Hormone researchers revolt

Criticizing recent negative studies of replacement therapy, some scientists are holding out for more data

Tabitha Powledge(tam@nasw.org)
Aug 21, 2003

Dismayed at what they regard as an unreasoning and unwarranted backlash against long-term sex hormone replacement for middle-aged women, hormone researchers are planning a counterattack. The researchers are trying to organize new studies they hope will answer lingering questions about hormones' long-term benefits and risks arising from recent negative clinical investigations. Many believe the results would be different this time.

Would-be revisionist researchers acknowledge that they face enormous hurdles with funders, regulators, the media, and perhaps women themselves. "These things tend to be self-fulfilling prophecies," complained Frederick Naftolin, who directs the Yale University Center for Research in Reproductive Biology and has been a vigorous critic of the studies and the ways they have been interpreted. "You get people talking about how the issue has been settled and it becomes settled."

The current backlash against hormone replacement therapy (HRT) resulted from a cascade of large-scale studies reporting small increases in breast cancer, coronary heart disease, stroke, and pulmonary embolism in women on HRT. Revisionist researchers argue that the studies are mostly worthless for answering the most urgent questions: whether long-term HRT begun early, at the menopausal transition, could postpone at least some of the diseases of aging, and whether different hormone regimens would yield healthier results.

They point out that the average age of study subjects entering the massive US Women's Health Initiative (WHI) was 63, long past menopause, and note that many of those women would already have been on the road to heart disease and other disorders. The scientists also point out that much other research—observational human studies and animal research—suggests that different hormone formulations, such as lower doses of estrogen alone, or estrogen plus cyclical progesterone, might be beneficial. The WHI used Prempro, a pill taken daily that contains synthetic progesterone and conjugated horse estrogens.

Wulf Utian, executive director of the North American Menopause Society (NAMS), told The Scientist that a committee from his group is putting together a list of urgent research that remains to be done on HRT. "There is a recognition by the committee that hormones have potential risks but certainly have potential benefits," he said. Committee members are drawn from both critics and supporters of the controversial human studies, and the report is expected in September, he said.

Among the questions the NAMS group wants answered are whether hormones could help postpone diseases of aging with tolerable risks if women began long-term HRT at the menopausal transition, when their sex hormones decline, rather than years later. They also believe hormone formulations and routes of administration different from those most commonly used now need investigating. There is evidence that these strategies might lead to better results not just from other research but also from the big recent studies themselves.

"But the dilemma, given the extremely negative spin that the media have taken on the whole subject, and the decline in sales throughout the pharmaceutical industry, is whether those companies would step to the plate and put money into expensive projects," Utian said.

Naftolin and other researchers have joined with the Kronos Longevity Research Institute to seek funding for a clinical trial of transdermal and oral hormone replacement for prevention of cardiovascular disease with study subjects who are perimenopausal. If support is forthcoming and regulatory issues can be settled, the multicenter trial might begin as early as next year.

The researchers plan to examine surrogate indications of disease progression, such as thickening of the carotid artery wall, rather than clinical events like heart attacks or strokes. Kronos's Mitchell Harman acknowledges that surrogate endpoints will not satisfy all critics, but notes that looking for statistically significant differences in clinical events among placebo and treatment groups of younger women would take ten years and 50,000 subjects.

The WHI, which involved well over 16,000 postmenopausal women, reported small increases in invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism in women taking Prempro, which has been by far the most commonly prescribed HRT in the United States. Because of these risks, the National Institutes of Health shut down the study in July 2002, two years early, even though there were observed benefits, among them a reduced incidence of hip fracture and colon cancer.

The WHI, a randomized double-blind clinical trial, issued final reports on cardiovascular data in the August 7 issue of the New England Journal of Medicine; they confirmed that Prempro does not protect the heart. The same week, Lancet published the United Kingdom's Million Women observational study, which confirmed once more a link between HRT and breast cancer, but also revealed risk differences that appeared to be related to hormone formulation and route of administration. The largest risk was in women on combination oral HRT like Prempro.

Marcia Stefanick of Stanford, one of the WHI principal investigators, concedes readily that many scientific questions about HRT remain up in the air, but she's dubious about getting them all resolved. A study that was big enough and lengthy enough to evaluate the long-term effects of different hormone regimens on perimenopausal women's liability to cardiovascular disease, cognitive decline, decreased quality of life, and other burdens of aging would soon encounter unacceptable increases in breast cancer, she said.

The specter of breast cancer would keep institutional review boards (IRBs)—local regulatory bodies that oversee and must approve human subjects research at US institutions—from allowing them. "There's just no IRB in this country that would accept that risk even if 30 years down the road you're going to show that you've saved more women from heart disease," she predicted.

On the subject of more HRT research, Stefanick is voting with her feet. "I think we've answered the estrogen and progestin question for the areas that I'm interested in studying, so for me personally I'm going in a different direction," she said. Stefanick is turning her research attention to topics she regards as far more vital for women's health: obesity and exercise.