Broken Promises: The History of HRT

July 29, 2011

By Dr. Carolyn Dean MD ND

BROKEN PROMISES: THE HISTORY OF HRT

It’s only in the past one hundred years, since the lifespan of women has almost doubled, that we have been able to focus on menopause and what it means to women. What follows is the history of HRT and how menopause came to be called a disease. According to modern medicine, labeling menopause a disease meant a drug had to be found to “cure” it.

Menopause Is Born
In 1821, a century before the isolation of estrogen, a French physician named de Gardanne invented the term menopause to describe the phenomenon of this transition phase in a woman’s life and the problems thereof. (His book was titled De la ménopause, ou de l’âge critique des femmes, which might be translated as On Menopause, or The Critical Age for Women.) Over the next 100 years, many researchers around the world searched for the “cure.” In the late 1800s, doctors experimented with testicular extracts for men and ovarian extracts for women. It wasn’t until the early 1900s that doctors realized that the ovaries produce two hormones, later called estrogen and progesterone.

Contraception Research
Inhibiting fertility was a focus of much research, and the first positive results were reported in 1919. Subcutaneous implants of ovaries from pregnant rabbits were injected into deer, rendering them infertile. It took eight years more years of research to achieve temporary sterility in mice by using oral ovarian extracts.

Progesterone contraception reached a successful conclusion in 1937 when researchers at the University of Pennsylvania were able to prevent ovulation in a rabbit. Over the next several decades several synthetic estrogens and progestins were developed., In 1956 Planned Parenthood funded the first controlled trial with a contraceptive pill containing norethynodrel. But in 1957 Enovid‚ the norethynodrel-containing oral contraceptive, was approved and marketed only for the treatment of menstrual disturbances, and not as an oral contraceptive. In 1960 the FDA approved the use of Enovid as the first oral contraceptive pill specifically to prevent pregnancy. In 1964 the second oral contraceptive, ethinyl estradiol, was approved by the FDA, and by 1965 there were already more than 2.3 million oral contraceptive users.

Curing Menopause
In 1929, the first American doctors to attempt to treat menopause symptoms were Drs. E. L. Severinghaus and J. Evans. Their treatment of choice was a derivative from the amniotic fluid of cattle. In 1930, a German doctor, Bernhard Zondek found that urine from pregnant mares contained water-soluble estrogens. Other researchers realized that decomposed and hydrolyzed pregnant mare’s urine contained estradiol., By 1933, a product made from the urine of pregnant women, Emmenin (which contained water-soluble estrogens, but mostly estriol glucuronide), became the first estrogen replacement product marketed in the United States. But work began immediately on producing a less expensive version from pregnant mare’s urine.

In 1939, diethylstilbestrol (DES) was marketed as a more potent form of estrogen than Emmenin. By 1948, it was advertised as having therapeutic value for the prevention of pregnancy complications, such as toxemia, low birth weight, and early pregnancy loss. Approximately two million women were exposed to DES during pregnancy in those years. The text in major medical journals in the 1950s describing DES read, “Recommended for routine prophylaxis in ALL pregnancies . . . Bigger and stronger babies . . . No gastric or other side effects.” It wasn’t until 1953 that a controlled trial using DES showed it had no clinical benefit in preventing complications during pregnancy.

By 1942 the higher-dose Premarin—1.25milligrams—was introduced to the U.S. public. Six years later, in 1948, the lower doses of Premarin—0.625 milligram and 0.3 milligram—were made available. In the 1950s, Ayerst Laboratories funded a massive campaign to educate doctors on menopause, menopausal symptoms, and the consequences of estrogen loss—and on the use of its product Premarin to treat menopausal symptoms.

In the 1960s the use of estrogen replacement therapy (ERT) escalated to include about 12 percent of all postmenopausal women. Premarin use grew 170 percent from 1963 to 1966, and it became the #1 dispensed drug in America. The spurt in ERT use was given a boost in particular when Dr. Robert A. Wilson published his article “No More Menopause” in Newsweek magazine in January 1964.

Feminine Forever: The Marketing of Menopause
Spurred on by his popular article on menopause in Newsweek in 1964, Dr. Robert Wilson promised millions of women in his 1966 book that they could be Feminine Forever. In this book, he promoted estrogen to American women, and he widely educated women and doctors to believe that “Menopause is an estrogen-deficiency disease.” By naming menopause a deficiency disease, the next step was to advise replacement therapy in the form of Premarin. The very basis of estrogen treatment belied the fact that producing lower levels of hormones with age is a normal part of life.

According to the New York Times in July 2002, Ronald Wilson reported that his father’s research foundation, book, and speaking tours were funded by Wyeth-Ayerst, the makers of Premarin. I have a vintage copy of Feminine Forever, and I see no acknowledgement or disclosure that his promotion of estrogen was sponsored by Wyeth-Ayerst.

In his book, Dr. Wilson expresses his “sympathy” to women, who should not be “condemned to witness the death of their own womanhood” but who should be allowed to “remain fully feminine—physically and emotionally—for as long as they live.” He lauded the major medical breakthrough that allowed women “the opportunity to remain a complete woman.” He referred to himself as a “gallant knight” on a mission to help women through their “loss of womanhood.” He even goes so far as to compare himself to Dr. Ignaz Semmelweiss, who, after examining women with severe post-surgical infections, urged fellow doctors to wash their hands before performing surgery. Semmelweiss’s advice was ridiculed and he was fired and castigated. Wilson announced his frustration that the world was ignoring his “medical procedure of tremendous value to every woman.” So what did he do? He went directly to the people—with the backing of the makers of Premarin, and without the necessary science to proceed—and he spearheaded an extensive experiment on women.

Much of the book is patriarchal and patronizing and very, very dated considering what woman have accomplished in the last forty years. Wilson even advises women to take Premarin to prevent their husbands from having extramarital affairs. His opinion: “In truth, an extramarital affair may not, in the literal sense of the term, involve any infidelity at all. For a man may loyally maintain a deep love for his wife and yet feel the need for a kind of thrill that a wife with her aura of comfortable domesticity cannot give.” By some miracle, Premarin was supposed to change a housewife into a vamp who keeps her man. Please!

But the PR worked, and within ten years of the publication of Feminine Forever, Wyeth-Ayerst’s Premarin was the fifth-leading prescription drug in America. Obviously, such commercial promotion under the guise of “friendly” advice from a trusted doctor is hardly “scientific”; it denies patients the right to proper scientific evidence of the harmful effects of estrogen, while only promoting the so-called benefits. Today, “friendly” promotion for HRT still appears in the form of commercial endorsements from popular singers and actresses, people whom the public admire and whose example they follow.

Give Men Estrogen for Heart Disease
“If estrogen deficiency’s a disease, all men have it!” says Dr. Susan Love, breast surgeon and author, who loves to take pot shots at the menopause industry. In fact, some researchers used men in the very first clinical trial to prove that estrogen prevented heart attacks. Researchers had long felt that women had less heart disease before menopause because of estrogen. Back in 1973, they were so sure that estrogen was associated with heart health that they enrolled a group of men and put them on estrogen. They were shocked to find that early in the trial those men on estrogen were experiencing more heart attacks than those on placebo. The trial had to be stopped. Instead of wondering if the same would occur in women, they just shrugged their shoulders and said that maybe the dose of estrogen was too high. As you’ll read later, not until the 2003 analysis of the Women’s Health Initiative study was there an admission that hormone replacement can, indeed, increase the risk of cardiovascular disease.

Estrogen Side Effects Accumulate
By 1968 there were numerous reports of an increased risk of cardiovascular disease and strokes with the use of high-dose oral contraceptives. Within a few years, oral contraceptives containing less than 50 mcg ethinyl estradiol, when compared to those containing more than 50 mcg, showed a lower risk; many women switched to the lower dose pills. Studies of women on estrogen also revealed an increased incidence of endometrial cancer. By 1972 there was a moratorium on the use of estrogen, alone, for menopause. The shocking news that DES was causing an increase in cancer added fuel to the anti-estrogen lobby.

The DES Story
DES was pulled from the market in 1971 when babies born to DES users were found to have increased incidence of cancer of the reproductive organs. It has taken over thirty years, a whole generation, to come to this conclusion. In 1977 a DES registry was formed to collect information regarding the use of DES and to alert women who had used DES in their pregnancy to inform their children. DES children were developing genital tract lesions and gynecologic cancers in their adulthood.

Breast Cancer Surfaces
It wasn’t until the late 1980s that reports of breast cancer with the continued use of ERT surfaced. We now know that breast cancer takes fifteen to twenty years to develop from its original inception. In the early 1990s tamoxifen, an estrogen receptor modulator, was touted first for treating and later for preventing breast cancer. It is being recommended to healthy women even though we have no idea of the long-term effects. What we do know, however, is that it was labeled a carcinogen in 1996. It has the unusual distinction of being able to cause and cure the same condition.

The Search for Benefits of ERT
With all the negative side effects of estrogen being reported, the pharmaceutical industry pushed to find some benefits. Several studies were reported in 1980. One study showed a 60 percent reduced risk of hip and wrist fractures in women taking ERT, another study showed inhibition of postmenopausal bone loss. Several studies implied that the risk of endometrial cancer could be reduced by adding a second hormone to the ERT regimen—synthetic progesterones called progestin. Epidemiologic reports of lessened cardiovascular risk with ERT also appeared at this time. By the late 1980s, estrogen became available as a transdermal patch. All in all, by the mid-1990s researchers had claimed that postmenopausal estrogen may be useful in the prevention of the following diseases: Alzheimer’s disease, age-related eye disease, colon cancer, tooth loss, diabetes, and Parkinson’s disease.

Estrogen on Trial
Several large-scale hormone trials were finally initiated to prove or disprove the safety of hormone replacement and its possible benefits:

1. The Heart Estrogen/Progestin Replacement Study (HERS). Between February 1993 and September 1994, twenty HERS centers recruited and randomized 2,763 women to study estrogen in relation to heart disease.
2. The Women’s Health Initiative (WHI) clinical trial and observational study, sponsored by the National Institutes of Health, followed over 161,000 postmenopausal women for over ten years. The objective of the clinical trial was to evaluate the effects of postmenopausal estrogen use, dietary patterns, and calcium and vitamin D supplements on overall mortality, cardiovascular disease, breast cancer, colon cancer, osteoporosis, and other disease processes.
3. The Women’s Health, Osteoporosis, Progestin, Estrogen Study (Women’s HOPE Study) evaluated the effects of low-dose HRT on menopausal symptoms and osteoporosis.
4. The British Million Women Study looked into estrogen and progestin effects in the largest group ever studied.
5. New clinical trials on a selective estrogen receptor modulator (SERM)—the drug raloxifene—were begun. This drug is considered a second-generation SERM (after tamoxifen). Trials on osteoporosis prevention, heart disease prevention, and breast cancer prevention were initiated with this drug.

The Verdict on Estrogen
The news was increasingly unfavorable for ERT and HRT from the late 1990s onward. After estrogen was found to cause uterine cancer, the spate of trials in the 1980s showing some benefits of estrogen did not hold up under closer scrutiny and with much larger study populations.

1997: Data published in The Lancet (the British medical journal) from fifty-one epidemiological studies indicated an increased risk of breast cancer with postmenopausal estrogen use.[EN10]
1998: The Heart Estrogen/Progestin Replacement Study (HERS) found no heart benefit to women who took HRT and had cardiovascular disease. And women given HRT showed an increased risk of a second cardiovascular event during the first year on HRT compared to women given a placebo.
2002: The HERS study was extended and still showed no cardiovascular benefit of HRT in postmenopausal women with previous history of cardiovascular disease.
2002: The estrogen/progestin portion of the WHI study originally scheduled to end in 2005 was halted because of an increased incidence of invasive breast cancer and an excess of risk vs. benefit. The study also showed a decreased risk of colorectal cancer and fractures but an increased risk of venous thromboembolism.
2003: Further analysis of the WHI study indicated that there was an increase in the risk of cardiovascular events and breast cancer in women taking estrogen plus progestin.

The British Million Women study also found that women who are taking estrogen/progestin increased the density of their breast tissue. This may lead to incorrect mammogram readings and possibly make mammograms less reliable in detecting small cancers.

Reaction to the Women’s Health Initiative Announcement
As mentioned above, a full three years before the study was supposed to be completed the estrogen/progestin arm of the Women’s Health Initiative study had to be halted. Ethical review boards constantly review statistics from studies, and in the WHI study it became obvious that there was an increased incidence of invasive breast cancer in the HRT group. There was also an increased risk of thromboembolism—the formation of blood clots that can travel to other parts of the body such as the brain and heart, causing stroke or heart attack.

Often bad news in studies doesn’t reach the public, but there were no holds barred in reporting this distressing information. Over six million American women were taking estrogen-progestin pills in 2002. They, along with the doctors who were prescribing these drugs, were shocked to hear that HRT was proving to be more harmful than beneficial. However, anyone keeping up on the literature had seen the writing on the wall. The negative findings in the 1997 Lancet review and the 1998 report on HERS were only the tip of the iceberg. Even with those studies, the message from HRT proponents was always that we needed more studies and more proof. In July 2002 irrefutable proof was there for everyone to see.

Later analysis of the WHI results, published in May 2004, revealed that the risk of dementia doubled in women sixty-five and older who were taking HRT. Prompted by press releases and news reports that hormones might prevent Alzheimer’s, many doctors began prescribing for this “off-label” condition. (Off-label means that a drug is prescribed for non-FDA–approved indications.)

WHI and Premarin Alone
Women who have had hysterectomies take Premarin without progestins and account for about eight million Premarin users. The Premarin-alone arm of the WHI study was allowed to continue until 2004. However, it too was prematurely halted in February 2004, because there was an increased risk of stoke, a significantly increased risk of deep vein thrombosis, and no observable benefit to coronary heart disease.

The only benefit was a reduced risk of hip and other fractures. However, when analyzing the actual bone fracture statistics, the report said that the increased benefit for the bones is based on a total of six fewer hip fractures. In the 10,739 women studied there were only eleven cases of hip fracture for women on Premarin and only seventeen cases in women taking placebo. It is hard to see how these figures—involving only six people—can be called statistically significant results that allow the study authors to say that Premarin has a beneficial effect in preventing hip fractures.

Dr. Barbara Alving, acting director of the National Heart, Lung, and Blood Institute said, “These findings confirm that Premarin-alone therapy should not be used to prevent chronic disease.” She also said, “We believe the findings support current FDA recommendations that hormone therapy only be used to treat menopausal symptoms and that it be used at the smallest effective dose for the shortest possible time.” Researchers remind women that the study’s results are only evidence of what happens to women when they take continuous Premarin for 6.8 years.

Why WHI Happened
Decades of advocating for women’s health by grass-roots, feminist groups brought about the 1991 government-funded WHI study, according to Abby Lippman, Professor of Epidemiology at McGill University and Co-Chair of the Canadian Women’s Health Network (CWHN). In Dr. Lippman’s opinion, “Women were concerned by the increasing medicalization of women’s lives and by physicians’ tendency to push ‘pills for prevention’ of everything from hot flashes to memory lapses.” Lippman is a women’s advocate who derives her remarks from communication with a variety of women’s groups. She stated that women across North America “believed that federally-funded research was the only way to get results not tainted by pharmaceutical company interests, and they argued that this unbiased information was what women needed if they were to make informed decisions about their health.”

Dr. Lippman also remarked, “Without the intervention of the U.S. National Women’s Health Network and others, millions more would be getting prescriptions for HRT merely due to what the Network has called the ‘triumph of marketing over science.’” Drug companies have been spending billions in advertising to doctors in Canada and the United States, and to the American public, lauding the wondrous effects of HRT. Beyond spreading the message that HRT is not going to prevent chronic disease, Dr. Lippman says, “Pills for healthy people can be dangerous! And the burgeoning advertisements and other marketing activities of pharmaceutical companies are serious, potentially lethal, threats to our well-being.”

This is not just Dr. Lippman’s opinion; many women who are approaching the magic age of fifty have noted the habitual response of doctors. One glance at your age, one ear to hear a few of your nonspecific complaints, a quick peek at their watch, and out comes a prescription pad for HRT.

WHI and the Stock Market
Bad news spreads faster on Wall Street than it does in doctor’s offices. While many doctors remained equivocal about the results of the WHI study, it only took a few hours for the stock market to react. Shares of Wyeth, the makers of the $2 billion dollar drug (in 2001 sales) used in the study, fell by 19 percent. The company’s public relations team responded to the news by emphasizing that it was the combination pill of Premarin and progestin (Prempro) that was at fault and not their Premarin.
Wall Street and WHI Premarin-Alone Study

By March of 2004, the Premarin-alone arm of the WHI study showed no ability to prevent heart disease and even showed a higher risk of stroke. According to one newspaper account, Wyeth heaved a sigh of relief because at least Premarin did not show an increase in breast cancer or heart attack as did the combination pill.[EN12] By giving investors this “encouraging” news, Wyeth prevented another stock market plunge. By the end of the day Wyeth stock was only down 11 percent from two years ago, before the first announcement about Prempro. In actual sales figures, for the drugs themselves, sales of Prempro fell from $888 million in 2001 to $292 million in 2003. In the same two-year period, Premarin sales fell from $1.2 billion to $984 million.

The findings of the Premarin arm of the WHI study could still change, however, since women in the study will be followed until 2007. It must be remembered that it takes fifteen to twenty years for cancer to develop; the WHI trial only began in 1991 and it really should run until 2011. We also know that women have been taking Premarin since the 1950s, paralleling the increased incidence of breast cancer.

Healthier Women Choose Premarin
In a 2002 interview, Dr. Marcia Stefanick of Stanford University, who led the team of researchers on the WHI study, said the results of the WHI study would not necessarily reflect the general population because of overwhelming evidence in past decades that “estrogen users were by and large a healthier group of women, and so we have what we call the healthy user bias effect [leading to] the incorrect belief that estrogen or estrogen and progestins would prevent heart disease.”[EN13] Dr. Stefanick also noted that women who take hormones are also more likely to take better care of themselves through diet, exercise, and keeping their weight down. She commented that these are the approaches that “we now would like to encourage women to recognize as a better approach to preventing heart disease.” So, in fact, it may not be the hormones that prevent heart disease as much as the diet and exercise habits of the women who take them.

No More Magic Bullets
Previously approved only for menopausal symptoms and osteoporosis prevention by the FDA, HRT has been promoted by drug companies as the magic bullet for many other conditions. Using the results of small industry-funded studies showing possible protective advantage in aging, cancer, and heart attacks, drug company reps were pushing HRT for off-label conditions. Essentially, we are back in the mid-1970s when researchers realized that estrogen alone was causing endometrial cancer, and we mustn’t forget those decades-old results. Since that time, estrogen alone has only been recommended to women who have had a hysterectomy, as it is not an option for women who still have their uterus.

Dr. Victoria Kusiak, Wyeth’s North American medical director, has stated, “We certainly think that the significant finding from the study was that there was no increased risk of breast cancer.” As a physician, I do not gain confidence enough from this to recommend Premarin—though it does give me more confidence to suggest alternatives! We’ll get to those alternatives, which include natural hormone replacement, in Chapters 11 to 13.

Advice from the FDA
About a year and a half after the announcement that Prempro was doing more harm than good, and before we learned that Premarin was not as beneficial as some thought, the FDA launched a nationwide campaign “to provide better health information to women about the use of hormones to treat symptoms of menopause.” The campaign was directed at the more than ten million women using ERT and HRT and the two million women per year who enter menopause. Six months after the Prempro study was halted, the FDA advised women and health care professionals that “menopausal hormone therapy is associated with an increased risk of heart disease, heart attacks, strokes, and breast cancer.” The warning emphasized that these products are not approved for heart disease prevention. (Yes, this repeats what has been said above—the point is that the concern about the use of HRT expressed earlier is also the FDA’s concern.)

The FDA’s press release goes on to say that, “because there are few “proven” alternatives for the relief of hot flashes and vaginal atrophy, menopausal hormone therapies have an important role in women’s health.” But, as it hastens to add, “It is very important that women realize that this beneficial therapy also carries significant risks. Our recommendation is that if you choose to use hormone therapy for hot flashes or vaginal dryness, or if you prefer it to other treatments to prevent thin bones, take the lowest dose for the least duration required to provide relief.” Labeling of hormones will also change and will “clarify that these drugs should be used only when the benefits clearly outweigh risks.”

Questions to Ask Your Doctor, Nurse, or Pharmacist
The FDA provides a list of nine questions to ask your health care practitioner. Number two is: “Are there other things I can use or do?” But the FDA has already stated that “because there are few ‘proven’ alternatives for the relief of hot flashes and vaginal atrophy, menopausal hormone therapies have an important role in women’s health.”
Question nine asks, “Do you have any advice to help me: Exercise, Stop smoking, Eat right, Sleep better, Reduce stress?” At no place in any of the FDA’s educational literature (which is paid for by taxpayers, by the way) is there any mention of the vitamin, mineral, herbal, homeopathic, or other non-drug therapies—many of which, in fact, have proven useful in menopause both in scientific studies and in ample anecdotal clinical cases.

Bailing on HRT
After the announcement about the dangers of HRT in July 2002, millions of women stopped their medications. From about six million users of combined therapy in 2002, by July 2003 there were only about 3.3 million. The number of women taking estrogen alone is estimated at about 6.7 million.

Since July 2002, millions of women and concerned practitioners are exploring the many and varied alternatives to HRT and finding answers.

Edited excerpt from Hormone Balance (Adams Media, 2005 by Dr. Carolyn Dean)

Dr. Carolyn Dean is a recognized authority in both conventional and alternative medicine. As the well-known author Hormone Balance: A Woman’s Guide to Restoring Health and Vitality, Dr. Dean is an expert in hormone balancing. She currently offers private telephone wellness consultations through her website at .
Dr. Dean is also an authority in the treatment of bowel disease, yeast overgrowth, and magnesium deficiency as evidenced by the 2005 publication of three of her ten books, IBS for DUMMIES, The Yeast Connection and Women’s Health, and The Miracle of Magnesium. Dr. Dean is the medical advisor to yeastconnection.com. She has researched and treated this condition for three decades.

You can reach Dr. Dean for wellness consultations on all types of health concerns or autographed copies of her books through her website http://drcarolyndean.com/.

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