Where Do We Go From HRT?

With hormone replacement therapy (HRT) under fire, researchers who study women's reproductive health and aging are heading back to the drawing board. Last month, scientists from a wide range of disciplines gathered to pose questions about the biology of menopause and to identify areas of research that could lead to potential therapies.

David Ginsburg earns his living thinking about genes and genetic studies at the University of Michigan, Ann Arbor. So when he heard epidemiologists describe a large, long-term, multiethnic study on the symptoms and disorders associated with menopause that didn't include a search for the genes involved, he recognized that they were not fully exploiting an "incredibly powerful genetic tool." With a small change in protocol--enrolling the sisters of the current crop of study volunteers--the scientists should be able to use their data to identify genetic factors that control menopause itself. "Those genes would be of enormous interest to this group," says Ginsburg.

The group in question--scientists who study women's reproductive health--convened last month to reassess their options after the bad news from HRT studies. In July 2002, officials halted the Women's Health Initiative (WHI)--one of the largest clinical trials seeking to determine whether HRT protects postmenopausal women from cardiovascular disease--when the data suggested that HRT was increasing the incidence of heart disease and breast cancer. Many researchers still say that some form of HRT will prove beneficial in women who start treatment early enough; the WHI focused on those who had already undergone menopause, not those currently in transition (see Hormone Replacement Therapy: The Last Waltz or a New Step?). Until then, scientists have returned to square one: revisiting what we know about menopause and aging and brainstorming about where future research should focus.

The conference, sponsored by the National Institutes of Health's National Institute on Aging (NIA) and Office of Research on Women's Health, assembled experts in hormone function, bone, immunology, the brain, the cardiovascular system, and fat--areas of study that often don't overlap. The type of cross-cutting revelation provided by Ginsburg--a geneticist seeing something that epidemiologists hadn't yet, for example--is just the sort of interaction the organizers were hoping for. "For the past 10 years, [the focus on women's health] has been solely about hormone replacement therapy," says workshop organizer Frank Bellino of NIA. Researchers "hit a wall" after the WHI study shut down, he says. Now they need to put their heads together to figure out the broad questions that need asking--and determine how scientists from previously isolated fields can contribute to that quest.

Linda Fried, a geriatrician at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, set the tone of the meeting by outlining one of the most important unsolved puzzles regarding women's health: the relation between menopause and aging. In menopausal women, concentrations of estrogen and progesterone plummet. But men don't experience a reproductive transition like menopause; they continue to make sperm and testosterone throughout their lives. Yet they also get old.

And estrogen and progesterone--the types of hormones typically included in HRT--aren't the only chemicals that cause trouble, says Fried. As women move into menopause, inflammatory molecules and hormones exuded by the brain's pituitary gland also vacillate unpredictably in quantity, which can perturb health. Part of the problem, says Fried, is sorting out what each of these molecules does on its own. But in addition, she says, researchers should be thinking about them in concert. Her work typifies the point. Fried studies frailty, a condition of reduced muscle strength without a known underlying disease that pesters some postmenopausal women. She finds that in frail older women, three unrelated molecules--a sex hormone, a growth hormone, and an inflammatory molecule--show up in concentrations not seen in healthy female seniors, suggesting that, at least for frailty, researchers should be trying to understand how these different molecules collaborate.

How reproductive hormones interact with the immune system remains obscure, says Betty Diamond of Albert Einstein College of Medicine in New York City. Doctors have long observed that young women are much more susceptible to autoimmune disorders such as lupus than are women who have reached menopause, but details are only beginning to emerge. Diamond's group has found, for example, that in lupus-prone mice, high concentrations of estrogen encourage self-destructive immune cells to stick around the body longer than they should, she says.

But estrogen keeps young women's hearts healthy. Scientists need to understand the relations among age, sex hormones, and immunity so that they don't inadvertently precipitate one disorder while using hormones to protect against another, says reproductive endocrinologist Nanette Santoro, also at Albert Einstein. What's more, researchers still don't know whether the loss of protection from heart disease results from changes in the female reproductive system or from other age-related alterations.

The distribution of body fat also plays a role in the development of heart disease. And estrogen, it turns out, has a hand in controlling where women tuck their fat. During menopause, the loss of estrogen redistributes body fat from under the skin, where it is relatively harmless, to around the waist, where it leads to "metabolic syndrome": a condition that raises blood pressure, disrupts cardiovascular health, and sets the stage for diabetes. And scientists don't understand the molecular underpinnings of these events, says adipose researcher Molly Carr of the University of Washington, Seattle.

One way the repositioned fat can link to heart disease is through a complicated dalliance with the immune system, says immunologist Russell Tracy of the University of Vermont in Burlington. Abdominal fat stimulates certain immune cells to start inflammatory rumbles, he has found, which ultimately foster heart trouble. Thus by redistributing body fat, menopause might take a roundabout way to clogging arteries.

In many cases, researchers pursuing a single hormone or biological pathway--as the WHI did--might be missing the big picture, the workshop participants agreed. "We can no longer think about single hormones in isolation," said Santoro. And scientists shouldn't even focus solely on hormones. They need to rethink the long-held idea that sex hormones are "WD-40 for aging women," says Santoro, and begin to appreciate the dynamic, complex physiology of aging female bodies.

As investigators continue to investigate the connections among menopause, aging, and women's health, perhaps interdisciplinary workshops such as this one will be the WD-40 that keeps their work running smoothly.

Mary Beckman is a freelance writer in southeast Idaho, where the incessant squawking of magpies drowns out the ticking of her biological clock.