[The U.S. Department of Health, Education, and Welfare Public Health Service presents T - 1780, V - 1780, MCMLXIX]

[A National Medical Audiovisual Center Production]

[Celso-Ramon Garcia, M.C.]

[Dr. Garcia:] I am Celso-Ramon Garcia, Professor of Obstetrics and Gynecology at the University of Pennsylvania. 

It is my position that the oral contraceptives when prescribed, used, and supervised properly

present the function for which they were designed with acceptable minimal morbidity.

[Louis Lasagna, M.D.]

[Dr. Lasagna:] My name is Louis Lasagna, I'm a clinical pharmacologist from the Johns Hopkins University School of Medicine. 

In my opinion the unpleasant side effects and the very real hazards associated with the oral contraceptives

are of sufficient magnitude as to constitute a real deterrent to their use as a birth control technique.

[Sheldon Segal, M.D.]

[Dr. Segal:] I am Sheldon Segal. I'm the Director of the Biomedical Division of the Population Council

at the Rockefeller University in New York.

I shall act as moderator of the discussion of this important and timely topic.

[Music]

[Concepts and controversies in modern medicine]

[The Oral Contraceptives]

[Host:] Welcome to the exploration of concepts and controversies in modern medicine, 

one of a series of programs dedicated to examining the uncertain,

candidly recognizing that much of today's teaching is necessarily based upon opinion,

and that the opinions of eminent physicians in a given field vary widely. 

The National Medical Audiovisual Center believes that openly airing such opposing views 

is a basic responsibility of medical communications.

Dr. Sheldon Segal, Director of Population Council, Rockefeller University,

will act as moderator of this presentation. 

[Dr. Segal:] American women are interested in oral contraceptives. 

They are using these drugs at the rate of over 2500 tons a year. 

It is estimated that perhaps one out of every three American women married between the age of 15 and 44,

has used or is using the oral contraceptive.

It is being prescribed by virtually every physician in the country. 

On the other hand, we are well aware of the fact that women using this drug

are not normal with respect to many laboratory parameters of medical normalcy or of physiologic function. 

We know, for example, that several of the circulating hormones

are not within the normal range in women using oral contraceptives; 

this refers to example to the circulating level of glucocorticoids.

We are aware of the fact there's an evidence 

of altered carbohydrate metabolism for women using oral contraceptives,

at least a significant percentage of them. 

There's also evidence of decreased liver function 

as evidenced by certain laboratory tests. 

How is it then, that in the face of this rather perplexing enigma,

physicians continue to prescribe the drug 

and feel that they are doing so for the well-being of their patients? 

These are some of the issues we would like to explore.

We will first have a statement from Dr. Garcia.

[Dr. Garcia:] The ease, convenience and utter effectiveness of the steroid contraceptive

is universally felt to distinguish it from other forms of contraception.

[Celso-Ramon Garcia, M.D.]

Never before in the history of the world have the untoward effects

of pharmacological agents so consistently

and so confusingly been presented to a more sophisticated world. 

[inaudible] these issues are the fears of the unknown itself,

criticisms from the persons opposing contraception in any form,

and the bias of medical attitudes, 

the belief that pregnancy is good and not associated with hazards,

and then, further, moral issues are entertained.

Basically the education of physicians imbues him with the philosophy,

the need, to preserve life and to avoid harmful approaches. 

This, moreover, is extended to mean that errors of omission

are less serious, less ominous,

than the errors and the acts of comission. 

Active contraception, because of this philosophy, 

cannot be favored openly. 

The concept of health however, must consider the composite

of physical, mental, and social well-being,

rather than mere absence of infirmity and disease. 

The oral contraceptive by virtue of its utter effectiveness, 

and the convenience which it entertains,

contributes to the health of the individual,

despite the many disadvantages that have been pointed to. 

The irresponsible adverse comments about potential harmful effects

do not contribute to the health of the individual. 

Many of these accusations have been made. 

Moreover, an unabated population press is also menacing. 

Actions of the pill affect all body systems to a greater or lesser degree. 

These actions are a resultant of the combination of the end results

of both direct effects on target organs as well as the indirect effects, 

which are mediated by alterations induced in the endocrinologically active areas. 

The metabolic alterations that have been discussed

and pointed to as occurring with the use of the oral contraceptives

have all been shown to be reversible when these agents are discontinued. 

Many of the reported effects are very difficult to classify

as to whether they are drug-induced or nondrug-induced. 

Causality and association may not be synonymous. 

The epidemiologic studies of themselves do not resolve the matter convincingly,

Although there are massive data, there are no truly comparative studies 

nor are the statistics of sufficient validity

to resolve the association and causality controversy with absolutism.

Clinical judgment is very much required.

Physicians cannot shirk their responsibility.

They must use care and continued supervision in prescribing and in supervising

and caring for the subjects using this form of contraception. 

There is no effective, no more effective approach to contraception that can be pointed to,

and prevention of pregnancy must be considered an all or none principle. 

The purported risks of oral contraceptives are of small incidence,

and by and large are outweighed by the apparent risks

associated with pregnancy and even the toll of daily living. 

No pharmacological agent can be considered to be totally safe. 

Individuality is cherished, making an ideal contraceptive almost impossible to achieve.

Many more effective and convenient ones are needed.

[Dr. Segal:] Dr. Lasagna, would you make your opening statement please?

[Dr. Lasagna:] Yes, since the beginning of the modern era of chemotherapy, 

since the time of Paul Ehrlich, let us say,

those interested in the development of new chemicals have been searching for magic bullets, 

[Louis Lasagna, M.D.]

for drugs that would pick out the offending microorganism

or would hit a specific organ in the body,

and leave relatively untouched the rest of the body, 

leave the patient relatively unharmed. 

Almost without exception, perhaps without exception one should say,

this dream of a magic bullet has not been fulfilled. 

Drugs are more like buckshot than they are like magic bullets, 

and the oral contraceptives in my opinion illustrate this beautifully. 

As has been already said, they seem to hit almost every cell in the body. 

With each passing year we have become aware of the ability 

of these chemicals to affect many parts of the body. 

We have heard of changes in the skin, changes in the hair, 

alterations in libido, 

not always in the appropriate direction.

We've heard of changes in the liver, 

disturbances in blood-clotting,

with thromboembolic phenomena manifesting themselves 

in various parts of the body. 

We've heard of depression apparently associated

with some women with the use of the pill. 

We've heard of severe and excruciating migrainous headaches

developing in some women for the first time on starting oral contraceptives. 

We are now beginning to develop more and more a fear

of the potential for development of cancer in either the breasts or the genital tract 

in women exposed for years to these hormones. 

Now when one takes all of those reports, 

and this buckshot capacity of these powerful chemicals,

and combines that with the knowledge that other methods of contraception are available,

which, while are not quite as effective as the oral contraceptives, 

are nevertheless, in the hands of many women extraordinarily effective, 

I believe it irresponsible for a physician to look upon these pills

as a method of first choice for most or all women desiring birth control.

[Dr. Segal:] Well, we have an interesting situation here in which Dr. Lasagna,

you believe that it's irresponsible for physicians to be prescribing the pill

as the contraceptive of first choice,

and you Dr. Garcia, believe that it's irresponsible

to be criticizing the potential hazards of the pill.

[Dr. Lasagna:] I said not for all women as a method of first choice, 

I believe it is the method of first choice for some.

[Dr. Segal:] Right.

I think that there probably exists a difficulty here

in defining just what the precise position of each discussant is. 

Perhaps I could help to resolve this by asking two pointed questions, one to each of you.

To you, Dr. Lasagna, I would ask do you believe that the oral contraceptives 

as are now being used should be withdrawn from the market?

And to you, Dr. Garcia, do you believe that the safety of these drugs

is adequate to permit their widespread use without medical prescription? 

Dr. Lasagna?

[Dr. Lasagna:] Well, I have for some years now

been beating the drum, trying to alert people to the possible hazards

of the oral contraceptives.

I have never and do not today espouse to physicians

that these medicaments should be removed from the market.

I think they continue to play a very important role in birth control.

[Dr. Garcia:] There is no question that the controversy that exists

is really not as deep as it appears at first glance. 

On the one hand, it's a matter of how one weighs out the relative merit.

There is no question that, as I indicated in my opening statement, 

that the physician cannot shirk his responsibility. 

He has to supervise his patients adequately, completely.

He cannot just prescribe the oral contraceptive, 

nor can the oral contraceptive be dispensed over the counter, nor in slot machines. 

There are sufficient warnings from the studies and epidemiological reviews,

and while they do not point with absolute [inaudible],

I quite concur that these must not be left unheeded.

One must continue to review the problem with this very much in mind. 

However, the aspect of the hazards of not taking the oral contraceptives

and when I say not taking the oral contraceptive, 

I am really referring to not taking or not using really effective methods of family planning. 

And when you get down below six pregnancies per 100 women a year,

you are dealing with relatively effective methods.

Above this, and most of the methods that have been evaluated

and not associated with the need for a physician,

are in the category of being relatively ineffective. 

And when you're dealing with this, as I indicated also,

the need for considering the philosophy that contraception is an all or none principle, 

when a woman comes to me she, doesn't want to be half-safe, 

she wants to have complete protection, this is what she's asking for. 

The unwanted pregnancy raises the great scepter

[Celso-Ramon Garcia, M.D.]

and I think here we have increases in maternal and fetal mortality, 

we have increases in other morbidities, 

we have increased hazard of the induced abortion itself, 

even in the best of hands there are hazards with this approach. 

There are increases in the undesirable marriages

that might result without the availability of effective contraception. 

There are also the trauma and other features

with regard to illegitimacy and the increase in the undesirable parental behavior

towards the offspring, which I've seen with great frequency in our society today.

[Dr. Segal:] Dr. Garcia, I don't think there's any argument about the relative advantages

to the woman and to the society at large derived from the use of contraception. 

I think it's sometimes unfortunate that people consider as synonyms

contraception on the one hand and oral contraception on the other. 

Many of the benefits in terms of maternal health of which you speak

are derived from virtually all effective contraception,

and for women in many of our socioeconomic classes, effective contraception includes 

not only oral contraception but the intelligent use of the diaphragm,

use of the intrauterine device, 

and in fact the intelligent use of the method of periodic abstinence. 

But I think that from the response that both of you made,

it's clear that you have each weighed the equation of relative risk and benefit,

and come to the conclusion that there is enough safety in the use of oral contraception

to warrant the continuation of its use in the country. 

So let us focus now on the question of these hazards and risks, 

so that those in the audience can make their own judgments

about this balance of the hazards on the one hand

and the effectiveness and usefulness on the other.

[Dr. Lasagna:] I'd just like to comment on...

[Dr. Segal:] Sure.

[Dr. Lasagna:] Dr. Garcia's statement about women wanting 100 percent protection, 

I don't think all women want 100 percent protection,

and I think this is one of the reasons why there is such a tremendous variability 

in the reports in the literature on the effectiveness of such things as condoms and diaphragms. 

I think the condom and the diaphragm used compulsively 

represent extraordinarily effective techniques. 

But if you're casual about their use, 

if you want a child or two sometime in the future

and don't really care all that much whether it occurs a year from now or two years from now,

I think one has a different approach to the use of these mechanical devices

than the woman who has had four or five children, considers her family complete,

and is darn likely to be compulsive about the use of these techniques. 

So that I think in the interest of individualizing our approach to these women,

I think it would be unfortunate to give the impression that every woman wants 100 percent protection...

[Louis Lasagna, M.D.]

furthermore, if I can just complete my thought,

with the oral contraceptives one doesn't have 100 percent protection,

at least not with the sequential ones, which in my experience, 

the number of anecdotal reports I've come across,

talking with patients, with obstetricians, the failure rate is significant there.

The protection is far from complete.

[Dr. Garcia:] Well, I quite agree that one has to individualize; 

however, I again, the point that one might take at issue here,

mainly that the patient that has four or five pregnancies

could likewise be categorized as being in the upper age group,

where she's going to fall within the category of having greater risk

with taking the oral contraceptives. 

So it's not such a simple matter, and as a gynecologist,

I don't know what your experience is as a clinical pharmacologist,

but as a gynecologist, 

when I query my patients they want an all or none sort of reassurance

and very few of them elect to take sequential modalities.

[Dr. Segal:] Can we pass now to the question of the hazards themselves, 

you pointed to Dr. Lasagna's worldwide reputation as a clinical pharmacologist,

so perhaps we should ask him about some of these issues 

that have been raised with respect to the safety of the pill. 

Let's take the cancer issue first.

Where does that stand and what are the real facts in that situation, Dr. Lasagna?

[Dr. Lasagna:] I don't think there are a lot of hard facts to go on here.

We have a long background of experimental evidence suggesting that hormones

can be utilized in a number of animal models

to produce things like breast cancer, that's clear. 

The relevance of these studies to the use of these hormones

in the variety of clinical states in which they have been used 

for a long time is unclear to me. 

I think we're beginning to have reports on certain changes 

in the cells in the cervix that make one at least worry more 

than we've been worrying in the past,

and in my opinion at the moment the issue is an open one. 

I think with the background that we have on what these hormones can do in the laboratory,

it would be foolish to assume that we have no worries, 

but I also would say that at the moment, the evidence implicating these oral contraceptives 

in the production of any kind of cancer is lacking. 

I think the evidence, for example, is much more compelling 

in regard to thromboembolic disease.

[Dr. Segal:] Still for a moment on the cancer issue--on the basis of the animal work isn't it more likely that the real concern is the breast rather the cervix?,

[Dr. Lasagna:] I think so, yes.

[Dr. Segal:] And have there been any clinical observations,

or let me put it even more fundamentally, 

has anyone actually done a study that would give us some idea

as to whether or not there is a causal relationship?

[Dr. Lasagnal:] I'm not aware of any. 

It's a great pity, I think, that so little attention has been paid

to the setting up of prospective studies to monitor all these things

that we're concerned about and that we have a hard time making definite statements about,

because we're stuck with retrospective analysis.

[Dr. Segal:] You've been mostly involved with this.

[Dr. Garcia:] Attempts to set up prospective studies have been, in later years, tried... 

One of the greatest difficulties, and one of the things that

I think is new to most of the scientific world in clinical lines of investigation,

that is to sample a denominator that is as vast as is required

to measure small changes in the numerator, 

is indeed a task that I don't know if it would ever be accomplished

or not with reference to the oral contraceptives. 

There's so many other factors that come into the bias of selection and the like,

that it's difficult to do this, and what's more to try to have a truly controlled population

that is not using the steroid contraceptive [inaudible] is likewise very difficult

because the steroid contraceptive group feel more compelled

because of the adverse [inaudible] to come back to be seen more frequently. 

While those on other techniques are much more difficult to follow

and this has been one of the greatest pitfalls that we've had in trying to arrange for prospective studies. 

I don't know how to get around that.

[Dr. Segal:] But I think that there are good epidemiologic methods

to account for this bias or to take it into account

in setting up the design of the study. 

But let me turn to another issue, 

I think the one that has been most firmly established among the possible serious consequences 

of the use of oral contraception has been the epidemiologic studies and indications 

of an increased risk of thromboembolic disease associated with the use of the drug. 

In studies both in Britain, and now on the basis of the recent report by

the Advisory Committee of Obstetrics and Gynecology of the Food and Drug Administration 

confirmed here in the United States.

Can you tell us how that stands and what your view of that issue is, Dr. Garcia?

[Dr. Garcia:] I...there is a strong warning that this presents.

I don't know that this conclusively proves that there is a cause and effect relationship,

and I think that as I indicated previously, epidemiologic reviews will not do this. 

We're still lacking many of the mechanisms to explain the occurrence of these thromboembolic and other effects,

and until this gap has been bridged to demonstrate the mechanism of action that will produce the effect,

we still will not have a cause and effect relationship,

but nonetheless these studies are very carefully designed

and performed according to sound epidemiologic principles,

and consistently, although with different variants of incidence and points of comparison. 

We have a concurrence with all of the studies indicating an association between the use of oral contraceptives 

and the occurrence of thrombophlebitis, 

and also consistently that risk is seen greater in the older age group than the younger age group.

[Dr. Lasagna:] May I comment on the quality of the evidence linking the contraceptives to...oral contraceptives to clotting, 

one thing I know something about is the difficulty of linking drugs 

to side effects that are said to be associated with them.

But in my opinion, the evidence on this point is so good as to be very compelling,

at least it's so much better than we usually have for other drugs 

that I think one can't ignore the evidence. 

The evidence exists in my opinion, not only in the form of epidemiologic data, 

but in the clotting studies that have been done,

which in almost all instances have shown a change in women taking these pills 

in the direction of increased clotting. 

The peculiar distribution of some of these clots that they're seeing, 

women coming in with clots in the veins of their arms, a most unusual phenomenon. 

Clots in the vertebral arteries in young women, 

a most unusual neurological picture, and then the challenge cases, 

the women who develop recurrent thrombophlebitis each time they're given the pill. 

There aren't a lot of those,

but there are enough I think to represent a legitimate challenge type of evidence.

[Dr. Garcia:] But this sort of bizarre type of location of thromboembolic phenomenon is not new, 

it's just that it hasn't been focused attention on in association 

with the use of oral contraceptives, number one, 

and secondly we have to also consider that...

[Dr. Segal:] I'm afraid, Dr. Garcia, I'm not going to let you finish your thought because our time is up. 

In the few seconds left to us,

I'd like to attempt a brief summary of this discussion. 

It seems to me that we have reached a consensus

that this is a type of medication that does involve risk. 

Both participants agree that the risk is not so great 

to warrant removal of these drugs from the physician's armamentarium. 

I think that both agree also, however, 

that when these drugs are used, they must be used under very careful supervision 

and although the point wasn't raised I feel confident that both would agree 

that the labeling instructions required 

by the Food and Drug Administration should be adhered to very strictly. 

As with all drugs, there is a question of relative risk versus relative advantage in determining safety. 

On that basis and by that definition,

it seems that there is an element of safety 

sufficient for continuation of the use of oral contraceptives.

[Host:] We thank Dr. Celso-Ramon Garcia, Dr. Louis Lasagna, and Dr. Sheldon Segal 

for their interesting analysis of a critical problem in patient care. 

In subsequent programs, we shall continue to record equally significant concepts and controversies in modern medicine, 

The opinions expressed on this program do not necessarily constitute endorsement 

by the Department of Health, Education and Welfare, the Public Health Service or its constituents.

[Music]

[Celso-Ramon Garcia, M.D., Professor of Obstetrics and Gynecology, Hospital of the University of Pennsylvania]

[Louis Lasagna, M.D., Associate Professor of Medicine and of Pharmacology and Experimental Therapeutics, Johns Hopkins University School of Medicine]

[Sheldon Segal, M.D., Director, Population Council, Biomedical Division, Rockefeller University]

[concepts and controversies in modern medicine]

[The End, T-1780, V-1780, MCMLXIX]