Anonymous
01-30-2006, 10:35 PM
LEDA at Harvard Law School
The Rise and Fall of Estrogen Therapy:
The History of HRT
Carla J. Rothenberg
Harvard Law School, Class of 2005
April 25, 2005
This paper is submitted in satisfaction of the Food and Drug Law course requirement and the third-year written work requirement.
Abstract: This paper explores the history of hormone replacement therapy (“HRT”). It focuses on the development and marketing of HRT drugs, the regulation of HRT by the Food and Drug Administration (“FDA”), and the effect medical studies have had on the development, marketing, and regulation of HRT over the years.
First, a discussion of the difficulty of defining menopause is explored.
Second, the early history, treatments, and attitudes towards menopause are described.
Next, the discovery, manufacture, and FDA approval of estrogen are detailed. The subsequent section examines how the pharmaceutical industry created a perception of menopause as a disease in all midlife women.
Then, the cost-benefit analysis of HRT is explored through medical studies’ connection of HRT to various diseases.
Finally, the aftermath of the landmark Women’s Health Initiative study is discussed, followed by a few concluding thoughts on what we can learn from the history of HRT.
Introduction
Apparently, in the year 2005, women are still a mystery, even to themselves. Presently, millions of American women near, at, or beyond menopause are confused over estrogen, the female hormone – or, more specifically, estrogen as hormone replacement therapy (“HRT”). Estrogen products were first approved by the Food and Drug Administration (the “FDA”) in 1941 for the direct symptoms of menopause: hot flashes and night sweats, vaginal dryness and atrophy.
In the following decades, estrogen (either alone or combined with progesterone) had acquired a reputation as an antidote to many of the illnesses and afflictions of aging, and even as a preventative drug for such diseases as osteoporosis, heart disease, and Alzheimer’s.
Scores of observational and case studies supported the overwhelmingly positive view of hormone replacement therapy, and naturally drug makers and their advertising agencies enthusiastically embraced estrogen as well. After all, this was a billion dollar business.
This is not to say that hormone replacement therapy didn’t have its share of ups and downs in the 60-plus years since it was FDA-approved.
It did: links to uterine cancer led to a course-correction – the addition of progesterone to help mediate some of the complications for women who still had a uterus (i.e. no hysterectomy).
And later, more links to other cancers presented themselves. But not until the Women’s Health Initiative study was abruptly halted in 2002 were many of the long-heralded benefits of hormone replacement therapy seriously questioned.
Ever since the premature stop of the WHI study, estrogen has been thrown back into the world of the unknown. The benefits of temporary use of estrogen for which it was initially-approved in 1941 have not been heavily challenged; rather, the major criticism of HRT today focuses on the risks and effects of long-term use for menopausal symptoms as well as for diseases and purposes other than menopause.
The current question is how women should weigh the risks and benefits of using estrogen, because the advice and scientific findings are uncertain at best. An analysis of this question is beyond the scope of this paper (and the knowledge of this author); rather this paper focuses on the history of hormone replacement therapy.
What is menopause?
Since hormones, up until recently, have been promoted as a cure-all for the symptoms of menopause, a good starting question is what is menopause, and what are the symptoms of menopause? If we believe that taking hormones can eliminate a whole range of real or potential problems, then a long regimen of hormones may seem very attractive.
But if hormone therapy can only deal with a more limited range of symptoms, the wisdom of taking hormones for years may not be as salient.
Menopause, in its most simple definition, is the time in every woman’s life when her period stops, and a woman has technically “reached” menopause when she has not had a period for 12 months in a row.[1] Meno is derived from the Greek word for month, and pause is derived from the Greek work pauses, or halt.[2]
It is a normal part of aging for women, and it occurs generally between the ages of forty-two and fifty-eight years old, with the median age at 51.[3] During menopause, a woman slowly produces less of the hormones estrogen and progesterone.[4]
Although not every woman going through menopause experiences a noticeable change as a result of the decreased estrogen and progesterone levels other than cessation of menses, many women do experience various symptoms, and varied degrees of symptoms.[5] This is why menopause is often referred to as “the change” or “the change in life.”[6]
But one of the problems of referring to menopause as a “change,” other than simply referring to having a monthly period and then not having one, is that many people (including the medical profession) conflate aging with menopause. Menopause is not synonymous with a woman’s midlife; rather it is an event of her midlife.
As a result, many well-respected medical organizations have lists of symptoms that vary wildly and include many symptoms that are best viewed as part of aging instead of specific to menopausal women.[7] There are a few symptoms that everyone can agree on, though. These symptoms may include one or more of the following, both as a woman approaches menopause, and also continuing through menopause:[8]
Changes in the menstrual cycle, such as a difference between the time between periods or a different flow.
Hot flashes (also known as “hot flushes"), which includes getting warm in the face, neck and chest.
Night sweats. (Both hot flashes and night sweats are also referred to as vasomotor symptoms).
Vaginal changes, also referred to as vulvar and vaginal atrophy, when there is dryness, itching, burning, or thinning of the vagina; these changes are also associated with sex becoming painful.
Women who experience significant problems from these symptoms are about 5-15% of the menopausal population.[9] Most of the other supposed mental and physical symptoms of menopause, such as depression, irritability, and sleeplessness are either equally as applicable to midlife men as they are women, or the peak of their occurrence in women preceded menopause and are the result of chronological age or premenstrual syndrome.[10]
The loss of estrogen at menopause has also been highlighted as the major cause for osteoporosis, or thinning of the bones, and thus osteoporosis has been listed by the FDA as a symptom of menopause.[11]
But osteoporosis, which may lead to loss of height and bone breaks, is as much due to old age as it is to a decrease in estrogen, and as such, can be conflated as a symptom that is specific only to menopause.[12]
The Early History of Menopause and its Treatments
One of the earliest known references to menopause is from an Egyptian medical text dated 2000 B.C.: “If a menopausal woman has pain or makes trouble, pound her hard on the jaw.”[13] Today’s woman going through menopause would almost certainly object, not only to the violence but also to the mere temporary distraction from a sometimes painful, long experience with menopause!
Present treatments for difficult menopausal symptoms do not involve a good hard smack, but rather are more likely to be a mixture of diet, exercise, herbal remedies, and prescription remedies.[14] A medical textbook from the era of Renaissance Europe, almost 500 hundred years ago, reflects a similar treatment to today’s standards, recommending an herbal remedy with exercise.[15]
Specifically, the medical text recommended a “decoction of myrrh and apples” for women who were experiencing problems with menopause, and if that did not work, “a cure may sometimes also be affected by pouring some of this same substance into her sandals, and urging the patient to walk.”[16]
In the 1899 Merck Manual Diagnosis & Therapy, a coarse brown powder named Ovariin was prescribed for “climacterica,” which is another name for menopause, and other ovaries-related problems.[17]
Ovariin was an oral medicine derived from the dried and pulverized ovaries of a cow, and though a primitive attempt at medicating menopausal symptoms, the director of the NIH Women’s Health Initiative, Dr. Jacques Rossouw, believes that it may have had some estrogenic effect.[18] The 1899 Merck Manual also contained an additional twenty-eight treatments for woman’s climacteric.[19]
One of the conclusions from this observation is that menopause is not necessarily a phenomenon of the modern age, as doctors, pharmaceutical companies and writers might suggest.
One school of thought argues that as a result of the considerable increase in average life expectancy in the past 100 years, women have “outlived their ovaries,” and thus menopause is simply an artifact of an unexpected recent increase in life span beyond reproductive age.[20] However, there is a fair amount of credible research countering such assertions.
For example, an article by Thomas Perls and Ruth Fretts in the Annals of Human Biology suggests that just because the average life span has increased over the years, it does not mean that there were not plenty of adults living into what we would consider “old age,” and in fact, the mitigating factors of increased death at childbirth a hundred years ago had a skewing effect on the average life expectancy.[21] The article goes on to refute the “outliving one’s ovaries” explanation by arguing:
Firstly, though average life expectancy has increased markedly in just the past century, the human life span has been significantly longer than the age of menopause, probably since the time menopause evolved.
There is no evidence to indicate that we have done something special as a species in even the past millennium that would facilitate a doubling or tripling of the human life span.
Certainly there is evidence from Ancient Greece indicative of elder statesmen living well into their 80s and early 90s. Secondly, if menopause was simply an artefact, we would not expect, over the course of evolution, a natural selection for genes that influence when menopause occurs.
Contrary to this supposition, genetics does appear to play a role in the timing of menopause; and finally, the nonadaptive hypothesis begs the question of why would the reproductive system fail long before other systems, such as the cardiovascular system?[22]
As such, since menopause is not necessarily a new phenomenon, rather just a more noticeable increase in the incidence of menopause, it is not surprising when books from more than a century ago discuss menopause at length. Some books from more than a century ago viewed menopause as a period of adjustment rather than a disease, and they also wrote about the “change” in validating terms.[23] For example, in George Napheys’ 1869 book The Physical Life of Women: Advice to the Maiden, Wife, and Mother, he wrote that:
after a certain number of years, a woman lays aside those functions with which she has been endowed for the perpetuation of the species, and resumes once more that exclusively individual life which has been hers when a child.
The evening of her days approaches, and if she has observed the precepts of wisdom, she may look forward to a long and placid period of rest, blessed with health, honored and loves with a purer flame than any which she inspired in the bloom of youth and beauty.[24]
French physicians of the same time also viewed menopause in a positive light, seeing it as a return to more carefree days, and referring to this period as le retour d’age, meaning a return to youth before the time of fertility.[25] In this same spirit, some doctors of the time were urging their female patients to “view menopause as an opportunity to reclaim their lives and to avoid harsh medicines, as hot flashes were natural and not an illness.”[26]
And in a interesting view that seems to fit nicely in with contemporary recommendations by the FDA and women’s health organizations, Thomas Graham wrote in his 1837 book, The Diseases of Females, that with the exception for attention to diet and exercise, “little or nothing is required for the management of ordinary cases.”[27]
Though these books do exist, and some doctors viewed menopause in a positive light, for the most part, this attitude really was an exception to the rule; through the late 1960s and the beginning of the women’s movement, overall attitude of menopause was that people didn’t discuss it and it was generally an embarrassing problem.[28]
Women, prior to the women’s movement in the 1970s, were thought to be ruled by their hormones and thus were inferior to men, making menopause a shameful secret.[29]
Women were embarrassed to admit they were going through menopause, and thus did not seek advice for menopausal symptoms, because it would signal the end of their active life.[30]
The Discovery and Manufacture of Estrogen
The modern treatment of menopausal symptoms can be traced back to the pharmaceutical company Merck & Co., Inc., because Merck was the leader in the field of capitalizing on the use of animal glands in medicine.[31]
Through the time of World War II, however, drug companies were small-time concerns, making patent medicines that people could buy over the counter at pharmacies, while doctors were likely to use pills and potions made to their own recipe.[32]
The pharmaceutical revolution changed this around the time of World War II, with the discovery and large-scale production of sulfanilamide, and subsequently penicillin, streptomycin, and an explosion of antibiotic products.[33]
At first, it was not research by pharmaceutical companies, but rather research by scientists, such as Dr. Charles Edouard Brown-Sequard, Dr. Edgar Allen, and Dr. Edward Doisy, that led to the current formulation of estrogen.[34]
Dr. Brown-Sequard’s announcement in 1889 that he had “rejuvenated himself” by injecting “sensitive parts of his body” with a mixture of guinea pig and dog testicle extracts, led to a flurry of research during the 1890s into the field of sex gland extracts as a fountain of youth.[35]
In particular, Dr. Allen and Dr. Doisy teamed up to unlock the key of estrogen research.[36] From 1923 through 1938, they established the existence of estrogen and described its effects, as well as identified all of the female hormones and the relations among them.[37]
By the end of their research, the field of hormone research was hot for scientists as well as pharmaceutical companies develop new drugs they could market.[38]
The drug manufacturers saw the hormone research as having the potential for curing a wide range of ills, but also having major benefits for those who were not suffering from any problems in the first place.[39]
The drugs had the potential for use for menopause, menstruation, beautiful unwrinkled skin, thicker hair, more passionate sex, curing infertility, and birth control, just to name a few.[40]
Drug manufacturers believed that their profits would skyrocket as a result of these drugs, and went out courting scientists, especially biochemists such as Dr. James Bertrand Collip.[41] Dr. Collip, co-discoverer of insulin in 1922, was courted by W.J. McKenna of Ayerst[42] Laboratories in 1929, and in 1930 the partnership of Collip and Ayerst Labs produced its first product.[43]
The product, called Emmenin, was derived from the late-pregnancy urine of Canadian women, and was introduced in 1930 as the “first orally effective estrogen.”[44] However, Ayerst labs almost immediately looked for a new source, because “low activity, high cost, and problems of taste and odor lessened the chances for long-term survival of the product.”[45]
Stallions were the next source tried, because they were said to have the most potent estrogen in their urine of any living animal, despite the fact that stallions are male; however, the stallions frequently kicked over their collection buckets, making them an economically unsound source for sustained collection.[46]
Mares, in contrast, proved to be a much better collection source, and their urine was “at least two and one half times the potency of human urine.”[47]
Ayerst dubbed the product Premarin, which is just a contraction of the drug’s description: PREgnant MARes’s urINe.[48]
In Germany at the same time, a rival team financed by the well-established and wealthy pharmaceutical drug company Schering was also working on
Adlph Butenandt, a scientist backed by Schering, also used human pregnancy urine to derive the raw materials for a product called Progynon.[50] Progynon, which was essentially the same product as Ayerst’s Emmenin, was marketed to German women for the treatment of night sweats and hot flashes.[51]
Similar to the Ayerst story, Schering gave up on the human pregnancy urine as a source, and soon switched to a mare’s urine product called Progynon 2.[52] Based on Butenandt’s work, by 1938, Schering scientists Hans Inhoffen and Walter Hohlweg synthesized ethinyl estradiol, which remains the most popular estrogen used in birth control to this day.[53]
In order to prevent Schering from obtaining a patent on estrogen (and as an effect of their countries’ World War II rivalry), a team of English chemists, including Charles Dodds, developed a formula for a cheap[54] yet powerful synthetic, nonsteroidal estrogen and released the formula to the public in the British magazine Nature on February 5, 1938.[55]
This estrogen, diethylstilbestrol (“DES”), had the same effects as estrogens derived from animals and plants, but was three times more powerful; additionally, anyone could make it because Dodds had relinquished his own patent rights when he published the formula.[56] In publishing his formula, Dodds was conforming to the British custom at the time (and his own opinion) that scientific work was done by scientists working for the public good; thus such discoveries should be made available to the public without having to pay high prices to proprietary pharmaceutical companies.[57]
From the beginning, though, Dodds was concerned about the cancer-causing potential of DES, as well as any harmful noncancerous effects of introducing a foreign substance into the complex female reproductive cycle.[58]
Other scientists confirmed Dodds’ suspicions. Even as early as 1932, data suggested that estrogens induced mammary cancer in mice,[59] and throughout the 1930s, there were already numerous warnings published in prestigious journals about Butenandt’s estrogens.[60]
In December 1939, the Journal of the American Medical Association published editorials urging a thorough investigation of DES prior to approval by the Food and Drug Administration (“FDA”), after the journal caught wind of rumors that many requests to market DES were being filed at the FDA, because of the possibility of carcinogenesis and the risk of putting it on the market due to the unknown long-term effects.[61] One of the editorials, “Estrogen Therapy – A Warning,” remarked:
Regarding conflicting reports about DES...apparently a thorough investigation of this compound is in order before it can be prescribed for routine therapy...The possibility of carcinoma induced by estrogens cannot be ignored...it appears likely that the medical profession may be importuned to prescribe to patients large doses of high potency estrogens, such as [DES], because of the ease of administration of these [products].[62]
A second editorial in the same issue of JAMA was written by the Council on Pharmacy and Chemistry that discussed negative side effects of DES.[63] In observing DES in menopausal use, various side effects, such as “nausea, vomiting, abdominal stress, anorexia, and diarrhea...associated with the gastrointestinal tract...[and] were frequent enough to alarm not only the patients but also the investigators.”[64] In conclusion, the Council warned that:
because the product is so potent and because the possibility of harm must be recognized, the Council is of the opinion that it should not be recognized for general use... at the present time...and that its use by the general medical profession should not be undertaken until further studies have led to a better understanding of the functions of the drug.[65]
Another editorial in JAMA four months later commented on the use of small doses of estrogens to treat patients in order to avoid toxic side effects.[66]
The editorial stated: “It would be unwise to consider that there is safety in using small doses of estrogens, since it is quite possible that the same harm may be obtained through the use of small doses of estrogen if they are maintained over a long period.”[67]
Regardless of such warnings in scientific journals, thirteen drug companies had applied to the FDA to market DES by 1940.[68] After all, DES was cheap, effective in oral form, an excellent copy of natural estrogens and containing all the same powers, and best of all, unpatented![69] Thus, DES was available for anyone who wanted it without charge (i.e. no licensing fees or royalties) and limited research costs.[70]
There was huge potential for high profit margins because most traditional overhead costs were eliminated, even though the companies would still have to incur marketing and production costs.[71]
The FDA, however, put the drug companies in a catch-22. The FDA let the companies know that it would turn down any application, but that the companies had the right to protest.
[72] A protest by the companies was not really a good option, because the warnings about cancer that were published in scientific journals were not yet widely known by the public; once the media caught wind of the cancer warnings, it would almost certainly be brought to the public’s attention, backfire in the companies’ collective face, and shut the door to DES marketing permanently.[73]
The other option was for the companies to quietly withdraw their applications, regroup, and make another attempt to get approval later; this is exactly what the companies did on December 30, 1940, and the withdrawal was approved the by the FDA on January 17, 1941.[74]
Instead of individually fighting the FDA in the public domain, the drug manufacturers held a meeting and decided the best course would be to withdraw all of their applications from the FDA and wage a targeted campaign as a group.[75]
This group was to become the precursor to the formation of the official pharmaceutical lobbying group in 1951, Big Pharma, the powerful industry lobby.[76]
The companies agreed that pooling their resources was essential in order to gather a master file on DES and work towards winning government approval the next time around.[77] Four companies – Eli Lilly, Winthrop, Upjohn, and Squibb – led the effort and were known as the “Small Committee” and would do the bulk of the work on behalf of all of the companies.[78]
J.A. Morrell of Squibb himself collected 257 articles on DES showing the drug’s use in clinical situations.[79] By gathering articles showing the clinical use (i.e. how doctors would use the drugs with their human patients), rather than articles solely about laboratory tests on animals, the committee wanted to emphasize to the FDA that DES would be safe for specified uses in humans.[80]
Also, by stressing the clinical (i.e. human) impact of DES, the Small Committee wanted to keep attention away from the theoretical concerns and published animal studies showing that DES was well-known for causing cancer.[81]
The doctors of these (and other) pharmaceutical companies were only one part of the DES campaign. The other part involved Carson Frailey, the Washington lobbyist-publicist who was the executive vice president of the trade group the American Drug Manufacturers Association and had been an industry official since the 1920s.[82]
Frailey knew all the right people in the middle levels of government – the civil servants and bureaucrats who would be around long after their politically-appointed bosses and the presidents who appointed them were gone.[83]
Frailey started out by organizing a meeting on January 28, 1941.[84] The meeting’s purpose was to gather doctors from across the country so that they would write to the FDA in favor of DES approval; fifty-four doctors agreed to write to the FDA, describing their clinical experiences with a total of more than 5,000 patients.[85]
Only four doctors felt that DES should not be approved.[86] After five months, the lobbying campaign seemed to be having the desired effect, because on May 12, 1941, Frailey sent letters to the Small Committee members saying: “The time now seems propitious to suggest that you re-file [your] new drug application for [DES]. I am making no commitments that the application will be permitted to become effective, but the suggestion offered has official background.”[87]
The FDA officially approved DES for use in four types of treatments on September 19, 1941, including menopausal symptoms.[88] Once DES was approved for a few limited uses, the law permits DES to be used by physicians for off-label purposes in an experimental capacity; the FDA does not interfere with a doctor’s right to practice medicine, even though the doctor might be using a legal drug for purposes other than which it had been approved by the FDA.[89]
Thus, immediately after the FDA’s initial approval of DES for use with menopausal women, pharmaceutical companies and physicians became more interested in using DES to prevent miscarriages, and began using it for this purpose.[90] Even though the doctors were legally permitted to use DES in this off-label capacity, in 1947, the FDA officially approved DES for use in preventing miscarriages – which later proved to be the most controversial and harmful use of DES.[91]
Dr. Allen and other scientists, meanwhile, had been continuing to research, focusing on the role of estrogens in female cancers.[92]
In April 1941, just as the FDA was reexamining applications from Eli Lilly, Squibb, and several other drug companies to approve estrogen products for the treatment of menopause, Allen published an article in the journal Cancer Research on the propensity of estrogens to cause cervical cancer in animals, and concluded that estrogen was a carcinogen: “The high incidence of cervical cancer in these experimental groups emphasizes that estrogen is a very important factor, not merely an incidental one, in cervical carcinogenesis.”[93] Allen went on to point out that one reason why in other studies the incidence of cervical cancer in mice had been low is that “mammary cancer appears at an earlier age than does cervical cancer, and consequently animals may die of the former; i.e., many of them do not live long enough fro the cervical cancer to develop.”[94]
Thus, by the time the FDA was considering approval of estrogen products, it should have been aware that there were multiple well-run animal studies going on at major research centers showing the ability of DES to cause cancer as well as interfere with the normal development of the sexual and reproductive systems of offspring born to pregnant animals treated with DES.[95]
Despite this knowledge, the FDA approved, in 1941, the use of DES for the treatment of menopausal symptoms and menstrual disorders.[96]
DES and other estrogen products were approved for use under the newly revised Food, Drug and Cosmetic Act, which in 1938 underwent a major change in its standard of approval before companies could sell the product to the public.[97]
The new standard now required that the drugs up for approval met certain showings of purity, strength, consistency, and safety (though, not of effectiveness).[98]
In fact, DES was the first drug that was not life-saving to be tested under the new standard.[99] The new standards were not necessarily a bad thing for the pharmaceutical industry; in fact, with the government’s seal of approval giving “ethical backing” to new drugs, it helped to increase the sales of drugs.[100]
Menopause as a “disease”
Prior to the synthesis of estrogen and its use as a medical treatment, the medical profession was rather uninterested in middle-aged women.[101]
Any complaint that middle-aged women brought to their doctors was seen as part of the transition from youth to old age and could be blamed on menopause.[102]
But for the most part, doctors did not have any miracle cure for the symptoms of menopause, nor any label to define what women were experiencing.[103]
In modern medicine, however, the medical industry has “discovered” the middle-aged woman and her disease.[104] As Ivan Illich describes in his book, Limits to Medicine:
In the detection of sickness, medicine does two things: it “discovers” new disorders, and it ascribes these disorders to concrete individuals.
To discover a new category of disease is the pride of the medical scientist. To ascribe the pathology to some Tom, Dick, or Harry is the first task of the physician acting as a member of a consulting profession.
Trained to “do something” and express his concern, he feels active useful, and effective when he can diagnose disease.[105]
For most of the last fifty-plus years since the estrogen has been an FDA-approved treatment for menopausal symptoms, the middle-aged woman was no longer ignored, but became a prime target for the treatment of her new disorder: estrogen deficiency syndrome.[106]
Estrogen therapy was thus a useful tool help to replace a biological deficiency of estrogen that started at midlife.[107]
Since all women aged 40-60 go through menopause, the number of patients afflicted with estrogen deficiency syndrome (at the time and in the future) was enormous – the ultimate discovery!
And with the discovery of this new disease, the doctor would feel “active, useful and effective” because every middle-aged woman who came through his office would be diagnosed and treated.
Therefore, during the second half of the twentieth century, the medical industry had determined that the middle-aged woman, in her normal state, was sick; the idea of normal aging in women had been collapsed into a definition of pathology.[108]
The perception of menopause had changed from simply the end of menstruation or a life stage, to one of an illness that no woman can escape.[109]
Menopause, like hypothyroidism and diabetes, was a deficiency disease and therefore it, too, could be treated with a replacement therapy.[110]
As one physician said in late 1975, even in the face of a possible estrogen-cancer link, “I think of the menopause as a deficiency disease, like diabetes.
Most women develop some symptoms, whether they are aware of them or not, so I prescribe estrogens for virtually all menopausal women for a indefinite period.”[111]
This change in perception of menopause can be linked, as it is in many other new “disorders” like erectile dysfunction and irritable bowel syndrome, to a marketing phenomenon by pharmaceutical companies called “if you build it, they will come.”[112]
Because pharmaceutical companies have a profound influence on the ways people define and understand diseases, the “if you build it mentality” is often successful in creating a new disease class.[113]
After all, pharmaceutical companies have tremendous resources to invent drugs where none existed before, design clinical research to position those drugs in the marketplace, fund patient and professional groups who speak through the popular media, and vigorously promote awareness of their medicines and the ailments they are designed to treat. [114]
An executive in drugs marketing noted that “it’s not just about branding the drug; it’s branding the condition and, by inference, a branding of the patient...What kind of patient does a blockbuster create?
We’re creating patient populations just as we’re creating medicine, to make sure that products become blockbusters.”[115]
An article in the British Medical Journal agreed, and labeled the pharmaceutical companies’ behavior “disease-mongering” because the companies are really selling drugs to essentially healthy people.[116]
Drug companies campaign to raise awareness among doctors and consumers about a given disorder with the implicit understanding that there is a cure, and the cure is, of course, the pharmaceutical company’s new drug.[117]
Hormone replacement therapy is probably one of the best examples of the “if you build it, they will come” phenomenon, because vast numbers of women have taken it to prevent health problems associated with a “risk factor” that literally every woman will experience if she lives long enough: menopause.[118]
As a result, the use of hormone replacement therapy was successfully marketed as not only a treatment for menopausal symptoms of estrogen deficiency, but also as a preventative therapy to stave off any adverse effects from estrogen deficiency that come with menopause.
Although estrogen therapy was approved for treatment of menopausal symptoms in 1941, the real takeoff for marketing and prescribing estrogen did not happen until more than two decades later.[119]
The female population in the 1940s, 50s and 60s had been primed since birth to accept their proper role in society as a mother, caregiver, and housewife and were thus the perfect target for the marketing of estrogen.[120]
The middle-aged woman during these decades had already fulfilled most of her major purposes by bearing and raising children, and only had the role of housewife left after her children were grown and left the house.[121]
In the 1960s, the medical industry picked up on the opportunity to exploit the many housewives who suffered from what Betty Friedan dubbed “the problem that has no name,” namely that of the emotional trauma over society’s perception of her diminishing feminine role. [122]
Since biologically these midlife women were going through menopause, any emotional or physical complaint would be seen as a symptom of menopause.[123]
Thus, during the 1960s, midlife women were targeted by a flurry of advertisements for tranquilizers and antidepressants promising a cure for the symptoms of menopause.[124]
These advertisements created a stereotype of the menopausal woman as beset with psychological devils, anxious about her femininity and her waning attractiveness, and grieving over the loss of her ability to bear children.[125]
By creating a medical condition, pharmaceutical companies had ingeniously diagnosed the menopausal woman as ill and in need of treatment.[126]
The success of this campaign is evident from the numbers of drugs designed to treat the menopausal woman’s mental condition: during this period, women were more likely than men to be using psychotropic drugs;[127] from 1966-1971, the use of tranquilizers such as Valium had increased 110% and antidepressants had increased by 320%;[128] and from 1966-1971, 17% of all women (compared to 8% of men) had been prescribed psychotropic drugs and the median age for women using them was 44 years.[129]
The widespread prescription of tranquilizers and antidepressants to housewives eventually led to its practice being discredited, but not before the way had been paved for acceptance of the next category of drugs that would “treat” menopause.[130]
The prominent gynecologist Dr. Robert A. Wilson made it his personal crusade to continue the legacy of treating menopause as a disease that could respond to medical treatment.[131]
Wilson wrote a book in 1966 called Feminine Forever that identified the previously unrecognized and widespread health threat of estrogen deficiency, and proposed a solution to this problem.[132] Wilson’s work seems, by today’s standards, transparently misogynistic.[133]
He called menopause a state of “living decay,” unabashedly touting estrogen as a way to make older women more attractive and “pleasant to live with.”[134]
Wilson wrote that the “tragedy of menopause” is that it “often destroys her character as well as her health.”[135]
Wilson wanted to save women from this horrible fate by having women use estrogen from “puberty to grave” in order to abolish menopause and keep women “feminine forever.”[136]
He was playing into the fantasy of a fountain of youth and was succeeding.
Wilson can also be viewed as a savvy entrepreneur and an evangelist.[137] There is no doubt that Wilson made money from the sale of his book (100,000 copies sold in the first seven months alone) and the thousands of patients that flocked to him to be treated (by 1966 he said he had treated 5,000 women with estrogen).[138]
But Wilson’s self-image – that of a medical saint – was likely what drove his desire to spread his message.[139] He had founded a private trust in 1963, the Robert Wilson Research Foundation, for the purpose of promoting estrogens.[140]
Wilson recruited the makers of hormones to support not only his book but also his foundation and his many public appearances.[141]
Three such drug manufacturers contributed to his foundation in 1964: $17,000 from Searle, since Wilson was trying to show that their oral contraceptive, Enovid, was a way to prevent menopause if indefinitely used; $8,700 from Ayerst, the maker of the estrogen Premarin; and $5,600 from the Upjohn Corporation, whose progestin drug Provera Wilson was testing for use in menopause.[142]
And 1964 was not the only good fundraising year: the Wilson Foundation received funding totaling more than $1.3 million from the pharmaceutical industry.[143]
In November 1966, Wilson received a slap on the wrist from the FDA, who pronounced Wilson “unacceptable as an investigator for drugs in the menopause” because he was disseminating promotional material claiming hormones has been shown to be effective to “‘prevent aging,’ a condition for which they had never been proved to work.”[144]
Despite FDA’s disapproval of Wilson, his theory on menopause was not easily quashed. Feminine Forever was widely excerpted in such popular women’s magazines as Vogue, and during the late 1960s and early 1970s more than 300 articles promoting Wilson’s message on estrogen use appeared in women’s magazines.[145]
Drugmakers, too, ran with Wilson’s message through various means.
Ayerst Laboratories helped to fund the writing of Feminine Forever, provided Wilson with editorial assistance, and even surreptitiously bought enough copies at retail to push it onto the best-seller lists.[146]
Ayerst then kept the buzz going around the tantalizing title and Wilson’s promise of staying young and sexy well after the book was out of print.[147]
Ayerst and other pharmaceutical companies wove Wilson’s message throughout advertisements, confirming the menopausal woman as anxious about aging and emotionally unstable, both of which can be corrected with estrogen therapy.[148]
A 1972 promotional film said: “The physical alterations that are associated with the menopause may induce emotional changes.
When a woman develops hot flashes, sweats, wrinkles on her face, she is quite concerned that she is losing her youth – that she may indeed be losing her husband.”[149] From just a small sample of print ads for estrogen therapy, Wilson’s message comes across loud and clear:[150]
The menopausal woman in the 1950s and 1960s ads is sad, anxious, and emotionally out of control. Typical of such images is a 1960 ad by Hoffman-La Roche Laboratories for the drug Marplan showing a sad woman in a barren, dreary city with the caption: “When ‘change of life’ seems the end of life.
With the advancing years, woman’s vulnerability to depression often becomes intense. The future looms insecure: menopausal symptoms spark somatic concern. And as she faces losing a symbol her femininity, even suicidal panic may supervene.”
An Ayerst ad also displays three very depressed looking women with the caption: “The Estrogen Deficient Woman: The Needless Martyr.”
The “treated” menopausal woman in other ads is a happy, trouble-free wife standing proudly next to her husband, because otherwise she would have emotional and physical problems and be a burden to those around her.
An ad for Hoffman-La Roche’s Menrium says: “His wife has a lot of different menopausal symptoms, but only a few really irritate him. Her hot flashes, her vertigo, her palpitations -- that’s her problem.
What really bothers him is her nervousness, her irritability, and her excessive anxiety, often expressed by endless “book-shuffling, chain-smoking, reading-lamp” insomnia!...[Menrium] takes care of the vasomotor symptoms as well as the emotional symptoms.
That means the symptoms that bother his wife the most. And the symptoms that irritate him the most. So, to help them both get through menopause, remember Menrium.”
In ads from the 1950s-1970s, women who have been treated with estrogen therapy have happy, smiling faces. All of these women have been “cured” by hormones, giving women a “sense of well-being” or “joie de vivre,” and making women “feel better.”
For example, one ad notes: “Her days and evenings are full. It’s a busy, involved, normal life.”
The ads were quite effective: doctors were willing to jump on the estrogen bandwagon, absorb the messages and prescribe the menopausal woman with drugs for her condition.
This was despite the fact that estrogen had been approved for menopausal symptoms before the 1962 amendments to the Food, Drug, and Cosmetics Act required a stronger show of safety.[151]
The successful public marketing of many tenuous benefits of estrogen had also preceded the 1962 requirements for contraindications, side effects and effectiveness, or any restrictions on what companies could claim in ads.[152]
Doctors have always been able to prescribe FDA-approved medications for off-label uses as they see fit, and for whichever patients and conditions they choose.[153] Neither the FDA nor states (who license doctors) have ever had any authority over doctor’s decisions.[154]
Thus, doctors could be convinced of estrogen’s off-label benefits through ads, or samples sent by pharmaceutical companies, or expensive dinners and “consulting fees” paid for by the drug makers.[155]
The well-run marketing campaigns by pharmaceutical companies had created a general accepted characterization of menopausal women as estrogen deficient, and thus there were many doctors who prescribed estrogen therapy for long-term replacement of estrogen.[156]
In 1976, two researchers, who the previous year had linked estrogen to uterine cancer, commented on this practice:
The ‘estrogen forever’ philosophy has fortunately not dictated the standard of therapy of the menopause [in the Medical Center where the researchers works]...
Yet well-meaning physicians frequently prescribe these hormones, giving some patients estrogen even before the menopause and continuing it in some for the duration of their lives.
Adverse effects may become...manifested only after years of exposure...By then many patients have become psychologically addicted to estrogen and...object to its discontinuance. These chronically exposed women are uniquely jeopardized.[157]
Also worthy of note is that although every middle-aged woman could be diagnosed as being estrogen-deficient, it was the middle-class Caucasian women who were the particular objects of interest to the pharmaceutical companies.[158]
This subset of women was health-conscious and likely to see a doctor regularly.[159] They also had more disposable income at midlife than any other stage and could afford to pay for medical services.[160]
Finally, middle-class Caucasian women placed high value on their physical attractiveness.[161] Their health and attractiveness were regarded as assets, important to their social status and sexual marketability because, in society’s eyes, when women reach middle-age their worth is unavoidably declining.[162]
The harsh societal view of aging women, and specifically middle-class Caucasian women, was ripe for exploitation by the medical industry.
Thus a middle-aged, middle-class Caucasian woman was, and still is, especially susceptible to messages that target those fears and promise prevention of illness or everlasting youthful femininity.[163]
Not surprisingly, advertisements were not the only method used to reach the pharmaceutical companies’ target audience.
The outstanding New York public relations woman, Sandra Gorney, was hired by Ayerst Labs and did quite a spectacular job of legitimizing and iconizing the philosophy of Feminine Forever for a decade after its publication.[164]
Ayerst Labs provided a “service for media” through the Information Center on the Mature Woman – which Sandra Gorney was hired to direct.[165] Magazine and newspaper editors frequently published features on current menopause questions and controversies supplied by Gorney, whose style was breezy and readable but authoritative.[166]
Gorney’s free newsletters and background papers were attributed, if at all, to the Information Center on the Mature Woman, even though, to Gorney’s credit, her mailings to the media did acknowledge the Ayerst support.[167]
According to some calculations, the sales of Premarin, Ayerst’s hormone replacement drug, doubled or even tripled in the wake of Feminine Forever and the PR of Sondra Gorney and stayed at record-breaking levels until the mid 1970s.[168]
By 1975, Wyeth's product, Premarin, had become the fifth leading prescription drug in the United States.[169]
Celebrity endorsements by Lauren Hutton and Patti LaBelle were another way to capture public attention and legitimize the treatment of menopausal symptoms with hormone replacement therapy: in the 1980s, these women appealed to health-conscious concerns about disease prevention and women’s determination to remain vital beyond middle age.[170]
They endorsed the idea that HRT would not only help women get past the hot flashes and other symptoms of menopause (including, Hutton broadly hinted to Parade Magazine, looking older and feeling cranky) but, used long-term, it would also protect them from Alzheimer’s, heart disease, stroke, osteoporosis, and colon cancer.[171]
From these endorsements, the message came across loud and clear: it was admirable to take HRT, and it was questionable not to take it.[172]
The pharmaceutical companies had (and still have) another way of reaching the public: medical experts who appear on morning shows and give interviews to magazines and newspapers.[173]
This was a sneaky way of promoting the benefits of hormone therapy without having to identify any connection to the drug company, and needless to say, a successful route under the cloak of legitimate, independent, professional opinion.[174] The public goes unaware of such connections, of course.
But on November 20, 2002, reporter Sharyl Attkisson “outed” two of the most widely quoted menopause experts, Dr. Lila Nachtigall and Dr. Wulf Utian on the CBS Evening News, making them publicly acknowledge their receipt of financial support from the makers of Premarin and other hormones.
[175] Both Nachtigall and Utian signed a disclosure statement a few weeks earlier, in connection with a speaking appearance at a workshop on menopausal hormone therapy at the NIH, that required them to declare whether they had any financial ties to drug companies.[176]
Neither doctor acknowledged any such connections on this disclosure statement.[177] However, as Attkisson reported:
The selling of HRT was a coup...but a lot of the claims weren’t backed by serious science...women never knew the same doctors promoting the wonders of HRT often had a vested interest in the drug’s success. Much of the information that got into print was bolstered by quotes from respected experts such as Dr. Nachtigall...Readers weren’t told that Nachtigall is also a paid speaker for at least eleven drug companies including Wyeth[178] – the biggest maker of HRT drugs....Dr. Utian, another widely quoted specialist who is Director of the North American Menopause Society, has, as it turns out, gotten large grants and support from Wyeth.[179]
Although both doctors denied that financial support meant they were biased, Dr. Utian even commented that “when you see a magazine article and see a quotation from an expert, I think it’s almost impossible to know whether there’s a conflict of interest or not.[180]
This is not to say that every medical expert cannot be trusted to be unbiased, or completely free from ties to pharmaceutical companies, but rather that their advice should be questioned in the first place to see if it is biased.
But because the public is generally unaware that pharmaceutical companies have such success shaping public opinion, the huge marketing efforts by pharmaceutical companies like Ayerst paid off – the rhetoric of a panacea for a whole host of female concerns from aging to diseases was accepted by a medical profession and public that were willing to buy into the drug-company-created fantasy: Premarin became the number one prescribed in the United States in 1992, and 1997 it became the first Wyeth product to reach $1 Billion in sales – even with the ups and downs after 1975, Premarin remained in the top 50 prescribed drugs from 1966 until 2002.[181]
The Tumultuous Cost-Benefit Analysis of HRT
“For the midlife woman, [the medical treatment for menopause is a] paradox, for it contains both potential benefit and potential harm. The trick is to gain the first, while avoiding the second.” – Sandra Coney, author of The Menopause Industry[182]
The ability of women to competently parse out information about their new “disorder” has been nearly impossible. The complexity of the issues and risks of hormone replacement therapy has made a decision regarding its use a daunting task to tackle alone.
Thus women have had to rely on the mediating influence of their physicians, or alternatively, the simplified versions of medical wisdom in the mass media. The estrogen story was such a nice fairytale that it is almost too bad that at present, the story is falling apart piece by piece.
Pharmaceutical companies made a miraculous fountain-of-youth drug, physicians were happy to pass along the dream to their willing and “needy” patients, and women were buying into the dream of youth and attractiveness.
1975: Estrogen linked to increased uterine cancer
DES, one of the estrogens used (either in combination with progesterone or alone) in hormone therapy for menopausal women, took a big hit in 1971: studies connecting women’s DES use to prevent miscarriages during pregnancy with vaginal cancer in their daughters were published in the New England Journal of Medicine.[183]
Four years later, the FDA withdrew its approval of the use of DES during pregnancy.[184] Cancer experts saw at once that the significance of the 1971 study, and subsequent studies by the same doctors, went far beyond the conclusions relating to DES in pregnancy; these studies had shown that estrogen could be “seed” as well as “fertilizer” to cancer in humans, meaning that it could cause cancer as well as help it to grow.[185]
As a result, scientists at the National Institutes of Health held a conference in 1971 to talk about the basis for the use of estrogen as a therapy for menopausal women.[186] The conference deplored the lack of data on menopause and noted the uncertainty of benefits from estrogen therapy, but also concluded that “...the association of abnormal and elevated estrogens and abnormalities of the endometrium (the lining of the uterus) is very suggestive...”[187] In 1973, Medical Letter, the Consumer Reports of prescription drugs, cautioned:
The manufacturer’s advice to ‘Keep Her on Premarin’ seems unwise...References frequently cited in promotions of estrogens...present personal opinion...or poorly controlled studies...or no criteria for defining such vaguely characterized states as melancholy, diminished sense of well-being, and decreased vitality...The Medical Letter advises against the routine prescribing of estrogens during and after the menopause because there is no adequate evidence that such treatment is beneficial, and because...estrogens may promote or aggravate cancer in some women.[188]
Then, in 1975, just before the completion and publication at the end of the year of conclusive studies showing the link between estrogen replacement therapy and endometrial cancer, Novak’s Textbook of Gynecology came to conclusions that previewed the result of the studies:
...estrogens can be of importance in the development of cancer in those organs and tissues which are normally estrogen dependent, e.g. the genital tract and breasts...Any gynecologist who spends time in the pathology laboratory can be impressed the large number of postmenopausal endometria in which extreme degrees of hyperplasia and even endometrial adenocarcinoma are observed in women who have a history of prolonged estrogen therapy.[189]
Finally, in December of 1975, the New England Journal of Medicine published a series of articles comparing the risks of developing endometrial cancer between menopausal women who used estrogen for hormone replacement therapy and those who did not use estrogen.[190] The difference in risk of developing endometrial cancer between the two groups was dramatic: those who used estrogen therapy for five years or less were 5 times more at risk than non-users, and the risk kept increasing as the duration of the therapy increased, so that those who used estrogen for more than seven years were at 14 times the risk of non-users![191]
Ayerst Labs, however, less than two weeks after the publication of these studies, was bold enough to send out a “Dear Doctor” letter to physicians arguing that the articles were “weak studies,” and reassuring them that the link between estrogen therapy and cancer was not firmly established.[192]
Some doctors did not need to be reassured by Ayerst because they were already dismissing the studies as not showing a direct link of estrogens to cancer. [193]
Those doctors who have been liberal in their prescription of estrogens, giving them to virtually all menopausal women for indefinite periods, said that in their views the benefits of hormones still outweigh the risks.
The doctors who traditionally have been more conservative in prescribing estrogens, restricting them to women with severe menopausal symptoms, for a period of one to four years, said that the drug is clearly useful for such women even if it may increase their risk of developing cancer of the endometrium.[194]
Despite any flaws in the endometrial cancer studies’ design, the increase in cancer risk was “too high to be explained away by even major methodological flaws.”[195] The FDA seemed to agree, because on December 16 and 17, 1975, it convened a hearing in front of its advisory committee on obstetrics and gynecology to discuss the recent evidence linking endometrial cancer with estrogen use by menopausal women.[196]
A third study was presented to the committee, concluding that “among postmenopausal women who took estrogen the risk of developing endometrial cancer was greater than their combined risk of developing cancers of the breast, lung, ovary and colon.”[197]
Additionally, the panel heard a report showing the incidence of endometrial cancer in the San Francisco bay Area had increased by 50 percent from 1969 to 1979, after restricting the study to women over 50; the results were most obvious in upper socio-economic groups, where use of estrogens is most prevalent.[198]
It was also reported at the conference that other cancer registries showed similar increases in endometrial cancer rates.[199]
On January 8, 1976, the FDA announced that it would release new warning labels for estrogen products used to treat menopausal and post-menopausal women, which would “emphasize the newly reported increased risk of cancer of the uterus associated with prolonged use of estrogen products, particularly in post-menopausal women.”[200]
And that same day, after Ralph Nader’s Health Research Group had brought the Ayerst letter to the attention of the FDA, the agency released an announcement reprimanding Ayerst and calling the letter it sent to doctors “misleading in view of the recent and widely publicized discussion regarding estrogen therapy in women.” [201]
The FDA also required in 1976 that that each package of estrogen contain an insert warning of the risks of estrogen.[202] If the doctors disliked the attention they were getting before from the link to uterine cancer, the action by the FDA was certain to annoy doctors.
The studies’ conclusion that the apparently beneficial drug that had been given to well women could cause cancer naturally led to the inference that their doctors could not necessarily be trusted: doctors had given their healthy female patients assurances that the estrogen was safe, but this evidently was not the case.[203]
The American College of Obstetrics and Gynecology worried that the inserts in estrogen packages would further cause a rift in the doctor-patient relationship, because the information in the inserts about risks circumvented the normal process where doctors decided how much information to give to patients.[204]
By 1975, it was estimated that about 25 million prescriptions for estrogen therapy were written by doctors,[205] quadruple the amount prescribed in 1972.[206] Needless to say, the increased risk of cancer had the potential for widespread consequences.
Additionally, in 1974, there had been a report that had linked estrogen with gallbladder disease; the relative risk of estrogen users was two and a half times that of non-users.[207]
The decline in hormone therapy prescriptions was evidence of the growing accumulation of evidence against estrogen: From 1975-9176, estrogen use declined by 18% from 1975-1976, and another 10% from 1976-1977.[208] By 1980, the number of annual estrogen prescriptions had fallen by 50%[209]
Also, under pressure from grassroots activists as well as the FDA, Ayerst altered the Premarin advertising claims to include only menopausal symptoms such as hot flashes, night sweats, and vaginal dryness as indications of the drug.[210]
After the uterine cancer scare in 1975, scientists concluded that although estrogen is the major hormone player in menopause, since its use in treating menopausal symptoms like hot flashes and vaginal dryness have been quite effective, there had to be a way to mediate its effect on the uterus.[211]
Estrogen is the hormone that allows the lining of the uterus to build up in preparation for pregnancy.[212] If estrogen were the only hormone available, the lining of the uterus would continue to build up, which would put women at greater risk for endometrial cancer.[213] Progesterone is the hormone that causes the lining to shed when no fertilization of the egg occurs.[214]
Pharmaceutical companies learned a few years later from preliminary epidemiology studies that they could add progesterone to the estrogen therapy drugs to offset the risks of endometrial cancer.[215] The addition of progesterone to estrogen, known as “opposed therapy,” induced a regular bleed, helping to avoid the dangerous buildup of the lining that occurred under influence and hopefully protecting the uterine lining from cancer.[216]
Drug companies successfully campaigned physicians to use this new combined hormone replacement therapy in women who still had their uterus, and by 1988, a significant shift in prescriptions had taken place from unopposed estrogen to opposed therapy.[217]
The problem with adding progesterone to the estrogen was that although postmenopausal women continue to produce some estrogen, there is essentially no progesterone production post-menopause because the function of progesterone is no longer necessary.[218]
Thus no one could predict exactly what adding progesterone would do to a postmenopausal woman, because it was essentially a foreign hormone to the woman at that point in her life.[219]
The most noticeable effect was that progesterone caused 25% of women who used this opposed therapy to experience premenstrual syndrome, and many women also started to begin menstruating again.[220] The return of menstruation is the most common reason women give for discontinuing the use of HRT for those who have already stopped menstruation.[221]
1976: Estrogen linked to breast cancer
In 1976, breast cancer was added to the growing lists of diseases that estrogen therapy caused in menopausal women.[222] The first report of a higher risk of breast cancer in estrogen patients was especially alarming, because of the higher incidence of breast cancer among women (especially older women), and the poor prognosis for even early-stage breast cancer.[223]
Even a moderate increase of breast cancer among women using hormone replacement therapy could have an enormous effect, because breast cancer is the most common cancer among women.[224]
Currently, the Susan G. Komen Breast Cancer foundation notes that the chance of getting breast cancer increases as women get older, from a 1/36 chance when a woman is 50, to a 1/23 chance when the woman is 70, to a 1/7 chance of ever getting breast cancer.[225]
The biology of breast cancer is still not well understood, but many experts believe that estrogen stimulates the growth of cancer in cells in the breast and that progesterone might add to estrogen’s effect, thus increasing the risk of breast cancer dramatically.[226]
The effects of estrogen and progesterone on breast cancer were unclear through the 1970s, when studies showed no elevation in risk, and through the 1980s when several studies showed small elevations in risk, especially for long-term users; only in the 1990s were doctors’ suspicions about the increased risks of breast cancer due to estrogen and progesterone more clearly borne out in studies.[227] For example, a 1989 Swedish study found that after nine years’ use women using estrogen-only hormones had nearly twice the rate of breast cancer compared to women not using hormones, and the risk increased with the addition of progesterone so that women using a combination of estrogen and progesterone had four times the rate of breast cancer compared to nonusers.[228]
On their follow-up of women in this study in 1992, the researchers again found that the risk they discovered in 1989 remained – the risk of combined estroge
The Rise and Fall of Estrogen Therapy:
The History of HRT
Carla J. Rothenberg
Harvard Law School, Class of 2005
April 25, 2005
This paper is submitted in satisfaction of the Food and Drug Law course requirement and the third-year written work requirement.
Abstract: This paper explores the history of hormone replacement therapy (“HRT”). It focuses on the development and marketing of HRT drugs, the regulation of HRT by the Food and Drug Administration (“FDA”), and the effect medical studies have had on the development, marketing, and regulation of HRT over the years.
First, a discussion of the difficulty of defining menopause is explored.
Second, the early history, treatments, and attitudes towards menopause are described.
Next, the discovery, manufacture, and FDA approval of estrogen are detailed. The subsequent section examines how the pharmaceutical industry created a perception of menopause as a disease in all midlife women.
Then, the cost-benefit analysis of HRT is explored through medical studies’ connection of HRT to various diseases.
Finally, the aftermath of the landmark Women’s Health Initiative study is discussed, followed by a few concluding thoughts on what we can learn from the history of HRT.
Introduction
Apparently, in the year 2005, women are still a mystery, even to themselves. Presently, millions of American women near, at, or beyond menopause are confused over estrogen, the female hormone – or, more specifically, estrogen as hormone replacement therapy (“HRT”). Estrogen products were first approved by the Food and Drug Administration (the “FDA”) in 1941 for the direct symptoms of menopause: hot flashes and night sweats, vaginal dryness and atrophy.
In the following decades, estrogen (either alone or combined with progesterone) had acquired a reputation as an antidote to many of the illnesses and afflictions of aging, and even as a preventative drug for such diseases as osteoporosis, heart disease, and Alzheimer’s.
Scores of observational and case studies supported the overwhelmingly positive view of hormone replacement therapy, and naturally drug makers and their advertising agencies enthusiastically embraced estrogen as well. After all, this was a billion dollar business.
This is not to say that hormone replacement therapy didn’t have its share of ups and downs in the 60-plus years since it was FDA-approved.
It did: links to uterine cancer led to a course-correction – the addition of progesterone to help mediate some of the complications for women who still had a uterus (i.e. no hysterectomy).
And later, more links to other cancers presented themselves. But not until the Women’s Health Initiative study was abruptly halted in 2002 were many of the long-heralded benefits of hormone replacement therapy seriously questioned.
Ever since the premature stop of the WHI study, estrogen has been thrown back into the world of the unknown. The benefits of temporary use of estrogen for which it was initially-approved in 1941 have not been heavily challenged; rather, the major criticism of HRT today focuses on the risks and effects of long-term use for menopausal symptoms as well as for diseases and purposes other than menopause.
The current question is how women should weigh the risks and benefits of using estrogen, because the advice and scientific findings are uncertain at best. An analysis of this question is beyond the scope of this paper (and the knowledge of this author); rather this paper focuses on the history of hormone replacement therapy.
What is menopause?
Since hormones, up until recently, have been promoted as a cure-all for the symptoms of menopause, a good starting question is what is menopause, and what are the symptoms of menopause? If we believe that taking hormones can eliminate a whole range of real or potential problems, then a long regimen of hormones may seem very attractive.
But if hormone therapy can only deal with a more limited range of symptoms, the wisdom of taking hormones for years may not be as salient.
Menopause, in its most simple definition, is the time in every woman’s life when her period stops, and a woman has technically “reached” menopause when she has not had a period for 12 months in a row.[1] Meno is derived from the Greek word for month, and pause is derived from the Greek work pauses, or halt.[2]
It is a normal part of aging for women, and it occurs generally between the ages of forty-two and fifty-eight years old, with the median age at 51.[3] During menopause, a woman slowly produces less of the hormones estrogen and progesterone.[4]
Although not every woman going through menopause experiences a noticeable change as a result of the decreased estrogen and progesterone levels other than cessation of menses, many women do experience various symptoms, and varied degrees of symptoms.[5] This is why menopause is often referred to as “the change” or “the change in life.”[6]
But one of the problems of referring to menopause as a “change,” other than simply referring to having a monthly period and then not having one, is that many people (including the medical profession) conflate aging with menopause. Menopause is not synonymous with a woman’s midlife; rather it is an event of her midlife.
As a result, many well-respected medical organizations have lists of symptoms that vary wildly and include many symptoms that are best viewed as part of aging instead of specific to menopausal women.[7] There are a few symptoms that everyone can agree on, though. These symptoms may include one or more of the following, both as a woman approaches menopause, and also continuing through menopause:[8]
Changes in the menstrual cycle, such as a difference between the time between periods or a different flow.
Hot flashes (also known as “hot flushes"), which includes getting warm in the face, neck and chest.
Night sweats. (Both hot flashes and night sweats are also referred to as vasomotor symptoms).
Vaginal changes, also referred to as vulvar and vaginal atrophy, when there is dryness, itching, burning, or thinning of the vagina; these changes are also associated with sex becoming painful.
Women who experience significant problems from these symptoms are about 5-15% of the menopausal population.[9] Most of the other supposed mental and physical symptoms of menopause, such as depression, irritability, and sleeplessness are either equally as applicable to midlife men as they are women, or the peak of their occurrence in women preceded menopause and are the result of chronological age or premenstrual syndrome.[10]
The loss of estrogen at menopause has also been highlighted as the major cause for osteoporosis, or thinning of the bones, and thus osteoporosis has been listed by the FDA as a symptom of menopause.[11]
But osteoporosis, which may lead to loss of height and bone breaks, is as much due to old age as it is to a decrease in estrogen, and as such, can be conflated as a symptom that is specific only to menopause.[12]
The Early History of Menopause and its Treatments
One of the earliest known references to menopause is from an Egyptian medical text dated 2000 B.C.: “If a menopausal woman has pain or makes trouble, pound her hard on the jaw.”[13] Today’s woman going through menopause would almost certainly object, not only to the violence but also to the mere temporary distraction from a sometimes painful, long experience with menopause!
Present treatments for difficult menopausal symptoms do not involve a good hard smack, but rather are more likely to be a mixture of diet, exercise, herbal remedies, and prescription remedies.[14] A medical textbook from the era of Renaissance Europe, almost 500 hundred years ago, reflects a similar treatment to today’s standards, recommending an herbal remedy with exercise.[15]
Specifically, the medical text recommended a “decoction of myrrh and apples” for women who were experiencing problems with menopause, and if that did not work, “a cure may sometimes also be affected by pouring some of this same substance into her sandals, and urging the patient to walk.”[16]
In the 1899 Merck Manual Diagnosis & Therapy, a coarse brown powder named Ovariin was prescribed for “climacterica,” which is another name for menopause, and other ovaries-related problems.[17]
Ovariin was an oral medicine derived from the dried and pulverized ovaries of a cow, and though a primitive attempt at medicating menopausal symptoms, the director of the NIH Women’s Health Initiative, Dr. Jacques Rossouw, believes that it may have had some estrogenic effect.[18] The 1899 Merck Manual also contained an additional twenty-eight treatments for woman’s climacteric.[19]
One of the conclusions from this observation is that menopause is not necessarily a phenomenon of the modern age, as doctors, pharmaceutical companies and writers might suggest.
One school of thought argues that as a result of the considerable increase in average life expectancy in the past 100 years, women have “outlived their ovaries,” and thus menopause is simply an artifact of an unexpected recent increase in life span beyond reproductive age.[20] However, there is a fair amount of credible research countering such assertions.
For example, an article by Thomas Perls and Ruth Fretts in the Annals of Human Biology suggests that just because the average life span has increased over the years, it does not mean that there were not plenty of adults living into what we would consider “old age,” and in fact, the mitigating factors of increased death at childbirth a hundred years ago had a skewing effect on the average life expectancy.[21] The article goes on to refute the “outliving one’s ovaries” explanation by arguing:
Firstly, though average life expectancy has increased markedly in just the past century, the human life span has been significantly longer than the age of menopause, probably since the time menopause evolved.
There is no evidence to indicate that we have done something special as a species in even the past millennium that would facilitate a doubling or tripling of the human life span.
Certainly there is evidence from Ancient Greece indicative of elder statesmen living well into their 80s and early 90s. Secondly, if menopause was simply an artefact, we would not expect, over the course of evolution, a natural selection for genes that influence when menopause occurs.
Contrary to this supposition, genetics does appear to play a role in the timing of menopause; and finally, the nonadaptive hypothesis begs the question of why would the reproductive system fail long before other systems, such as the cardiovascular system?[22]
As such, since menopause is not necessarily a new phenomenon, rather just a more noticeable increase in the incidence of menopause, it is not surprising when books from more than a century ago discuss menopause at length. Some books from more than a century ago viewed menopause as a period of adjustment rather than a disease, and they also wrote about the “change” in validating terms.[23] For example, in George Napheys’ 1869 book The Physical Life of Women: Advice to the Maiden, Wife, and Mother, he wrote that:
after a certain number of years, a woman lays aside those functions with which she has been endowed for the perpetuation of the species, and resumes once more that exclusively individual life which has been hers when a child.
The evening of her days approaches, and if she has observed the precepts of wisdom, she may look forward to a long and placid period of rest, blessed with health, honored and loves with a purer flame than any which she inspired in the bloom of youth and beauty.[24]
French physicians of the same time also viewed menopause in a positive light, seeing it as a return to more carefree days, and referring to this period as le retour d’age, meaning a return to youth before the time of fertility.[25] In this same spirit, some doctors of the time were urging their female patients to “view menopause as an opportunity to reclaim their lives and to avoid harsh medicines, as hot flashes were natural and not an illness.”[26]
And in a interesting view that seems to fit nicely in with contemporary recommendations by the FDA and women’s health organizations, Thomas Graham wrote in his 1837 book, The Diseases of Females, that with the exception for attention to diet and exercise, “little or nothing is required for the management of ordinary cases.”[27]
Though these books do exist, and some doctors viewed menopause in a positive light, for the most part, this attitude really was an exception to the rule; through the late 1960s and the beginning of the women’s movement, overall attitude of menopause was that people didn’t discuss it and it was generally an embarrassing problem.[28]
Women, prior to the women’s movement in the 1970s, were thought to be ruled by their hormones and thus were inferior to men, making menopause a shameful secret.[29]
Women were embarrassed to admit they were going through menopause, and thus did not seek advice for menopausal symptoms, because it would signal the end of their active life.[30]
The Discovery and Manufacture of Estrogen
The modern treatment of menopausal symptoms can be traced back to the pharmaceutical company Merck & Co., Inc., because Merck was the leader in the field of capitalizing on the use of animal glands in medicine.[31]
Through the time of World War II, however, drug companies were small-time concerns, making patent medicines that people could buy over the counter at pharmacies, while doctors were likely to use pills and potions made to their own recipe.[32]
The pharmaceutical revolution changed this around the time of World War II, with the discovery and large-scale production of sulfanilamide, and subsequently penicillin, streptomycin, and an explosion of antibiotic products.[33]
At first, it was not research by pharmaceutical companies, but rather research by scientists, such as Dr. Charles Edouard Brown-Sequard, Dr. Edgar Allen, and Dr. Edward Doisy, that led to the current formulation of estrogen.[34]
Dr. Brown-Sequard’s announcement in 1889 that he had “rejuvenated himself” by injecting “sensitive parts of his body” with a mixture of guinea pig and dog testicle extracts, led to a flurry of research during the 1890s into the field of sex gland extracts as a fountain of youth.[35]
In particular, Dr. Allen and Dr. Doisy teamed up to unlock the key of estrogen research.[36] From 1923 through 1938, they established the existence of estrogen and described its effects, as well as identified all of the female hormones and the relations among them.[37]
By the end of their research, the field of hormone research was hot for scientists as well as pharmaceutical companies develop new drugs they could market.[38]
The drug manufacturers saw the hormone research as having the potential for curing a wide range of ills, but also having major benefits for those who were not suffering from any problems in the first place.[39]
The drugs had the potential for use for menopause, menstruation, beautiful unwrinkled skin, thicker hair, more passionate sex, curing infertility, and birth control, just to name a few.[40]
Drug manufacturers believed that their profits would skyrocket as a result of these drugs, and went out courting scientists, especially biochemists such as Dr. James Bertrand Collip.[41] Dr. Collip, co-discoverer of insulin in 1922, was courted by W.J. McKenna of Ayerst[42] Laboratories in 1929, and in 1930 the partnership of Collip and Ayerst Labs produced its first product.[43]
The product, called Emmenin, was derived from the late-pregnancy urine of Canadian women, and was introduced in 1930 as the “first orally effective estrogen.”[44] However, Ayerst labs almost immediately looked for a new source, because “low activity, high cost, and problems of taste and odor lessened the chances for long-term survival of the product.”[45]
Stallions were the next source tried, because they were said to have the most potent estrogen in their urine of any living animal, despite the fact that stallions are male; however, the stallions frequently kicked over their collection buckets, making them an economically unsound source for sustained collection.[46]
Mares, in contrast, proved to be a much better collection source, and their urine was “at least two and one half times the potency of human urine.”[47]
Ayerst dubbed the product Premarin, which is just a contraction of the drug’s description: PREgnant MARes’s urINe.[48]
In Germany at the same time, a rival team financed by the well-established and wealthy pharmaceutical drug company Schering was also working on
Adlph Butenandt, a scientist backed by Schering, also used human pregnancy urine to derive the raw materials for a product called Progynon.[50] Progynon, which was essentially the same product as Ayerst’s Emmenin, was marketed to German women for the treatment of night sweats and hot flashes.[51]
Similar to the Ayerst story, Schering gave up on the human pregnancy urine as a source, and soon switched to a mare’s urine product called Progynon 2.[52] Based on Butenandt’s work, by 1938, Schering scientists Hans Inhoffen and Walter Hohlweg synthesized ethinyl estradiol, which remains the most popular estrogen used in birth control to this day.[53]
In order to prevent Schering from obtaining a patent on estrogen (and as an effect of their countries’ World War II rivalry), a team of English chemists, including Charles Dodds, developed a formula for a cheap[54] yet powerful synthetic, nonsteroidal estrogen and released the formula to the public in the British magazine Nature on February 5, 1938.[55]
This estrogen, diethylstilbestrol (“DES”), had the same effects as estrogens derived from animals and plants, but was three times more powerful; additionally, anyone could make it because Dodds had relinquished his own patent rights when he published the formula.[56] In publishing his formula, Dodds was conforming to the British custom at the time (and his own opinion) that scientific work was done by scientists working for the public good; thus such discoveries should be made available to the public without having to pay high prices to proprietary pharmaceutical companies.[57]
From the beginning, though, Dodds was concerned about the cancer-causing potential of DES, as well as any harmful noncancerous effects of introducing a foreign substance into the complex female reproductive cycle.[58]
Other scientists confirmed Dodds’ suspicions. Even as early as 1932, data suggested that estrogens induced mammary cancer in mice,[59] and throughout the 1930s, there were already numerous warnings published in prestigious journals about Butenandt’s estrogens.[60]
In December 1939, the Journal of the American Medical Association published editorials urging a thorough investigation of DES prior to approval by the Food and Drug Administration (“FDA”), after the journal caught wind of rumors that many requests to market DES were being filed at the FDA, because of the possibility of carcinogenesis and the risk of putting it on the market due to the unknown long-term effects.[61] One of the editorials, “Estrogen Therapy – A Warning,” remarked:
Regarding conflicting reports about DES...apparently a thorough investigation of this compound is in order before it can be prescribed for routine therapy...The possibility of carcinoma induced by estrogens cannot be ignored...it appears likely that the medical profession may be importuned to prescribe to patients large doses of high potency estrogens, such as [DES], because of the ease of administration of these [products].[62]
A second editorial in the same issue of JAMA was written by the Council on Pharmacy and Chemistry that discussed negative side effects of DES.[63] In observing DES in menopausal use, various side effects, such as “nausea, vomiting, abdominal stress, anorexia, and diarrhea...associated with the gastrointestinal tract...[and] were frequent enough to alarm not only the patients but also the investigators.”[64] In conclusion, the Council warned that:
because the product is so potent and because the possibility of harm must be recognized, the Council is of the opinion that it should not be recognized for general use... at the present time...and that its use by the general medical profession should not be undertaken until further studies have led to a better understanding of the functions of the drug.[65]
Another editorial in JAMA four months later commented on the use of small doses of estrogens to treat patients in order to avoid toxic side effects.[66]
The editorial stated: “It would be unwise to consider that there is safety in using small doses of estrogens, since it is quite possible that the same harm may be obtained through the use of small doses of estrogen if they are maintained over a long period.”[67]
Regardless of such warnings in scientific journals, thirteen drug companies had applied to the FDA to market DES by 1940.[68] After all, DES was cheap, effective in oral form, an excellent copy of natural estrogens and containing all the same powers, and best of all, unpatented![69] Thus, DES was available for anyone who wanted it without charge (i.e. no licensing fees or royalties) and limited research costs.[70]
There was huge potential for high profit margins because most traditional overhead costs were eliminated, even though the companies would still have to incur marketing and production costs.[71]
The FDA, however, put the drug companies in a catch-22. The FDA let the companies know that it would turn down any application, but that the companies had the right to protest.
[72] A protest by the companies was not really a good option, because the warnings about cancer that were published in scientific journals were not yet widely known by the public; once the media caught wind of the cancer warnings, it would almost certainly be brought to the public’s attention, backfire in the companies’ collective face, and shut the door to DES marketing permanently.[73]
The other option was for the companies to quietly withdraw their applications, regroup, and make another attempt to get approval later; this is exactly what the companies did on December 30, 1940, and the withdrawal was approved the by the FDA on January 17, 1941.[74]
Instead of individually fighting the FDA in the public domain, the drug manufacturers held a meeting and decided the best course would be to withdraw all of their applications from the FDA and wage a targeted campaign as a group.[75]
This group was to become the precursor to the formation of the official pharmaceutical lobbying group in 1951, Big Pharma, the powerful industry lobby.[76]
The companies agreed that pooling their resources was essential in order to gather a master file on DES and work towards winning government approval the next time around.[77] Four companies – Eli Lilly, Winthrop, Upjohn, and Squibb – led the effort and were known as the “Small Committee” and would do the bulk of the work on behalf of all of the companies.[78]
J.A. Morrell of Squibb himself collected 257 articles on DES showing the drug’s use in clinical situations.[79] By gathering articles showing the clinical use (i.e. how doctors would use the drugs with their human patients), rather than articles solely about laboratory tests on animals, the committee wanted to emphasize to the FDA that DES would be safe for specified uses in humans.[80]
Also, by stressing the clinical (i.e. human) impact of DES, the Small Committee wanted to keep attention away from the theoretical concerns and published animal studies showing that DES was well-known for causing cancer.[81]
The doctors of these (and other) pharmaceutical companies were only one part of the DES campaign. The other part involved Carson Frailey, the Washington lobbyist-publicist who was the executive vice president of the trade group the American Drug Manufacturers Association and had been an industry official since the 1920s.[82]
Frailey knew all the right people in the middle levels of government – the civil servants and bureaucrats who would be around long after their politically-appointed bosses and the presidents who appointed them were gone.[83]
Frailey started out by organizing a meeting on January 28, 1941.[84] The meeting’s purpose was to gather doctors from across the country so that they would write to the FDA in favor of DES approval; fifty-four doctors agreed to write to the FDA, describing their clinical experiences with a total of more than 5,000 patients.[85]
Only four doctors felt that DES should not be approved.[86] After five months, the lobbying campaign seemed to be having the desired effect, because on May 12, 1941, Frailey sent letters to the Small Committee members saying: “The time now seems propitious to suggest that you re-file [your] new drug application for [DES]. I am making no commitments that the application will be permitted to become effective, but the suggestion offered has official background.”[87]
The FDA officially approved DES for use in four types of treatments on September 19, 1941, including menopausal symptoms.[88] Once DES was approved for a few limited uses, the law permits DES to be used by physicians for off-label purposes in an experimental capacity; the FDA does not interfere with a doctor’s right to practice medicine, even though the doctor might be using a legal drug for purposes other than which it had been approved by the FDA.[89]
Thus, immediately after the FDA’s initial approval of DES for use with menopausal women, pharmaceutical companies and physicians became more interested in using DES to prevent miscarriages, and began using it for this purpose.[90] Even though the doctors were legally permitted to use DES in this off-label capacity, in 1947, the FDA officially approved DES for use in preventing miscarriages – which later proved to be the most controversial and harmful use of DES.[91]
Dr. Allen and other scientists, meanwhile, had been continuing to research, focusing on the role of estrogens in female cancers.[92]
In April 1941, just as the FDA was reexamining applications from Eli Lilly, Squibb, and several other drug companies to approve estrogen products for the treatment of menopause, Allen published an article in the journal Cancer Research on the propensity of estrogens to cause cervical cancer in animals, and concluded that estrogen was a carcinogen: “The high incidence of cervical cancer in these experimental groups emphasizes that estrogen is a very important factor, not merely an incidental one, in cervical carcinogenesis.”[93] Allen went on to point out that one reason why in other studies the incidence of cervical cancer in mice had been low is that “mammary cancer appears at an earlier age than does cervical cancer, and consequently animals may die of the former; i.e., many of them do not live long enough fro the cervical cancer to develop.”[94]
Thus, by the time the FDA was considering approval of estrogen products, it should have been aware that there were multiple well-run animal studies going on at major research centers showing the ability of DES to cause cancer as well as interfere with the normal development of the sexual and reproductive systems of offspring born to pregnant animals treated with DES.[95]
Despite this knowledge, the FDA approved, in 1941, the use of DES for the treatment of menopausal symptoms and menstrual disorders.[96]
DES and other estrogen products were approved for use under the newly revised Food, Drug and Cosmetic Act, which in 1938 underwent a major change in its standard of approval before companies could sell the product to the public.[97]
The new standard now required that the drugs up for approval met certain showings of purity, strength, consistency, and safety (though, not of effectiveness).[98]
In fact, DES was the first drug that was not life-saving to be tested under the new standard.[99] The new standards were not necessarily a bad thing for the pharmaceutical industry; in fact, with the government’s seal of approval giving “ethical backing” to new drugs, it helped to increase the sales of drugs.[100]
Menopause as a “disease”
Prior to the synthesis of estrogen and its use as a medical treatment, the medical profession was rather uninterested in middle-aged women.[101]
Any complaint that middle-aged women brought to their doctors was seen as part of the transition from youth to old age and could be blamed on menopause.[102]
But for the most part, doctors did not have any miracle cure for the symptoms of menopause, nor any label to define what women were experiencing.[103]
In modern medicine, however, the medical industry has “discovered” the middle-aged woman and her disease.[104] As Ivan Illich describes in his book, Limits to Medicine:
In the detection of sickness, medicine does two things: it “discovers” new disorders, and it ascribes these disorders to concrete individuals.
To discover a new category of disease is the pride of the medical scientist. To ascribe the pathology to some Tom, Dick, or Harry is the first task of the physician acting as a member of a consulting profession.
Trained to “do something” and express his concern, he feels active useful, and effective when he can diagnose disease.[105]
For most of the last fifty-plus years since the estrogen has been an FDA-approved treatment for menopausal symptoms, the middle-aged woman was no longer ignored, but became a prime target for the treatment of her new disorder: estrogen deficiency syndrome.[106]
Estrogen therapy was thus a useful tool help to replace a biological deficiency of estrogen that started at midlife.[107]
Since all women aged 40-60 go through menopause, the number of patients afflicted with estrogen deficiency syndrome (at the time and in the future) was enormous – the ultimate discovery!
And with the discovery of this new disease, the doctor would feel “active, useful and effective” because every middle-aged woman who came through his office would be diagnosed and treated.
Therefore, during the second half of the twentieth century, the medical industry had determined that the middle-aged woman, in her normal state, was sick; the idea of normal aging in women had been collapsed into a definition of pathology.[108]
The perception of menopause had changed from simply the end of menstruation or a life stage, to one of an illness that no woman can escape.[109]
Menopause, like hypothyroidism and diabetes, was a deficiency disease and therefore it, too, could be treated with a replacement therapy.[110]
As one physician said in late 1975, even in the face of a possible estrogen-cancer link, “I think of the menopause as a deficiency disease, like diabetes.
Most women develop some symptoms, whether they are aware of them or not, so I prescribe estrogens for virtually all menopausal women for a indefinite period.”[111]
This change in perception of menopause can be linked, as it is in many other new “disorders” like erectile dysfunction and irritable bowel syndrome, to a marketing phenomenon by pharmaceutical companies called “if you build it, they will come.”[112]
Because pharmaceutical companies have a profound influence on the ways people define and understand diseases, the “if you build it mentality” is often successful in creating a new disease class.[113]
After all, pharmaceutical companies have tremendous resources to invent drugs where none existed before, design clinical research to position those drugs in the marketplace, fund patient and professional groups who speak through the popular media, and vigorously promote awareness of their medicines and the ailments they are designed to treat. [114]
An executive in drugs marketing noted that “it’s not just about branding the drug; it’s branding the condition and, by inference, a branding of the patient...What kind of patient does a blockbuster create?
We’re creating patient populations just as we’re creating medicine, to make sure that products become blockbusters.”[115]
An article in the British Medical Journal agreed, and labeled the pharmaceutical companies’ behavior “disease-mongering” because the companies are really selling drugs to essentially healthy people.[116]
Drug companies campaign to raise awareness among doctors and consumers about a given disorder with the implicit understanding that there is a cure, and the cure is, of course, the pharmaceutical company’s new drug.[117]
Hormone replacement therapy is probably one of the best examples of the “if you build it, they will come” phenomenon, because vast numbers of women have taken it to prevent health problems associated with a “risk factor” that literally every woman will experience if she lives long enough: menopause.[118]
As a result, the use of hormone replacement therapy was successfully marketed as not only a treatment for menopausal symptoms of estrogen deficiency, but also as a preventative therapy to stave off any adverse effects from estrogen deficiency that come with menopause.
Although estrogen therapy was approved for treatment of menopausal symptoms in 1941, the real takeoff for marketing and prescribing estrogen did not happen until more than two decades later.[119]
The female population in the 1940s, 50s and 60s had been primed since birth to accept their proper role in society as a mother, caregiver, and housewife and were thus the perfect target for the marketing of estrogen.[120]
The middle-aged woman during these decades had already fulfilled most of her major purposes by bearing and raising children, and only had the role of housewife left after her children were grown and left the house.[121]
In the 1960s, the medical industry picked up on the opportunity to exploit the many housewives who suffered from what Betty Friedan dubbed “the problem that has no name,” namely that of the emotional trauma over society’s perception of her diminishing feminine role. [122]
Since biologically these midlife women were going through menopause, any emotional or physical complaint would be seen as a symptom of menopause.[123]
Thus, during the 1960s, midlife women were targeted by a flurry of advertisements for tranquilizers and antidepressants promising a cure for the symptoms of menopause.[124]
These advertisements created a stereotype of the menopausal woman as beset with psychological devils, anxious about her femininity and her waning attractiveness, and grieving over the loss of her ability to bear children.[125]
By creating a medical condition, pharmaceutical companies had ingeniously diagnosed the menopausal woman as ill and in need of treatment.[126]
The success of this campaign is evident from the numbers of drugs designed to treat the menopausal woman’s mental condition: during this period, women were more likely than men to be using psychotropic drugs;[127] from 1966-1971, the use of tranquilizers such as Valium had increased 110% and antidepressants had increased by 320%;[128] and from 1966-1971, 17% of all women (compared to 8% of men) had been prescribed psychotropic drugs and the median age for women using them was 44 years.[129]
The widespread prescription of tranquilizers and antidepressants to housewives eventually led to its practice being discredited, but not before the way had been paved for acceptance of the next category of drugs that would “treat” menopause.[130]
The prominent gynecologist Dr. Robert A. Wilson made it his personal crusade to continue the legacy of treating menopause as a disease that could respond to medical treatment.[131]
Wilson wrote a book in 1966 called Feminine Forever that identified the previously unrecognized and widespread health threat of estrogen deficiency, and proposed a solution to this problem.[132] Wilson’s work seems, by today’s standards, transparently misogynistic.[133]
He called menopause a state of “living decay,” unabashedly touting estrogen as a way to make older women more attractive and “pleasant to live with.”[134]
Wilson wrote that the “tragedy of menopause” is that it “often destroys her character as well as her health.”[135]
Wilson wanted to save women from this horrible fate by having women use estrogen from “puberty to grave” in order to abolish menopause and keep women “feminine forever.”[136]
He was playing into the fantasy of a fountain of youth and was succeeding.
Wilson can also be viewed as a savvy entrepreneur and an evangelist.[137] There is no doubt that Wilson made money from the sale of his book (100,000 copies sold in the first seven months alone) and the thousands of patients that flocked to him to be treated (by 1966 he said he had treated 5,000 women with estrogen).[138]
But Wilson’s self-image – that of a medical saint – was likely what drove his desire to spread his message.[139] He had founded a private trust in 1963, the Robert Wilson Research Foundation, for the purpose of promoting estrogens.[140]
Wilson recruited the makers of hormones to support not only his book but also his foundation and his many public appearances.[141]
Three such drug manufacturers contributed to his foundation in 1964: $17,000 from Searle, since Wilson was trying to show that their oral contraceptive, Enovid, was a way to prevent menopause if indefinitely used; $8,700 from Ayerst, the maker of the estrogen Premarin; and $5,600 from the Upjohn Corporation, whose progestin drug Provera Wilson was testing for use in menopause.[142]
And 1964 was not the only good fundraising year: the Wilson Foundation received funding totaling more than $1.3 million from the pharmaceutical industry.[143]
In November 1966, Wilson received a slap on the wrist from the FDA, who pronounced Wilson “unacceptable as an investigator for drugs in the menopause” because he was disseminating promotional material claiming hormones has been shown to be effective to “‘prevent aging,’ a condition for which they had never been proved to work.”[144]
Despite FDA’s disapproval of Wilson, his theory on menopause was not easily quashed. Feminine Forever was widely excerpted in such popular women’s magazines as Vogue, and during the late 1960s and early 1970s more than 300 articles promoting Wilson’s message on estrogen use appeared in women’s magazines.[145]
Drugmakers, too, ran with Wilson’s message through various means.
Ayerst Laboratories helped to fund the writing of Feminine Forever, provided Wilson with editorial assistance, and even surreptitiously bought enough copies at retail to push it onto the best-seller lists.[146]
Ayerst then kept the buzz going around the tantalizing title and Wilson’s promise of staying young and sexy well after the book was out of print.[147]
Ayerst and other pharmaceutical companies wove Wilson’s message throughout advertisements, confirming the menopausal woman as anxious about aging and emotionally unstable, both of which can be corrected with estrogen therapy.[148]
A 1972 promotional film said: “The physical alterations that are associated with the menopause may induce emotional changes.
When a woman develops hot flashes, sweats, wrinkles on her face, she is quite concerned that she is losing her youth – that she may indeed be losing her husband.”[149] From just a small sample of print ads for estrogen therapy, Wilson’s message comes across loud and clear:[150]
The menopausal woman in the 1950s and 1960s ads is sad, anxious, and emotionally out of control. Typical of such images is a 1960 ad by Hoffman-La Roche Laboratories for the drug Marplan showing a sad woman in a barren, dreary city with the caption: “When ‘change of life’ seems the end of life.
With the advancing years, woman’s vulnerability to depression often becomes intense. The future looms insecure: menopausal symptoms spark somatic concern. And as she faces losing a symbol her femininity, even suicidal panic may supervene.”
An Ayerst ad also displays three very depressed looking women with the caption: “The Estrogen Deficient Woman: The Needless Martyr.”
The “treated” menopausal woman in other ads is a happy, trouble-free wife standing proudly next to her husband, because otherwise she would have emotional and physical problems and be a burden to those around her.
An ad for Hoffman-La Roche’s Menrium says: “His wife has a lot of different menopausal symptoms, but only a few really irritate him. Her hot flashes, her vertigo, her palpitations -- that’s her problem.
What really bothers him is her nervousness, her irritability, and her excessive anxiety, often expressed by endless “book-shuffling, chain-smoking, reading-lamp” insomnia!...[Menrium] takes care of the vasomotor symptoms as well as the emotional symptoms.
That means the symptoms that bother his wife the most. And the symptoms that irritate him the most. So, to help them both get through menopause, remember Menrium.”
In ads from the 1950s-1970s, women who have been treated with estrogen therapy have happy, smiling faces. All of these women have been “cured” by hormones, giving women a “sense of well-being” or “joie de vivre,” and making women “feel better.”
For example, one ad notes: “Her days and evenings are full. It’s a busy, involved, normal life.”
The ads were quite effective: doctors were willing to jump on the estrogen bandwagon, absorb the messages and prescribe the menopausal woman with drugs for her condition.
This was despite the fact that estrogen had been approved for menopausal symptoms before the 1962 amendments to the Food, Drug, and Cosmetics Act required a stronger show of safety.[151]
The successful public marketing of many tenuous benefits of estrogen had also preceded the 1962 requirements for contraindications, side effects and effectiveness, or any restrictions on what companies could claim in ads.[152]
Doctors have always been able to prescribe FDA-approved medications for off-label uses as they see fit, and for whichever patients and conditions they choose.[153] Neither the FDA nor states (who license doctors) have ever had any authority over doctor’s decisions.[154]
Thus, doctors could be convinced of estrogen’s off-label benefits through ads, or samples sent by pharmaceutical companies, or expensive dinners and “consulting fees” paid for by the drug makers.[155]
The well-run marketing campaigns by pharmaceutical companies had created a general accepted characterization of menopausal women as estrogen deficient, and thus there were many doctors who prescribed estrogen therapy for long-term replacement of estrogen.[156]
In 1976, two researchers, who the previous year had linked estrogen to uterine cancer, commented on this practice:
The ‘estrogen forever’ philosophy has fortunately not dictated the standard of therapy of the menopause [in the Medical Center where the researchers works]...
Yet well-meaning physicians frequently prescribe these hormones, giving some patients estrogen even before the menopause and continuing it in some for the duration of their lives.
Adverse effects may become...manifested only after years of exposure...By then many patients have become psychologically addicted to estrogen and...object to its discontinuance. These chronically exposed women are uniquely jeopardized.[157]
Also worthy of note is that although every middle-aged woman could be diagnosed as being estrogen-deficient, it was the middle-class Caucasian women who were the particular objects of interest to the pharmaceutical companies.[158]
This subset of women was health-conscious and likely to see a doctor regularly.[159] They also had more disposable income at midlife than any other stage and could afford to pay for medical services.[160]
Finally, middle-class Caucasian women placed high value on their physical attractiveness.[161] Their health and attractiveness were regarded as assets, important to their social status and sexual marketability because, in society’s eyes, when women reach middle-age their worth is unavoidably declining.[162]
The harsh societal view of aging women, and specifically middle-class Caucasian women, was ripe for exploitation by the medical industry.
Thus a middle-aged, middle-class Caucasian woman was, and still is, especially susceptible to messages that target those fears and promise prevention of illness or everlasting youthful femininity.[163]
Not surprisingly, advertisements were not the only method used to reach the pharmaceutical companies’ target audience.
The outstanding New York public relations woman, Sandra Gorney, was hired by Ayerst Labs and did quite a spectacular job of legitimizing and iconizing the philosophy of Feminine Forever for a decade after its publication.[164]
Ayerst Labs provided a “service for media” through the Information Center on the Mature Woman – which Sandra Gorney was hired to direct.[165] Magazine and newspaper editors frequently published features on current menopause questions and controversies supplied by Gorney, whose style was breezy and readable but authoritative.[166]
Gorney’s free newsletters and background papers were attributed, if at all, to the Information Center on the Mature Woman, even though, to Gorney’s credit, her mailings to the media did acknowledge the Ayerst support.[167]
According to some calculations, the sales of Premarin, Ayerst’s hormone replacement drug, doubled or even tripled in the wake of Feminine Forever and the PR of Sondra Gorney and stayed at record-breaking levels until the mid 1970s.[168]
By 1975, Wyeth's product, Premarin, had become the fifth leading prescription drug in the United States.[169]
Celebrity endorsements by Lauren Hutton and Patti LaBelle were another way to capture public attention and legitimize the treatment of menopausal symptoms with hormone replacement therapy: in the 1980s, these women appealed to health-conscious concerns about disease prevention and women’s determination to remain vital beyond middle age.[170]
They endorsed the idea that HRT would not only help women get past the hot flashes and other symptoms of menopause (including, Hutton broadly hinted to Parade Magazine, looking older and feeling cranky) but, used long-term, it would also protect them from Alzheimer’s, heart disease, stroke, osteoporosis, and colon cancer.[171]
From these endorsements, the message came across loud and clear: it was admirable to take HRT, and it was questionable not to take it.[172]
The pharmaceutical companies had (and still have) another way of reaching the public: medical experts who appear on morning shows and give interviews to magazines and newspapers.[173]
This was a sneaky way of promoting the benefits of hormone therapy without having to identify any connection to the drug company, and needless to say, a successful route under the cloak of legitimate, independent, professional opinion.[174] The public goes unaware of such connections, of course.
But on November 20, 2002, reporter Sharyl Attkisson “outed” two of the most widely quoted menopause experts, Dr. Lila Nachtigall and Dr. Wulf Utian on the CBS Evening News, making them publicly acknowledge their receipt of financial support from the makers of Premarin and other hormones.
[175] Both Nachtigall and Utian signed a disclosure statement a few weeks earlier, in connection with a speaking appearance at a workshop on menopausal hormone therapy at the NIH, that required them to declare whether they had any financial ties to drug companies.[176]
Neither doctor acknowledged any such connections on this disclosure statement.[177] However, as Attkisson reported:
The selling of HRT was a coup...but a lot of the claims weren’t backed by serious science...women never knew the same doctors promoting the wonders of HRT often had a vested interest in the drug’s success. Much of the information that got into print was bolstered by quotes from respected experts such as Dr. Nachtigall...Readers weren’t told that Nachtigall is also a paid speaker for at least eleven drug companies including Wyeth[178] – the biggest maker of HRT drugs....Dr. Utian, another widely quoted specialist who is Director of the North American Menopause Society, has, as it turns out, gotten large grants and support from Wyeth.[179]
Although both doctors denied that financial support meant they were biased, Dr. Utian even commented that “when you see a magazine article and see a quotation from an expert, I think it’s almost impossible to know whether there’s a conflict of interest or not.[180]
This is not to say that every medical expert cannot be trusted to be unbiased, or completely free from ties to pharmaceutical companies, but rather that their advice should be questioned in the first place to see if it is biased.
But because the public is generally unaware that pharmaceutical companies have such success shaping public opinion, the huge marketing efforts by pharmaceutical companies like Ayerst paid off – the rhetoric of a panacea for a whole host of female concerns from aging to diseases was accepted by a medical profession and public that were willing to buy into the drug-company-created fantasy: Premarin became the number one prescribed in the United States in 1992, and 1997 it became the first Wyeth product to reach $1 Billion in sales – even with the ups and downs after 1975, Premarin remained in the top 50 prescribed drugs from 1966 until 2002.[181]
The Tumultuous Cost-Benefit Analysis of HRT
“For the midlife woman, [the medical treatment for menopause is a] paradox, for it contains both potential benefit and potential harm. The trick is to gain the first, while avoiding the second.” – Sandra Coney, author of The Menopause Industry[182]
The ability of women to competently parse out information about their new “disorder” has been nearly impossible. The complexity of the issues and risks of hormone replacement therapy has made a decision regarding its use a daunting task to tackle alone.
Thus women have had to rely on the mediating influence of their physicians, or alternatively, the simplified versions of medical wisdom in the mass media. The estrogen story was such a nice fairytale that it is almost too bad that at present, the story is falling apart piece by piece.
Pharmaceutical companies made a miraculous fountain-of-youth drug, physicians were happy to pass along the dream to their willing and “needy” patients, and women were buying into the dream of youth and attractiveness.
1975: Estrogen linked to increased uterine cancer
DES, one of the estrogens used (either in combination with progesterone or alone) in hormone therapy for menopausal women, took a big hit in 1971: studies connecting women’s DES use to prevent miscarriages during pregnancy with vaginal cancer in their daughters were published in the New England Journal of Medicine.[183]
Four years later, the FDA withdrew its approval of the use of DES during pregnancy.[184] Cancer experts saw at once that the significance of the 1971 study, and subsequent studies by the same doctors, went far beyond the conclusions relating to DES in pregnancy; these studies had shown that estrogen could be “seed” as well as “fertilizer” to cancer in humans, meaning that it could cause cancer as well as help it to grow.[185]
As a result, scientists at the National Institutes of Health held a conference in 1971 to talk about the basis for the use of estrogen as a therapy for menopausal women.[186] The conference deplored the lack of data on menopause and noted the uncertainty of benefits from estrogen therapy, but also concluded that “...the association of abnormal and elevated estrogens and abnormalities of the endometrium (the lining of the uterus) is very suggestive...”[187] In 1973, Medical Letter, the Consumer Reports of prescription drugs, cautioned:
The manufacturer’s advice to ‘Keep Her on Premarin’ seems unwise...References frequently cited in promotions of estrogens...present personal opinion...or poorly controlled studies...or no criteria for defining such vaguely characterized states as melancholy, diminished sense of well-being, and decreased vitality...The Medical Letter advises against the routine prescribing of estrogens during and after the menopause because there is no adequate evidence that such treatment is beneficial, and because...estrogens may promote or aggravate cancer in some women.[188]
Then, in 1975, just before the completion and publication at the end of the year of conclusive studies showing the link between estrogen replacement therapy and endometrial cancer, Novak’s Textbook of Gynecology came to conclusions that previewed the result of the studies:
...estrogens can be of importance in the development of cancer in those organs and tissues which are normally estrogen dependent, e.g. the genital tract and breasts...Any gynecologist who spends time in the pathology laboratory can be impressed the large number of postmenopausal endometria in which extreme degrees of hyperplasia and even endometrial adenocarcinoma are observed in women who have a history of prolonged estrogen therapy.[189]
Finally, in December of 1975, the New England Journal of Medicine published a series of articles comparing the risks of developing endometrial cancer between menopausal women who used estrogen for hormone replacement therapy and those who did not use estrogen.[190] The difference in risk of developing endometrial cancer between the two groups was dramatic: those who used estrogen therapy for five years or less were 5 times more at risk than non-users, and the risk kept increasing as the duration of the therapy increased, so that those who used estrogen for more than seven years were at 14 times the risk of non-users![191]
Ayerst Labs, however, less than two weeks after the publication of these studies, was bold enough to send out a “Dear Doctor” letter to physicians arguing that the articles were “weak studies,” and reassuring them that the link between estrogen therapy and cancer was not firmly established.[192]
Some doctors did not need to be reassured by Ayerst because they were already dismissing the studies as not showing a direct link of estrogens to cancer. [193]
Those doctors who have been liberal in their prescription of estrogens, giving them to virtually all menopausal women for indefinite periods, said that in their views the benefits of hormones still outweigh the risks.
The doctors who traditionally have been more conservative in prescribing estrogens, restricting them to women with severe menopausal symptoms, for a period of one to four years, said that the drug is clearly useful for such women even if it may increase their risk of developing cancer of the endometrium.[194]
Despite any flaws in the endometrial cancer studies’ design, the increase in cancer risk was “too high to be explained away by even major methodological flaws.”[195] The FDA seemed to agree, because on December 16 and 17, 1975, it convened a hearing in front of its advisory committee on obstetrics and gynecology to discuss the recent evidence linking endometrial cancer with estrogen use by menopausal women.[196]
A third study was presented to the committee, concluding that “among postmenopausal women who took estrogen the risk of developing endometrial cancer was greater than their combined risk of developing cancers of the breast, lung, ovary and colon.”[197]
Additionally, the panel heard a report showing the incidence of endometrial cancer in the San Francisco bay Area had increased by 50 percent from 1969 to 1979, after restricting the study to women over 50; the results were most obvious in upper socio-economic groups, where use of estrogens is most prevalent.[198]
It was also reported at the conference that other cancer registries showed similar increases in endometrial cancer rates.[199]
On January 8, 1976, the FDA announced that it would release new warning labels for estrogen products used to treat menopausal and post-menopausal women, which would “emphasize the newly reported increased risk of cancer of the uterus associated with prolonged use of estrogen products, particularly in post-menopausal women.”[200]
And that same day, after Ralph Nader’s Health Research Group had brought the Ayerst letter to the attention of the FDA, the agency released an announcement reprimanding Ayerst and calling the letter it sent to doctors “misleading in view of the recent and widely publicized discussion regarding estrogen therapy in women.” [201]
The FDA also required in 1976 that that each package of estrogen contain an insert warning of the risks of estrogen.[202] If the doctors disliked the attention they were getting before from the link to uterine cancer, the action by the FDA was certain to annoy doctors.
The studies’ conclusion that the apparently beneficial drug that had been given to well women could cause cancer naturally led to the inference that their doctors could not necessarily be trusted: doctors had given their healthy female patients assurances that the estrogen was safe, but this evidently was not the case.[203]
The American College of Obstetrics and Gynecology worried that the inserts in estrogen packages would further cause a rift in the doctor-patient relationship, because the information in the inserts about risks circumvented the normal process where doctors decided how much information to give to patients.[204]
By 1975, it was estimated that about 25 million prescriptions for estrogen therapy were written by doctors,[205] quadruple the amount prescribed in 1972.[206] Needless to say, the increased risk of cancer had the potential for widespread consequences.
Additionally, in 1974, there had been a report that had linked estrogen with gallbladder disease; the relative risk of estrogen users was two and a half times that of non-users.[207]
The decline in hormone therapy prescriptions was evidence of the growing accumulation of evidence against estrogen: From 1975-9176, estrogen use declined by 18% from 1975-1976, and another 10% from 1976-1977.[208] By 1980, the number of annual estrogen prescriptions had fallen by 50%[209]
Also, under pressure from grassroots activists as well as the FDA, Ayerst altered the Premarin advertising claims to include only menopausal symptoms such as hot flashes, night sweats, and vaginal dryness as indications of the drug.[210]
After the uterine cancer scare in 1975, scientists concluded that although estrogen is the major hormone player in menopause, since its use in treating menopausal symptoms like hot flashes and vaginal dryness have been quite effective, there had to be a way to mediate its effect on the uterus.[211]
Estrogen is the hormone that allows the lining of the uterus to build up in preparation for pregnancy.[212] If estrogen were the only hormone available, the lining of the uterus would continue to build up, which would put women at greater risk for endometrial cancer.[213] Progesterone is the hormone that causes the lining to shed when no fertilization of the egg occurs.[214]
Pharmaceutical companies learned a few years later from preliminary epidemiology studies that they could add progesterone to the estrogen therapy drugs to offset the risks of endometrial cancer.[215] The addition of progesterone to estrogen, known as “opposed therapy,” induced a regular bleed, helping to avoid the dangerous buildup of the lining that occurred under influence and hopefully protecting the uterine lining from cancer.[216]
Drug companies successfully campaigned physicians to use this new combined hormone replacement therapy in women who still had their uterus, and by 1988, a significant shift in prescriptions had taken place from unopposed estrogen to opposed therapy.[217]
The problem with adding progesterone to the estrogen was that although postmenopausal women continue to produce some estrogen, there is essentially no progesterone production post-menopause because the function of progesterone is no longer necessary.[218]
Thus no one could predict exactly what adding progesterone would do to a postmenopausal woman, because it was essentially a foreign hormone to the woman at that point in her life.[219]
The most noticeable effect was that progesterone caused 25% of women who used this opposed therapy to experience premenstrual syndrome, and many women also started to begin menstruating again.[220] The return of menstruation is the most common reason women give for discontinuing the use of HRT for those who have already stopped menstruation.[221]
1976: Estrogen linked to breast cancer
In 1976, breast cancer was added to the growing lists of diseases that estrogen therapy caused in menopausal women.[222] The first report of a higher risk of breast cancer in estrogen patients was especially alarming, because of the higher incidence of breast cancer among women (especially older women), and the poor prognosis for even early-stage breast cancer.[223]
Even a moderate increase of breast cancer among women using hormone replacement therapy could have an enormous effect, because breast cancer is the most common cancer among women.[224]
Currently, the Susan G. Komen Breast Cancer foundation notes that the chance of getting breast cancer increases as women get older, from a 1/36 chance when a woman is 50, to a 1/23 chance when the woman is 70, to a 1/7 chance of ever getting breast cancer.[225]
The biology of breast cancer is still not well understood, but many experts believe that estrogen stimulates the growth of cancer in cells in the breast and that progesterone might add to estrogen’s effect, thus increasing the risk of breast cancer dramatically.[226]
The effects of estrogen and progesterone on breast cancer were unclear through the 1970s, when studies showed no elevation in risk, and through the 1980s when several studies showed small elevations in risk, especially for long-term users; only in the 1990s were doctors’ suspicions about the increased risks of breast cancer due to estrogen and progesterone more clearly borne out in studies.[227] For example, a 1989 Swedish study found that after nine years’ use women using estrogen-only hormones had nearly twice the rate of breast cancer compared to women not using hormones, and the risk increased with the addition of progesterone so that women using a combination of estrogen and progesterone had four times the rate of breast cancer compared to nonusers.[228]
On their follow-up of women in this study in 1992, the researchers again found that the risk they discovered in 1989 remained – the risk of combined estroge