toward menorrhagia. No. 40. MAMMA-PITUITARY CO. (Harrower.) Menorrhagia: Metrorrhagia; Subin- volution. Formula: Mammary Substance gr. 2^, Ergotin (Bonjean) gr. Pitui- tary (total) gr. 14 with Calcium Phos- phorus Co. q.s. ad. gr. v. Prescribe: R Mamma-Pituitary Co. (Harrower). No. C. Sig. 1, t.i.d., a.c., double 3 days before and during flow, omit for 1 week. Repeat. (Occasionally given 2 sanitablets every 3 hours during heaviest flow.) Effects: Antagonist to ovarian endo- crine function; uterine muscular tonic. Indications: Menorrhagia, metrorrha- gia, and prolonged or excessive menstrual or climacteric uterine hemorrhages. Remarks: In type of menorrhagia of ovarian origin this not merely regulates excessive flow, but also modifies con- ditions responsible for the hemorrhage. No. 41. LEYDIG CELL CO. (narrower.) Prostatic Hypertrophy: Impotence; Hypogonadism. Formula: Spermin Extract (from Leydig cells) gr. 2%, Thyroid gr. 1/16, Calcium Glycerophosphate and Calcium Phosphorus Co., aa q.s. ad. gr. v. 274 Prescribe: R Leydig Cell Co. (Har- rower). No. C. Sig. 1 q.i.d., a.c. Effects: Homostimulant of gonad endocrine function; lessens necessity for functional hypertrophy. Cell stimu- lant in impotence and senility. Indications: Prostatic hypertrophy, not due to present infection or ade- noma; prostatic hyperesthesia; asthenia of gonad origin; impotence and defi- cient gonad function; senility. Remarks: Originally used in experi- mental control of simple prostatic hypertrophy accompanying waning gonad function (prostates may take up their endocrine functions vicariously and become enlarged). No. 44. PAN-SECRETIN CO. ■ (Harrower.) Langerhansian Insufficiency: Dia- betes Mellitus; Glycosuria; Car- bohydrate Intolerance. Formula: Pancreas Islets (tail) gr. 3%, Secretin Extract (Duodenal) gr.1%. Prescribe: R Pan-Secretin Co. (nar- rower). No. C. Sig. 1 to 4 sanitablets with food 3 or 4 times a day. The dosage of this formula is best varied in rela- tion to the blood or urinary sugar, and preferably given in graduated fashion according to a chart which is supplied for the convenience of the profession. Effects: Stimulates pancreas (Lan- gerhiansian) hormone function and en- courages pancreas digestive (ferment) activity; increases carbohydrate toler- ance; reduces blood-sugar; controls glycosuria and polyuria; opposes endo- crine feature of pancreatic diabetes. Remarks: Has no effect comparable to insulin. Latter artificially stimulates 275 C.H. metabolism in all cases irrespec- tive of pancreatic endocrine status. Any benefit resulting from Pan-Secretin Co. (Harrower) comes from bettered pancreatic service thus encouraged, for ingredients alone or separately have no insulin-like effect when given by mouth in recommended dosage. Obviously cannot replace insulin, but has been used in thousands of cases to supple- ment it or to reestablish deficient pan- creatic activity. Its value depends largely upon pancreatic powers of re- cuperation. Has no immediate effect as does insulin upon coma, etc. Calcium Phosphorus Co. (Harrower) is a valua- ble adjuvant in diabetes (see No. 11). No. 47. PITUITARY CO. (Harrower.) Hypopituitarism: Infantilism; Hypo- gonadism. Formula: Pituitary (total), Pituitary (anterior lobe) aa gr. with Calcium Phosphorus Co., q.s. ad. gr. v. Prescribe: R Pituitary Co. (nar- rower). No. C. Sig. 1 q.i.d., a.c. Effects: Stimulates metabolism; in- creases cellular action and encourages gonad function in essential dyspituitar- ism. Indications : Adiposogenital dys- trophy; hypopituitarism; infantilism; eunuchoidism; gonad maldevelopment (hypogonadism) ; pituitary develop- mental dystrophies. Remarks: Contains a greater propor- tion of active glandular portion of pituitary (anterior lobe) than pituitary gland alone, so is more useful in hypopituitarism, which is an anterior lobe disease, than total gland products. 276 No. 48. PROSTATE CO. (Harrower.) Prostatic Disease : Hypertrophied Prostate; Prostatic Neurasthenia. Formula: Prostate (desiccated). Spermin Extract (Leydig cells), aa gr. 2, Nucleinic Acid gr. 14 With Calcium Phosphorus Co., q.s. ad. gr. vi. Prescribe: R Prostate Co. (nar- rower). Sig. 1, t.i.d., a.c. (Occasionally, increases in this dosage are helpful. Advisable to continue this for several months, omitting every fifth week.) Effects: Homostimulant to prostate and sex glands; sedative in prostatic irritability. Indications: Prostatic hypertrophy. Prostatic neurasthenia and following Prostatectomy. Senility. Latent pros- tatic insufficiency with or without an old posterior urethral or prostatic infection; prostatorrhea; gonad in- sufficiency with impotence, relative or actual. No. 49. PLACENTA CO. (Harrower.) Vomiting of Pregnancy: Nausea of Pregnancy; Placental Tox- emia. Formula: Placental Parenchyma gr. 5, Thyroid gr. 1/24 with Calcium Phosphorus Co. q.s. Prescribe: R Placenta Co. (nar- rower) . No. C. Sig. 2 sanitablets with charged water or ice, q.i.d. Effects: Antagonizes placental toxemia and sedates hyperemesis gravidarum. Artificially assists in establishing an immunity to placental Protein poisons. 277 Indications: Vomiting and nausea of pregnancy. Remarks: A remedy of unusual effi- cacy when other treatment has failed. Give by mouth when it can be retained, with or without sedative medication to prevent its loss. Morphine may be necessary to allow absorption. Minimum dosage usually 25 grains a day for 10 days. If, then, evident benefit has been initiated, continue treatment. No. 57. THYMUS-SPERMIN CO. (Harrower.) Arthritis : Arthritis Deformans ; Chronic Rheumatism ; Certain Dermatoses. Formula: Adreno-Spermin. Co. and Thymus Substance aa gr. 3. Prescribe: R Thymus-Spermin Co. (Harrower). No. C. Sig. 1, q.i.d., p.c. (Occasionally given in larger doses for a few weeks, then reduced to above.) Effects: Stimulates metabolism, antagonizes adrenal apathy and asthenia. (See No. 1.) Indications: Desiccated thymus is effective in certain chronic arthrites, including arthritis deformans, with the usual poor metabolism and deficient cell elimination. Later investigations show this influence valuable in chronic dermatoses, as psoriasis, eczema, etc. Remarks: Each ingredient has ren- dered service in arthritis deformans. Often prospects for results are not bright, though this treatment has been used without hope and as a last resort with good results; must be given per- sistently. Modify dosage by starting with routine dosage suggested, for a month, then omit 1 week and take 2, q.i.d. for a month, omit a month. Repeat. 278 No. 68. SPERMIN-HEMOGLOBIN CO. (Harrower.) Asthenic Anemia : Hypoad benia ; Malnutbition. Formula: Adreno-Spermin Co. and Hemoglobin (repurif.), aagr. 3. Prescribe: R Spermin-Hemoglobin Co. (Harrower). No. C. Sig. 1, q.i.d., a.c. Effects: Support to depleted adrenal function. Increases sympathetic tone, increases oxidation and " dynamos " (see No. 1). Hematinic reconstructant. Indications: Conditions of asthenia due to hypoadrenia with anemia and malnutrition. Low blood-pressure with anemia. Remarks: This formula has the well- known advantages of Adreno-Spermin Co., plus the effective hematinic hemoglobin. It has proved a remarkable tonic remedy in certain severe anemias. No. 70. GONAD CO. (Harrower.) Impotence: Asexualism; Hypo- gonadism. Formula: Adrenal (total) gr. Thyroid gr. 1/12, Pituitary (anterior lobe) gr. 1, Prostate and Spermin Ex- tract (from Leydig cells) aa gr. 1%, Calcium Phosphorus Co., q.s. ad. gr. vi. Prescribe: R Gonad Co. (Harrower). No. C. Sig. 1, q.i.d., a.c. Note: 3 to 8 sanitablets may be given daily. Effects: General cell stimulant through hypophysis, adrenals, thyroid, and gonads. Added anterior pituitary is especially helpful (dystrophia adipo- sogenitalis-hypopituitarism-is a gen- ital disorder benefited by organother- 279 apy). Antagonizes asthenia, general as well as sexual. Indications: Functional and endo- crine impotence; aspermia and ster- ility, asexualism and pre-senility, organic and acquired; hypogonadism; sexual neurasthenia. Remarks: Give in graduated dosage, as 1, t.i.d. for several weeks, then 2, t.i.d. for a longer period, followed, if necessary, by another period 3, t.i.d., in conjunction with associated treat- ment. Has no effect upon conditions with a psychic basis, nor influence on latent infections. As it is not rapid in its action, be sure to urge its pro- tracted use. No. 70a. SOL. GONAD CO. (Harrower.) Same formula as that above, but in ampules of a 4 per cent, nucleo- proteid solution for hypodermic injec- tion. Used to supplement the oral formula and given on alternate days during first month of treatment. No. 73. GONAD-OVARIAN CO. (Harrower). Hypo-ovarism : Sterility; Asexual- ism; Infantilism; Amenorrhea. Formula: Thyro-Ovarian Co., gr. 3, Spermin extract and pituitary (an- terior) aa gr. iy2. Prescribe: R Gonad-Ovarian Co. (Harrower). No. C. Sig. 1, q.i.d., a.c. If the patient is menstruating । or if there is a molimen, prescribe as No. 4, i.e., 1, t.i.d., a.c., for 10 days, double dose for 7 to 10 days before menses (or molimen), omit at onset of menses for a week. Repeat. 280 Effects ; Ovarian stimulant through endocrine function of ovaries plus gonad-stimulant effect of anterior pituitary and general sex and cell stimulant effect of spermin. Indications : Prolonged amenorrhea; infantilism; sex maldevelopment and hypofunction; lack of libido; the same as for Thyro-Ovarian Co., save that conditions are exaggerated. Remarks : Endocrine stimulation through all the glands involved in " the sex complex " is the only physio- logical hope in many cases of amenor- rhea and sexual apathy in women. No. 79. ADRENO-OVARIAN CO. (Harrower.) Dysovarism with Hypoadrenia. Formula : Thyro-Ovarian Co. with Adrenal gland gr. %. Prescribe : R Adreno-0 varian Co. (Harrower). No. C. Sig. 1, t.i.d. for 10 days, double dose for 7 to 10 days before menses, omit at onset for 10 days. Repeat. Effects : Ovaro-uterine regulator through ovarian hormone function, plus adrenal support. Indications : Ovarian dysfunction, amenorrhea, dysmenorrhea and condi- tions in which Thyro-Ovarian Co. Would be used with hypoadrenia and asthenia, low blood-pressure and cellu- lar apathy. Remarks : Helpful in asthenic girls and young women with ovarian insuffi- ciency, amenorrhea, etc. Also indicated in the menopause, especially when dysovarism is complicated with the: fatigue syndrome. 281 No. 85. RENAL CO. (Harrower.) Nephritis : Albuminuria ; Renal Insufficiency. Formula : Desiccated Renal Glomeru- lar Tissue and Pancreas Gland (total) aa gr. 2^. Prescribe : R Renal Co. (narrower). No. C. Sig. 1, q.i.d., a.c. Effects : Tends to reduce renal im- permeability ; lessens albumin elimi- nation through glomeruli ; stimulates renal efficacy ; encourages pancreatic and intestinal physiology. Indications : Acute and chronic Bright's disease with or without albu- minuria ; essential albuminuria with- out other renal (or local) findings ; deficient renal activity. Remarks: For years, renal substance has been recommended for nephritis and albuminuria. Various explanations are given for its usefulness. It has often reduced the urinary difficulties, clinical and laboratory, of nephritis. Addition of pancreas tends to reduce conditions aggravating the renal cells as well as to neutralize adrenal irrita- bility. 282 A THERAPEUTIC INDEX. IT IS to be understood that the ref- erences below are suggestive-an attempt to direct the reader to possi- bilities which may or may not be prac- ticable in a given case. The figures indicate references in the previous chapters, while the italic figures refer to the list numbers of the various formulas enumerated in the Ready Reference List-Chapter XXIII-fol- lowed by the page number in paren- theses. Achlorhydria 115, 12 (266). Acidosis 31, 11 (265). Adrenals, see Hypo- and Hyper-adrenia. Agalactia 59 , 3 (260). Albuminuria 85 (282). Alcoholism, see Hypoadrenia. Amenorrhea 74, 82, 241, 4 & (261), 73 (280), 79 (281). Anemia 120, 163, 254, 13 (267), 68 (279). Arthritis 57 ( 278). Asexualism 74, 240, 70 & 70a (279), 73 (280). Asthenia, see Hypoadrenia. Asthma 26 ( 272). Bed-sores 148, 24 (271). Biliary Insufficiency 5 ( 262), 22 ( 269). Bleeders 167, 24a (271). Blood-Pressure, 22, 82, 88, 131, 171. See Hypertension and Hypotension. Breasts, Painful 80, 4 d 4a (261). Bright's Disease 85 (282). Bronchial Asthma 26 (272). Bronchitis, Chronic 24 <6 24a (271). Burns 148, 154, 24 (271). Cachexia 124 , 68 ( 279). Calcium Insufficiency, see Hypocalcemia. Cancer 125, 193, 40 (274), 68 (279). 283 Cardiac Irritability, see Hyperthyroidism and Sympatheticotonus. Cardiocirculatory Asthenia, see Hypo- adrenia. Cellular Infiltration 91, 177, 8-9 (263), 18 (268). Chilblains 24 (271). Children, Defective 34, 40, 49, 2 (259). Chlorosis, see Anemia and Dysovarism. Colitis, see Mucous Colitis and Ulcers. Conjunctival Ulceration 153, 24 (271). Constipation 40, 91, 1 & la (258), If & lta (261). Convalescence, see Hypoadrenia. Corneal Ulcer 148, 154, 24 & 24a (271). Cretinisrp 38, 43, 2 (259), 8-9 (263). Deafness 91, 1 (258), 1/ (261). Debility, see Hypogonadism. Dementia Prsecox, see Insanity. Demineralization 31, 11 (265). Dermatoses 4 & (261), 8-9 ( 263), 57 ( 278). Developmental Dystrophies, see Children, Defective. Diabetes Mellitus 117, 198, 2 1 0, 11 (265), 44 (275). Diminutivism 44, 2 (259). Drug Addiction, see Hypoadrenia and Sympatheticotonus. Duodenal Ulcer 148, 152, 24 & 2Jta (271). Dysmenorrhea 74, 4 & Jta (261). Dysovarism 72, 75, 103, 108, 180, 195, 247, 4 & (261), 73 (280), 79 (281). Dyspepsia 112, 115, 12 ( 266), 15 ( 268). Dyspituitarism, see Hypopituitarism. Eczema 8-9 (263). Endocrinasthenia, see Hypoadrenia. Enteritis, see Mucous Colitis. Enuresis 8-9 (263). Epilepsy 45, 46 , 2 ( 259), 47 (276). See also Ovarian Epilepsy. Epistaxis, see Bleeders. Erethism, see Hyperovarism and Nympho- mania. Exophthalmic Goiter, see Hyperthyroidism. Fatigue Syndrome 18, 81, 1 & la (258). Flatulence 115, 12 (266), 15 ( 268). 284 Flooding 74, 82, 93, 49 (274). Follicular Conjunctivitis 154, 24 (271). Frohlich's Syndrome, see Hypopituitarism. Frigidity, see Asexualism. Gall-Stones 92, 22 (269). Gastric Ulcer 148, 24 (271). Glycosuria 103, 181, 205, 44 (275). Goiter, Endemic 127, 18 ( 268). Goiter, Pubertal 128, 132, 4 4« (261), 18 (268). Goiter, Simple 127, 18 (268). Gonad Insufficiency 219, 70 d 10a (219). Gonadopause 183, 217. Graves' Disease, see Hyperthyroidism. Growth Dystrophies, see Children, Defec- tive. Hay-Fever 24 2401 (271). Headache, Menstrual 88, 4 d 4a (261). Headache, Pituitary 9, 77, 89, 4 4® (261),. 47 (276), 73 (280). Headache, Thyroid 88, 8-9 (263), 18 ( 268). Hemophilia 167, 24a (271). Hemorrhage, Pulmonary 167, 2Jta (271). Hemorrhage, Uterine 74, 82, 40 (274). Hepatic Torpor 113, 5 (262), 22 (269). Hyperadrenia 88, 90, 173, 236, 6 (262). Hyperemesis Gravidarum 227, 49 (277). Hyperovarism 82, 190, IfO (274). Hyperpituitarism 237. Hypertension 82,88,171, 185, 29 or 30 (212). Hyperthymism, see Thymus, Persistent. Hyperthyroidism 33, 90, 99, 191, 254, 6 (262). Hypertrichosis 95. Hypoadrenia 17, 25, 26, 139, 1 d la (258), 79 (281), Hypocalcemia 145, 165, 251, 24 d 21/a (211). Hypochlorhydria, see Dyspepsia. Hypocholia 137, 22 (269). Hypogalactia 59, 3 (260). Hypogonadism 234, 10 d 10a (219). Hypopepsia, see Dyspepsia. Hypopituitarism 4? (276). See also Head- HypotenMon'S^S, 1 d la (258), 79 (281). Hypothyroidism 91, 177, 184, 191, 236, 249, 1 d la (258), 4 & ia (261), 8-9 (263), 18 (268). 285 Impotence 236, 239, 70 <g 70a (279). Indigestion 112, 12 (266), 15 ( 268), 22 ( 269), 23 (270). See alsp Ovarian Indigestion. Infantilism 34, 43, 7 4, 241, 2 (259), 70 d 70a (279), 73 d J,a (280 d 261). Infections, Focal 100, 246. Infiltration, Cellular 91, 177, 8-9 (263), 18 (268). Influenza, see Hypoadrenia. Insanity 28, 81, 89, 1 d la (258), J, d 4a (261). Intestinal Atonia 28, 136, 1 d la (258). Intestinal Protozoa 21, 107. Intestinal Stasis 28, 135, 1 d la (258), 5 (262). Intestinal Toxemia, see Hypocholia and Dyspepsia. Intestinal Ulceration 139, 24 (271). Lactation, Deficient, see Agalactia. Leg Ulcers 148, 152, 24 (271). Low Blood-Pressure, see Hypotension. Malaria, see Hypoadrenia. Maldevelopment, see Children, Defective. Male Gonadopause 183, 217, 70 70a (279). Malnutrition 113, 124, 166,5 (262), 15 ( 268). Mastodynia 80, 1, d J,a (261). Melancholia, see Insanity. Menopause 78, 85, 93, 95, 181, 196, 1, d l,a (261), 73 (280), 79 (281). Menorrhagia 74, 82, 93, 188, 195, 40 (271,). Menstrual Disorders, see Dysovarism. Metritis, Hyperplastic, 1,0 (274). Metrorrhagia 188, 197, 40 (274). Milk Production, see Agalactia. Mongolism 34 , 38 , 2 ( 259), 8-9 ( 263), 47 (276). Mucous Colitis 134, 141, 22 (269), 21,(271). Myasthenia, see Hypoadrenia. Myocarditis 6 ( 262). Myxedema 91, 184, 8-9 (263), 4 (261). Nausea of Pregnancy 227, 49 (227). Nephritis 85 ( 282). Neurasthenia 19, 26, 76, 89, 220, 1 & la (258), !, & Jta (261), 70 d 70a (279), 79 (281). Nose Infections, see Ulceration. Nymphomania Jfi (27Jt). 286 Obesity 53, 91, 179, 4 d 4a (261), 47 (276). Otitis Media 148, 251, 24 (271). Otosclerosis, see Tinnitus. Ovarian Dysfunction, see Dysovarism. Ovarian Epilepsy 47, 51, 58, 4 d 4a (261), 73 ( 280). Ovarian Indigestion 118, 196, 4 d 4a (261). Ozena 148, 253, 24 d 24a (271). Pancreatic Diabetes, see Diabetes Mellitus. Pancreatic Indigestion 115, 15 ( 268). Paralysis Agitans 146, 24 (271). Pernicious Anemia 125, 13 (267), 68 ( 279). Pituitary Disease, see Hypo- and Hyper- pituitarism. Placental Toxemia, see Vomiting of Preg- nancy. Postpartum Disorders, see Metrorrhagia and Subinvolution. Also Agalactia. Presenility, see Hypogonadism. Prostatic Hypertrophy 218, 221, 41 (274), 48 (277). Prostatic Neurasthenia 220, 48 (277). Protein Sensitization 106. Remineralization 11 (265). Renal Impermeability 85 ( 282). Rheumatic Arthritis 57 (278). Rheumatism 92, 1 (258), 4 ( 261). Run-Down Conditions, see Hypoadrenia. Sepsis, Chronic 148, 24 <f 24a (271). Sinusitis 148, 252, 24 (271). Speech Defects 42, 44, 2 (259). Sprue 140, 151, 252, 24 d 24a (271). Sterility 74, 240, 73 d 4a (280 d 261). Subinvolution 67, 3 (260), 40 (274). Sympatheticotonus 102, 110, 135, 254, 6 (262). Tetany 146, 24 (271). Thymus, Persistent 108. Thyroid, see Hypo- and Hyperthyroidism. Thyroid Function Test 104, 129, 10 (264). Tinnitus 91, 2 4 9, 8-9 ( 263), 18 ( 268). Tropical Hypoadrenia 21, 1 & la (258). Tuberculosis 18, 149, 157, 1 £ la (258), 24 a 24a (271). 287 Ulcers 144, 152, 252, 2J> & 24a (271), see also Hypocalcemia. Uterine Bleeding, see Menorrhagia. Uterine Fibroids 193, 194, 40 (274). Uterine Subinvolution, see Subinvolution. Varicose Ulcer 148, 152, 24 (271). Virilism 95. Vomiting of Pregnancy 227, J/9 ( 277). 288