Postmenopausal hormones

Hormone therapy: What happened?

Our assumptions about taking hormones after menopause have mostly been dashed. How did we get it so wrong?

In 2002, millions of postmenopausal women received the disconcerting news that a pill they’d been taking for long-term health benefits might be harmful instead. One portion of the Women’s Health Initiative (WHI) — the large controlled trial designed to address unanswered questions about hormone therapy — was cut short because of safety concerns. Five years into the eight-year study, it had become evident that estrogen and progestin (as Prempro) posed unacceptable risks for cardiovascular disease and breast cancer, even though it reduced the rates of colon cancer and fractures. As a result, medical advisory bodies that had once urged most postmenopausal women to consider hormone therapy now regard it as a last resort.

In putting several questions about postmenopausal hormones to rest, the WHI has raised another: How could a longstanding therapy have been so misguided? The answer is found in a century-long saga that says a lot about how the drug approval process, pharmaceutical company promotional activities, medical research, and the social and political climate can influence the standard of care in the United States.

In the beginning

The tale begins in 1889, when French neurophysiologist Charles Édouard Brown-Séquard reported, at age 72, that he had increased his strength, mental acuity, and sexual potency with injections of testicular extracts from animals. He suggested that women might get comparable benefits from ovarian extracts, and within a decade there were reports that such injections had indeed relieved hot flashes. The substance responsible was later identified and named “estrogen.”

In the 1920s, estrogen isolated from the urine of pregnant women became available for injections and later for pills, but there wasn’t enough human urine to supply the market. In the 1940s, Ayerst, a Canadian drug maker, found a way to tap another source — pregnant mares — whose copious urine could produce enough pills to fill millions of prescriptions. With a nod to the mares, Ayerst named its new drug Premarin. At that time, drug makers weren’t legally required to prove a product’s effectiveness, only that it posed no immediate danger to the user.

Premarin’s rise to prominence

When Premarin entered the U.S. market, the discomforts of menopause were considered an inconvenience to be endured, and dowager’s humps, hip fractures, heart disease, and senility were regarded as inevitable consequences of aging. To counter this perception, Wyeth, which had acquired Ayerst, mounted a massive effort to promote Premarin as a rejuvenating agent and mood stabilizer for postmenopausal women. During the 1950s, Premarin ads became a staple of medical journals, and sales representatives brought the message to doctors’ offices. By the mid-1960s, about 12% of all postmenopausal women were taking estrogen.

Physicians weren’t the only audience for the estrogen message. In Feminine Forever, gynecologist Robert Wilson appealed directly to women, enthusing that estrogen could “cure” menopause and make them look and feel healthier, younger, and sexier. The book, published in 1966, became a best seller, and Premarin prescriptions soared. Wilson’s son told The New York Times decades later that Wyeth-Ayerst had bankrolled the book’s publication.

Estrogen’s expanding use

In the early 1960s, Congress enacted a law requiring drug makers to prove the effectiveness of a product through clinical trials before it reached the market. The thousands of drugs already in use — Premarin included — were to be reviewed over the next decade. In 1972, Premarin and other estrogen products were deemed effective in relieving menopausal symptoms and “probably effective” against osteoporosis. Later, in 1986, the FDA approved Premarin for osteoporosis prevention on the basis of two clinical trials.

Manufacturers needed only 12-week studies for an estrogen to be approved for symptom relief and 24-month trials to secure approval for osteoporosis prevention. But many postmenopausal women stayed on estrogen much longer — some because their symptoms returned when they stopped taking the hormones, others for fear of missing out on purported health or cosmetic benefits.

Progestogens to the rescue

One adverse effect became apparent early on. Beginning in the mid-1960s, cases of endometrial cancer began to rise. In 1975, the New England Journal of Medicine published two studies showing that women taking postmenopausal estrogen had as much as 14 times the risk of endometrial cancer as women who did not take hormone therapy. Estrogen sales fell.

But physicians had a simple solution: Prescribe a monthly cycle of a progestogen — either natural progesterone or a synthetic version, known as a progestin — to counter the cancerous effect of estrogen alone. It worked. As a result, medical guidelines developed in the early 1980s advised doctors to prescribe a progestogen for postmenopausal women taking estrogen who had not had a hysterectomy. Meanwhile, epidemiological studies and biological evidence were building a case for estrogen as a cardioprotective agent.

By 1992 Premarin was the nation’s most widely prescribed drug. Millions of women were also taking a progestogen at a lower dose along with estrogen — even though progestogens were not approved for postmenopausal use. That changed in 1995, when the FDA approved Wyeth’s Premphase and Prempro, which combined Premarin with the progestin medroxyprogesterone acetate.

Decade of closer scrutiny

As hormone therapy became a fact of postmenopausal life, researchers became increasingly interested in its long-term effects. The Nurses’ Health Study (whose research strongly suggested that estrogen prevented heart disease) and other investigations provided a steady stream of data on the benefits and risks of long-term hormone use. It appeared to reduce the risk of osteoporosis and colon cancer, but apparently increased the risk of breast cancer, blood clots, and gallbladder disease. The evidence on heart disease and dementia was conflicting.

Most hormone therapy studies were observational; researchers compared the medical records of women who had used hormones with those who had not. Those studies were not conclusive — in part because women who chose to take hormones may have been healthier to begin with. To overcome this limitation, the National Institutes of Health and drug companies began controlled clinical trials in the early 1990s that randomly assigned postmenopausal women to take either hormone therapy or a placebo.

The results of the first such study, the Postmenopausal Estrogen/Progestin Intervention Trial, were enthusiastica lly proclaimed in 1995. Hormone therapy had improved HDL (good) cholesterol and lowered LDL (bad) cholesterol and clotting factors that contribute to heart attacks and strokes. But the study didn’t last long enough to determine whether these improvements paid off in fewer actual heart attacks, strokes, or blood clots. The picture began to darken in 1998, when the Heart and Estrogen/Progestin Replacement Study found that hormone therapy did not prevent heart attacks in women who already had heart disease. Moreover, women taking hormones had 50% more heart attacks during the first year. The results shocked estrogen enthusiasts.

WHI’s withering gaze

The Women’s Health Initiative was designed to settle once and for all the question of whether long-term hormone therapy could prevent heart disease and other degenerative conditions in healthy postmenopausal women. The Prempro arm of the trial found significant reductions in colorectal cancer (37%), hip fractures (34%), and spinal fractures (34%). But it also revealed increases in invasive breast cancer (29%), heart disease (24%), stroke (31%), blood clots in the veins (107%), and blood clots in the lungs (113%). As a result, the 16,000 women in the study were told in 2002 to stop taking the medication, and six million others taking Prempro on their own were urged to reconsider their decision with their doctors.

Hopes were dashed once again when additional data published in 2003 from the WHI indicated that Prempro did little to improve overall well-being or cognitive function. Worse, it doubled the risk of dementia in women over age 65.

What’s ahead for hormone therapy?

Is it over for Prempro? Although prescriptions dropped precipitously following the WHI’s results, Wyeth isn’t giving up. In July 2003, it launched two lower-dose versions of the hormone combination for the treatment of postmenopausal symptoms and prevention of osteoporosis. (There’s some evidence — but no proof — that the risks of Prempro are dose-related.) On the package label, women are advised to consider other ways to relieve vaginal dryness or prevent bone loss before choosing hormone therapy. They are also advised not to use estrogen-containing products to prevent heart disease.

Premarin and Prempro have dominated federally funded studies because they are the most commonly prescribed types of hormone therapy. They contain a unique mix of estrogens, some of which are unknown, and Prempro contains a unique progestogen. Some experts have serious reservations about these products and the combined regimen used in the WHI. Even so, we can’t assume other forms and regimens of estrogen and a progestogen are any safer. Limited data suggest they aren’t, and the Million Women Study (Lancet, Aug. 9, 2003) found that women taking postmenopausal hormone therapy, regardless of preparation, had an increased risk of breast cancer. Combined hormones posed three times as much risk as estrogen alone.
The legacy of the WHI is yet to be fully determined. Concern about an increased risk of stroke led the National Institutes of Health (NIH) to end the estrogen-only portion of the WHI in early March 2004. Although estrogen alone had no effect on heart disease or breast cancer risk, its effect on stroke risk was similar to that of the combined hormones. The NIH said this small increase in risk was unacceptable in a study of healthy women, leading it to terminate the estrogen trial one year short of its expected completion. WHI investigators are also following up with participants who took Prempro to see whether some groups of women might have benefited.

What now?

The WHI’s results were produced in large populations of women; the increased risk for an individual is small (see “Risks associated with taking Prempro”). Yet for most healthy women in midlife, the increased risk of breast cancer and cardiovascular disease is not an acceptable tradeoff for reduced risks of colon cancer and osteoporosis — especially since they can take other drugs to prevent osteoporosis and schedule regular screening to reduce colon cancer risk.

More than a century after it was conceived and millions of federal research dollars later, hormone therapy appears to be back where it started — as a short-term treatment for postmenopausal symptoms. But now we know more, thanks to focused women’s health research. The hormone therapy saga is a cautionary tale for postmenopausal women looking for alternatives to Prempro. We have even less evidence on the risks and benefits of other estrogen formulations. The cardinal rule of medicine, primum non nocere — first, do no harm — is a good one to apply.