Estrogen questions linger

It cost hundreds of millions of dollars and enlisted more than 160,000 postmenopausal women. Its best-known finding, that most women have nothing to gain from taking hormones, sent sales of estrogen pills plummeting a few years ago.

And yet, notes menopause researcher Elizabeth Barrett-Connor, articles challenging the Women's Health Initiative appear almost weekly. Over the phone, you can practically hear Barrett-Connor shaking her head. "I expect I'll spend the rest of my life explaining why they (critics) shouldn't be so opposed to the results," she says. Barrett-Connor, a professor of family and preventive medicine at the University of California-San Diego, served on the project's data safety monitoring board.

In medicine, as in most endeavors, old convictions die hard. And the Women's Health Initiative shot down a big one: the long-standing belief that postmenopausal hormone therapy protects women's hearts and brains.

Still, a coterie of gynecologists and other researchers refuses to give up on estrogen. At least two studies are trying to recruit hundreds of women to test the theory that when it comes to postmenopausal estrogen therapy, the sooner you start, the better.

The controversy shows no sign of letting up, even as the main phase of the Women's Health Initiative winds down with a flurry of publications this month and a conference Tuesday and Wednesday at the National Institutes of Health. The NIH is funding five more years' follow-up of participants, but it's unlikely that will lead to major revisions of the original conclusions.

"I think the WHI findings make it absolutely clear that nobody should be encouraging women to take hormones for the purpose of primary prevention of heart disease," says Stanford's Marcia Stefanick, head of the Women's Health Initiative's steering committee.

For years, gynecologists prescribed hormone replacement therapy, or HRT, thinking it would protect postmenopausal women from the ailments of age. "There's no question that a large percentage of the women taking hormone therapy before the WHI results, in the 1980s, 1990s, did not need hormone therapy," says the health initiative's JoAnn Manson, chief of preventive medicine at the Brigham and Women's Hospital.

HRT proponents cited so-called observational studies of postmenopausal women who chose whether to take estrogen or not. In study after study, estrogen users were healthier than non-users. Some studies suggested that estrogen therapy could protect postmenopausal women against dementia.

In light of the observational data, Wyeth in 1990 sought the Food and Drug Administration's OK to market Premarin for heart disease protection. But the FDA said no and called for a randomized trial, in which women would be randomly assigned to estrogen or a placebo.

Randomized trials are regarded as superior to observational studies because they minimize the chance that some characteristic of estrogen users, not estrogen itself, deserves credit for their better health. Indeed, 1990s research by Barrett-Connor and others found that estrogen users had fewer heart disease risk factors than non-users.

Questions about postmenopausal estrogen therapy's risks and benefits gave rise to the Women's Health Initiative. The National Heart, Lung, and Blood Institute funded it with $725 million; Wyeth provided the pills.

Postmenopausal women and their doctors were taken aback when the initiative reported in 2002 that Prempro, a combination of estrogen plus progestin -- a second hormone given to protect the uterine lining -- raised the risk for heart attack, stroke, blood clot and breast cancer. Less than two years later, a parallel study found that estrogen alone raised the risk of stroke, but not heart attacks or breast cancer.

The main problem with the Women's Health Initiative, skeptics say, was that the average age of hormone trial participants was about 63. By that time, the naysayers argue, atherosclerosis has too big of a head start on estrogen.

Another criticism: The initiative tested only Premarin and Prempro, which contain estrogen from pregnant mares' urine. The skeptics say the effects of estradiol, an estrogen made by premenopausal women's ovaries, remains to be seen.

In their defense, scientists with the Women's Health Initiative note that about 30% of hormone trial participants were in their 50s when they enrolled, and Premarin and Prempro were by far the world's top-selling brands of postmenopausal hormones.

A Wyeth-funded sub-study of women 65-79 who took part in the hormone trials brought more bad news: Hormone therapy did not protect women that age against a decline in cognitive function and actually increased dementia risk.

Given the estrogen-plus-progestin findings, the FDA began advising women to go on hormone therapy (HT) only to relieve menopausal symptoms and then only at the lowest dose for as short a time as possible. (The term hormone replacement therapy, which suggests that menopause is a deficiency requiring treatment, is now passe.)

But still, the believers have not been dissuaded. "Is the estrogen controversy over?" asked a headline in June in the Annals of the New York Academy of Sciences.

In the article, Mitchell Harman of the Kronos Longevity Research Institute and co-authors write: "Most women who start menopausal HT early in the menopause are candidates for prolonged continuation until or unless contraindications intervene."

Harman directs the privately funded $12 million Kronos Early Estrogen Prevention Study. The health initiative's JoAnn Manson is Harman's lead scientist at Harvard. The Kronos study aims to enroll 720 women ages 42 to 58 whose last menstrual period was six months to three years earlier. The women will be randomly assigned to Premarin, an estradiol patch, or no treatment for four years.

To make their case for studying estrogen in recently menopausal women, Harman and like-minded scientists cite the observational studies, animal experiments -- and the Women's Health Initiative.

In the Archives of Internal Medicine this month, the initiative published final data from the estrogen trial. Overall, women on estrogen had the same rate of heart attacks as those on the placebo. In women 50 to 59, the estrogen group had fewer heart attacks than the placebo group. But women in their 50s had so few heart attacks that the difference between the estrogen and placebo groups was not statistically significant.

Only when heart attacks, angioplasties and bypass operations were lumped together did the difference between the estrogen and placebo groups become statistically significant for women 50 to 59. Jacques Rossouw, the Women's Health Initiative project officer at the heart, lung and blood institute, downplays the finding. The decision to perform angioplasty mainly is triggered by the presence of angina, or chest pain. Estrogen is known to relieve the pain but not its root cause, he says.

Howard Hodis, head of the Early versus Late Intervention Trial with Estradiol, says the Women's Health Initiative has made it harder to recruit women for estrogen trials. "This has been one of the more disappointing aspects of WHI. Here we have all these immense remaining questions of women's health," says Hodis, a University of Southern California cardiologist and co-author of a 2001 study that found estradiol slowed or seemed to halt hardening of the arteries in healthy women just past menopause.

Hodis' $10 million study, funded by the National Institute on Aging, aims to enroll 504 women. Half will be assigned to an estradiol pill for three years; the rest, a placebo.

Like Harman's study, Hodis' isn't big or long enough to detect significant differences in heart attack rates. Instead, the studies will assess atherosclerosis in arteries with X-rays and/or ultrasound.

Menopause researcher Deborah Grady, a University of California, San Francisco internist who wasn't part of the Women's Health Initiative, says she doesn't see the point of Harman's and Hodis' studies.

"If it's true that estrogen is helpful right around menopause, maybe that's scientifically interesting," Grady says. But she questions whether that finding would have any practical use: "What then? You take it from 50 to 59? Then at some point it becomes dangerous? At what point is that? At age 60? How do we figure it out?"

To see more of USAToday.com, or to subscribe, go to http://www.usatoday.com

© Copyright 2006 USA TODAY, a division of Gannett Co. Inc.