PremproCounsel Legal Team Articles and Publications
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Gynecologists and Estrogen: an affair of the heart
Fugh-Berman* and Anthony R. Scialli†

ABSTRACT Although definitive studies have shown that hormone therapy in
menopausal women has no overall or cardiovascular health benefit, obstetrician-gynecologists continue to believe that estrogen benefits women’s health.This mistaken belief
may stem from cultural factors unique to obstetrics and gynecology, as well as from the
dependence of physicians on pharmaceutical companies for the provision and interpretation
of scientific information.

DESPITE AN OVERWHELMING AMOUNT of evidence to the contrary, many
physicians still believe that estrogenic hormones have overall health benefits.
In this essay, we describe both stasis and change in physician beliefs about
estrogen and explore some cultural factors within obstetrics and gynecology that
may render that specialty especially susceptible to views that are not supported
by data.

History
In 1947, Premarin (conjugated equine estrogens) became the first hormone
therapy (HT) approved by the FDA for the treatment of hot flashes. In the 1960s, estrogen was promoted as a youth-preserving treatment; a vigorous advertising
campaign aimed at physicians was fortified by the publication of a pharmaceutical
company–funded book, Feminine Forever, written by the gynecologist Robert
Wilson (1966) and aimed at consumers. Feminine Forever promised that estrogen would restore youth, health, beauty, and tractability to menopausal women: “Menopausal symptoms, such as weakening of the bones, dowager’s hump, gastro-intestinal disorders, heart trouble, hardening of the arteries, atrophy of the breasts and sexual organs, disturbed vision, wrinkling of the skin, pains in the joints, etc, can be avoided by premenopausal therapy and often cured by postmenopausal therapy.” The possible risks of estrogen were dismissed: “The myth that estrogen is a causative factor in cancer has been proven to be entirely false. On the contrary, indications are that estrogen acts as a cancer preventive. Certainly the continuation of regular menstruation throughout life has a healthful cleansing effect on uterine tissues and seemingly reduces the incidence of endometrial cancer.”

Premarin was widely prescribed in the 1960s but fell out of favor in the mid-
1970s, after it was shown to increase rates of endometrial cancer eight-fold. HT
was resurrected in the 1980s, when combination products were introduced;
progestins were added to counter estrogen’s proliferative effects on the endometrium. The revamped version of estrogen was promoted for menopausal health.

Estrogens are effective treatment for hot flashes but have always been prescribed for other reasons. Sales of estrogen-progestin products soared through the 1980s and 1990s. In 1986, 20.3 million prescriptions for noncontraceptive hormones were dispensed, 66 to 82% for menopausal HT (Hemminki et al. 1988). Prescriptions for menopausal HT increased to 58 million in 1995, and then rose further, to 90 million a year, between 1999 and June 2002 (Hersh, Stefanick, and Stafford 2004). The increasing rate of hormone prescriptions cannot be explained by an increase in the number of menopausal women or menopausal symptoms.

Gynecologists have always been the primary prescribers of HT in the United
States and other countries. Gynecologists may be more likely to see women with hot flashes than other physicians; nonetheless, a survey carried out in the early 1990s found that HT prescription rates for symptomatic women were similar among specialties. Gynecologists, however,were almost four times as likely as internists or family practitioners to prescribe hormones to women without symptoms (Stafford et al. 1997). In the United States in 2002, gynecologists wrote 70% of estrogen or estrogen-progestin prescriptions. A cross-sectional survey of 426 postmenopausal women in Iowa found that women who were patients of gynecologists were 2.6 times more likely to receive estrogens than were women who were patients of family practitioners (Levy et al. 2003).The belief that hormones promote health is not limited to the United States. In Estonia and Finland, gynecologists are also more likely than family practitioners to believe that all menopausal women should be offered hormones (Hemminki 2004).

Until very recently, menopausal HT was termed “hormone replacement therapy”
(HRT), or estrogen replacement therapy (ERT), if estrogen was used without
a progestin.This terminology implied deficiency. Gynecologists were targeted
by hormone manufacturers, who encouraged physicians to view the naturally
lower levels of estrogen in older women as an endocrine disorder, similar to diabetes mellitus or hypothyroidism. Gynecologists are more likely than family practitioners or internists to view menopause as an endocrine deficiency (Saver et al. 1997; Stafford et al. 1997), perhaps because gynecological literature is replete with statements such as:

"Nevertheless, more than enough evidence does exist to define the climacteric
as an endocrinopathy in which changes in hormonal profile are associated with
extensive pelvic and extrapelvic target tissue effects. (Utian 1987)
In recent years, there has been increasing recognition that ovarian failure and
the resultant postmenopausal syndrome represent an endocrinopathy."  (Stumpf and Trolice 1994)

Menopause is a pivotal time for all women, with subsequent health consequences affecting society as a whole, so every effort should be invested in favorable intervention during this period. Endocrine aging in women is accompanied by certain serious structural, metabolic, and functional health outcomes. Certain conditions are reversible with HT, and it is therefore legitimate to value HT as a pure antiaging therapy. (Shoham and Kopernik 2004)

Hormones and Health Promotion
By the early 1990s, pharmaceutical company efforts convinced gynecologists
that estrogens prevented cardiovascular disease, although not a single randomizedclinical trial with disease endpoints had ever been performed in women. The only randomized controlled trial of estrogen to prevent cardiovascular disease to date had been done in men; the Coronary Drug Project was stopped early because estrogen increased cardiovascular events (Stamler 1977). The belief that estrogen would benefit women was based on evidence that is not scientifically reliable for prescribing decisions. First, estrogen was observed to decrease total and LDL cholesterol, and to increase HDL cholesterol. Second, estrogen appeared to have antioxidant effects.Third, estrogen was associated with decreased arteriolar constriction. Fourth, estrogen treatment of experimental animals on high-fat diets appeared to prevent manifestations of vascular damage. Finally, several, though not all, observational studies had shown that women with cardiovascular disease were less likely to have used menopausal HT than women without cardiovascular disease.

None of this constituted proof that estrogen prevented heart disease in
women. In fact, in 1990 when Wyeth-Ayerst, the manufacturer of Premarin and
Prempro (equine estrogen 0.625 mg with medroxyprogesterone acetate 2.5 mg), sought FDA approval for a labeling change stating that Premarin prevented heart disease, the application was appropriately denied. Clinical studies of cholesterol or other surrogate markers cannot prove that a therapy reduces cardiovascular risk. Observational studies can never prove therapeutic effectiveness, because the choices that distinguish groups may be markers for other choices or circumstances that affect disease risk.

Data supporting the fact that women who chose to take estrogen were different from women who chose not to were available in the medical literature in the 1990s. Estrogen users had fewer cardiovascular risk factors than non-estrogen users prior to therapy and were more likely to make lifestyle changes that reduced cardiovascular disease risk than were non-users (Barrett-Connor 1991; Egeland et al. 1988; Kritz-Silverstein and Barrett-Connor 1996).

Despite the lack of reliable evidence supporting estrogen’s purported cardiovascular benefits, gynecologists believed that HT was more important for preserving health than smoking cessation. A survey asked 330 gynecologists, family practitioners, and general internists in Washington, Alaska, Montana, and Idaho to rank the importance of discussing eight disease prevention issues.

Gynecologists ranked mammography first and HT second, while family practitioners and internists ranked smoking cessation first (Saver et al. 1997). The sincerity of gynecologists’ belief in estrogen can be demonstrated by the fact that women gynecologists were more likely than other practitioners to use HT themselves (Frank and Elon 2003; McNagny,Wenger, and Frank 1997).

Gynecologists also minimized risks attributed to HT.A 1997 survey of managed
care providers in North Carolina found that gynecologists were less concerned
about the potential link between HT and breast cancer or thromboembolic
events than were family practitioners or internists (Exline, Siegler, and
Bastian 1998); another study found that gynecologists were significantly less
likely to express concern about thromboembolic risk than other physicians
(Rolnick et al. 1999).

The perceived strength of the evidence of benefits was so great that gynecologists believed that all menopausal women should be informed of the benefits.

A 1992 Technical Bulletin of the American College of Obstetricians and Gynecologists (ACOG) stated that although no large randomized drug trials had been conducted, “epidemiologic studies . . . strongly suggest that hormone replacement therapy decreases the risk of cardiovascular disease.” In May 1998,ACOG strengthened its recommendation:

Traditionally, hormone replacement therapy has been started in menopausal
women for treatment of vasomotor symptoms, mood disturbances, vaginal dryness, and osteoporosis prevention. However, because an increasing number of menopausal women are now better informed regarding menopausal changes and are beginning to embrace the concept of preventive health care, other additional benefits of hormone replacement therapy such as protection against cardiovascular disease and possible protection or delay in the onset of senile dementias make this option even more appealing.

By the end of the 20th century, some practitioners in other specialties were
swayed by the mounting promotion of menopausal estrogen therapy.A survey of 260 gynecologists, family practitioners, and general internists found that all
groups believed that menopausal estrogen benefited cardiovascular disease and
osteoporosis. Gynecologists, however, were significantly more likely than other
physicians to believe that HT benefited Alzheimer’s disease (Rolnick et al. 1999).

Randomized Controlled Trials of HT for Disease Prevention
The first major challenge to the premise that estrogen was cardioprotective was
the Heart and Estrogen/Progestin Replacement Study (HERS), a prospective,
randomized, double-blind study in 2,763 women with coronary disease.Women
with previous heart attacks or severe cardiovascular disease were chosen because this group was anticipated to benefit most. HERS was a secondary prevention study, a study that treats subjects at high risk of whatever disease outcome is being studied. (In contrast, primary prevention studies test interventions in the general population.) HERS found no benefit of hormones in preventing cardiovascular events at five years or at 6.8 years (Grady et al. 2002; Hulley et al. 1998).

Physician speakers, most of whom were paid by pharmaceutical companies,
were quickly dispatched to explain to gynecologists that estrogen was still expected to benefit healthy women, and that even women with heart disease
would have benefited had HERS lasted longer:

The results of HERS do not contradict the weight of epidemiological study
findings showing a primary protective CVD effect in longer-term HRT users.
Indeed, because of possible serious flaws in the study, a protective benefit of
HRT for secondary CVD prevention cannot be ruled out.The HERS findings
actually support the beneficial changes in lipoprotein profiles noted in the
majority of studies, and they confirm the well-established benefit on CVD
in long-term HRT users. (Thorneycroft 2001)

The hormone-treated group in HERS showed more cardiovascular events in
the first and second year, but fewer events in the fourth and fifth year, so hormone proponents recommended that women continue treatment in order to experience the late-occurring benefits. This argument was disingenuous. Cumulative events were similar in the hormone and the placebo group; the way women avoided having cardiovascular events in the fourth and fifth years was by having these events in the first or second year.The net effect of HT was not to decrease cardiovascular events, but rather to hasten them.

Gynecologists remained committed to estrogen. In 2000, a survey of 250
gynecologist members of the North American Menopause Society and 250
members of an Israeli menopause society found that 94.6% of the American
gynecologists recommended HT during menopause unless the treatment was
specifically contraindicated; rates of hormone recommendation were similar
among Israeli gynecologists (Kaplan et al. 2002). Another international study,
also conducted after HERS was reported, surveyed U.S. and European authors
of articles on HT and cardiovascular disease. Thirty-seven of 108 authors, representing gynecologists, cardiologists, internists, and nonphysician scientists,
responded. Asked to consider a risk modification of more than 20% as clinically
relevant, 57% of responders still thought that HT was beneficial for primary prevention, and about 30% thought it was beneficial for secondary prevention
(Rozenberg, Fellemans, and Ham 2001). Not one of the respondents believed
that HT could have an unfavorable effect (increasing risk 20%) on primary prevention, and only 2% thought it could have an unfavorable effect on secondary prevention.

The definitive study of hormone use in healthy postmenopausal women was
in progress at the time. As a consequence of activist efforts by the National
Women’s Health Network, a consumer advocacy group, the National Institutes of Health (NIH) designed and funded the Women’s Health Initiative (WHI), a large, prospective, randomized placebo-controlled trial of estrogen (with and without progestin) in healthy menopausal women. In July 2002, the combined estrogenprogestin arm of the WHI was stopped early because the treated group experienced higher rates of breast cancer, cardiovascular disease, and an increased index of overall harm (Writing Group for the Women’s Health Initiative Investigators 2002). In February 2004, the estrogen-only arm was halted early because of an increase in stroke among the treated group, and because estrogen failed to show any cardiovascular benefit. Later analyses showed that the estrogen-progestin combination doubled the risk of venous thrombosis and dementia (Cushman et al. 2004; Shumaker et al. 2004); representatives from NIH have stated that a trend towards increased dementia risk has also been noted in the estrogen-only arm.

WHI was a large, primary prevention trial that contained enough subjects
(more than 27,000) to answer the research question; used a design widely
acknowledged to be the standard in testing therapeutic efficacy; tested Prempro, the most popular hormone combination; and was monitored by a data safety monitoring board using pre-established criteria. Practitioners should have been satisfied that the question of estrogen as a health-protecting drug had been resolved. Instead, a storm of protest erupted from physicians who could not, or would not, believe the results. Objections to the WHI results (almost exclusively from gynecologists) were so widespread that the media characterized the WHI results as confusing and controversial.

In truth, there was no confusion about the data, which were monotonously
consistent with HERS and other randomized controlled studies.

Spinning the WHI Results
In the three years since July 2002, menopause “experts,” almost all of whom receive money from companies that sell HT products, have repeatedly written or lectured about the failings of the WHI. The fundamental theme throughout these arguments is that the women in the WHI were not normal, did not represent typical patients, and were not the sort of women likely to benefit from estrogen. Diverse versions of this argument were often combined to mimic an accumulation of evidence. Here are the most common arguments used in an attempt to refute the WHI findings.

Too Few Participants Close to Onset of Menopause

The first argument is that the WHI contained too few women close to the onset of menopause:  The WHI was a study of elderly women who were not representative of the population receiving hormone therapy. (Speroff 2003)

However, participants were not typical users of HRT. Women enrolled were asymptomatic and older (mean 63 years) than many women who take HRT (commonly in their early 50s). (Grimes and Lobo 2002)

This argument is based on the premise that estrogen prevents menopause-related illness, but only if therapy is started early, that is, before decrepitude has set in. The fundamental premise is false: there is no evidence that the onset of menopause is associated with ill health. Besides, more than 9,000 of the women (fully a third) in the WHI were in their 50s. In fact, the WHI is the largest randomized controlled trial ever done of women in this age group. Moreover, age and years since menopause made no independent contribution to the WHI results (Manson et al. 2003).

In other words, estrogen did not prevent cardiovascular disease in younger menopausal women any more than it did in older women.

Asymptomatic Women Are Not Normal