In Estrogen Research, Challenge Is To Cull Good From Bad

What to make of estrogen? Does the female sex hormone's potential to protect women, and even men, against an array of illnesses foreshadow a research bonanza? Or will its use, in natural and synthetic forms, always be compromised by serious side effects, including an increased risk of cancer? A steady flow of academic articles and announcements from university research centers indicates widespread interest in such questions, but the asking seems much easier than the answering. "Estrogen" is a generic term for synthetic substances and a family of natural hormones formed by the ovary, placenta, and testes; possibly by the adrenal cortex; and by certain plants. In the United States, estrogen replacement therapy generally derives from a mixture of natural hormones obtained from the urine of pregnant mares. Despite estrogen's well-established ability to protect against osteoporosis and cardiovascular disease, less than one-fifth of postmenopausal women ever take estrogen supplements (L.M. Salamone et al., Archives of Internal Medicine, 156:1293-7, 1996). They, and their physicians, are wary not only of such frequent side effects as vaginal bleeding and breast swelling and tenderness, but also of the higher risk of breast and endometrial or uterine cancer. Progesterone often is prescribed along with estrogen to blunt the latter's carcinogenic potential, but progesterone may adversely affect the cardiovascular system. In recent years, research into estrogen has yielded evidence of its possible role in protecting against conditions as varied as Alzheimer's disease, premenstrual syndrome, skin wrinkling and dryness, short-term memory loss, and hearing loss. Amid this welter of promising and worrying reports, two areas of strong research potential stand out. One is a family of plant compounds called phytoestrogens, some of which have the potential ability to occupy human estrogen receptors and may imitate the hormone's positive effects while blocking many negative effects. The other is a new class of drugs called selective estrogen-receptor modulators (SERMs), or "designer estrogens." The first SERM to hit the market is raloxifene hydrochloride (Evista) from Eli Lilly and Co. of Indianapolis. Approved late last year by the Food and Drug Administration for prevention of osteoporosis in postmenopausal women, the drug does not increase the risk of breast or endometrial cancer, may not cause menstrual-type bleeding or breast tenderness, and builds bone, although not to the same extent as estrogen does. It is not yet known if raloxifene prevents fractures, another positive effect of estrogen. However, raloxifene was associated in trials with an increased risk of venous thrombosis. Like the other SERMs currently in development, raloxifene does not treat hot flashes, and it may create them as a side effect. Other major pharmaceutical companies working on SERMs include Pfizer Inc. of New York City; Glaxo Inc. of Research Triangle Park, N.C.; SmithKline Beecham and Wyeth-Ayerst Laboratories, both of Philadelphia; and Zeneca Pharmaceuticals of Wilmington, Del. Zeneca holds the U.S. patent for the world's most widely prescribed medicine for the treatment of breast cancer, tamoxifen (trade name Nolvadex), which has been available for two decades. But tamoxifen's antagonistic or antiestrogenic effect on breast cancer cells does not extend to endometrial tissue. Like estrogen, tamoxifen is associated with an increased risk of uterine cancer, whereas raloxifene is not. "These selective receptor modulators may help us solve a dilemma for some women, because we may be able to provide the benefits of estrogen without its most serious side effects," says Peter J. Schmidt, an investigator in the behavioral endocrinology branch of the National Institute of Mental Health in Bethesda, Md. His recent research into the behavioral effects of the gonadal steroids showed that women suffering from premenstrual syndrome who were given hormone replacement plus an agonist of gonadotropin-releasing hormone experienced a significant increase in such symptoms as sadness, bloating, and irritability (P.J. Schmidt et al., New England Journal of Medicine, 338:209-16, 1998). Although none of the 35 women in the study responded to placebo, Schmidt cautions, "The story on mood is that estrogen, and steroids in general, do have effects but they may vary with individuals. There is a strong interaction with brain function as well as with gender, age, and past contacts with steroids." Schmidt and colleagues are now measuring the cognition-related, cerebral blood flow of a gonadotropin-releasing hormone agonist administered to normal people of both sexes. In previous research, they found that the agonist and ovarian steroid supplements modulated this neural activity in young women (K.F. Berman et al., PNAS, 94:8836-41, 1997). At the National Institute on Aging, principal investigator Susan Resnick and team documented the effects of estrogen on age-related changes in memory of 288 women from 1978 to 1994. Their examination of data from the Baltimore Longitudinal Study of Aging (BLSA), now in its 40th year, showed that women on estrogen supplements were significantly better at drawing a series of figures from memory than those who had never used any hormone-replacement therapy (S.M. Resnick et al., Neurology, 49:1491-7, 1997). The results of these and other studies that indicate the potential of estrogen to slow cognitive decline will be tested by double-blind, controlled clinical trials now in the planning stages with support from NIA. "We know that estrogens mean a lot more to the brain than just their influence on reproductive functions," said Bruce McEwen, professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University, during an October 7 minisymposium on estrogen and Alzheimer's disease at the New York Academy of Sciences. He explained that there are two types of estrogen receptors, alpha and beta. Located in different parts of the brain, they are thought to control both the growth and breakdown of synapses over time. Research has identified a set of estrogen antagonists that may bind to the receptors, thereby possibly exerting a negative effect on brain function. McEwen said ovarian steroids have been linked to a host of problems, including motor coordination, catamenial or menstruation-related epilepsy, premenstrual syndrome pain, and dementia. He added that the noradrenergic, serotonergic, cholinergic, and dopaminergic systems all could interact with estrogen, because all those neurotransmitters and their receptors are related to brain disorders and aging. "There are a lot of possibilities in developing pharmaceutical compounds that could act as both agonist and antagonist [to estrogen], possibly getting more specific responses," he commented. American Federation For Aging Research 1414 Avenue of the Americas New York, N.Y. 10019 Tel: (212) 752-2327 Fax: (212) 832-2298 http://www.afar.org For details on raloxifene (Evista): http://www.evista.com "The estrogen receptor is notoriously promiscuous," notes Barry Gehm, a research assistant professor in biochemistry at Northwestern University Medical School. "It's not as fussy about getting an exact fit to its receptor shape as other steroid receptors." He explains that a characteristic chemical structure of estrogen among the steroids is an "aromatic ring" of six delocalized, cyclical double bonds with a hydroxl group, all arranged on one plane. "If the receptor sees that [configuration], it may not be too picky about the rest of the molecule," he says. This relative likelihood of the receptor to accept foreign compounds as ligands is useful to development of both SERMs and phytoestrogens. For example, Gehm noticed the similarity of a synthetic estrogen's chemical structure to that of resveratrol, a natural compound found in grape skins. He and colleagues conducted in vitro tests that showed resveratrol binds to the estrogen receptor and is a phytoestrogen. The team reported that their finding may be relevant to the cardiovascular benefits of drinking wine (B.D. Gehm et al., PNAS, 94:14138-43, 1997). Phytoestrogens are found in soya products, in some Chinese traditional herbs such as the kudzu root, and in the fiber of whole grains, berries, fruit, vegetables, and flax seed. Women who regularly eat such foods may have a reduced risk of breast cancer, according to a recent trial of 288 women at the Queen Elizabeth II Medical Center in Perth, Australia (D. Ingram et al., Lancet, 350:990-4, 1997). Half the women were newly diagnosed with breast cancer, and half were randomly selected, healthy women. Urine samples showed that the healthy women had higher median excretion rates of all phytoestrogens than the cancer patients. Although several observational studies have yielded similar results, Gehm cautions that to conclude that phytoestrogens can act as antiestrogens in humans would be "a hand-waving argument, a rationalization that hasn't been clearly demonstrated." Another possible explanation for the Australian study's finding, he adds, is that people who start eating phytoestrogen-rich foods early in life may develop some desensitivity to estrogens in breast tissue that can provide protection later in life against tumors that target estrogen receptors. More research is needed to answer such questions, he says. For postmenopausal women who are not at high risk of developing breast cancer, a strong argument for estrogen supplements is the hormone's ability to raise the level of "good" cholesterol, or high-density lipoprotein (HDL), in the blood. This significantly reduces the risk of cardiovascular disease, the leading killer of women in the U.S. Recent in vitro research at Ohio State University indicates that one way estrogen helps to protect against heart disease is by inhibiting apoptosis, or programmed death of endothelial cells that line and cushion blood vessel walls (R.J. Alvarez, Jr. et al., Biochemical and Biophysical Research Communications, 237:372-81, 1997). In adults, blood vessel walls must be seamless to operate properly, and apoptosis plays a role in maintaining that condition. But with aging, a marked increase of apoptosis can occur, which may trigger a coagulation cascade, resulting in major thrombosis. Exactly how estrogen produced by younger women inhibits this clotting by moderating apoptosis is still not clear, according to Pascal J. Goldschmidt-Clermont, senior author of the apoptosis paper and director of the Heart and Lung Institute at Ohio State. "It has to do with the phenomenon of the susceptibility of the endothelial cells to the extracellular matrix," he says. The next question to explore is, "What is the role of the estrogen receptor in mediating these effects?" Eventually, he believes, estrogenlike molecules might be produced that could help to prevent atherosclerosis while reducing the risk of uterine cancer and, perhaps, of breast cancer. Tissue-specific estrogens might even be engineered to provide cardiovascular protection for men without producing the "feminizing" side effects of breast enlargement or changes in body fat distribution. SKIN THERAPY: Tania Phillips of Boston University Medical Center predicts that estrogen-like compounds will emerge to treat dermatological conditions. Among the less well-known potential benefits of estrogen is evidence that it may increase the collagen content of the skin, thus helping to protect against some of the wrinkling and dryness associated with aging and menopause. Tania J. Phillips, an associate professor of dermatology at Boston University Medical Center, performed a literature search of studies on estrogen and the skin for an address she gave in March at the American Academy of Dermatology's annual meeting in Orlando, Fla. She says an epidemiological study of more than 3,000 women indicated that those with a history of estrogen use had less wrinkling and drying of the skin than those who had never used estrogen supplements (L.B. Dunn et al., Archives of Dermatology, 133:339-42, 1997). Although Phillips thinks it likely that prescription drugs containing estrogenlike compounds will emerge to treat skin wrinkling and dryness, she adds, "The concern is, nobody really knows how much estrogen in these various compounds might be necessary to achieve a dermatological effect." A similar observation comes from Michael Murphy, a resident in the department of otolaryngology at the University of Washington Medical Center and lead author of a paper surveying research on gender and hearing loss for the online medical information service Medscape (M.P. Murphy, G.A. Gates, Medscape Women's Health, 2[10]:1997). Murphy says studies to date on the role of estrogen in hearing loss show no direct connection, perhaps because many factors can contribute to the condition. "It's really difficult to tease out the specific effects of estrogen." What needs to be done to address the issue of hearing loss in women is a randomized, clinical trial with estrogen supplements," Murphy notes. "I know it's been talked about. . . . You could control for other factors and isolate on that effect. But I think it's talked about almost wistfully." The length of time required by such a trial to establish any change in hearing is a stumbling block, he explains. Murphy's summation of estrogen and hearing loss is a comment that could apply to all the fragmented research into this complex and mysterious hormone: "You have to step back and say, What's the big picture in all this, what's to do? And I think it's about time to do that."

In Estrogen Research, Challenge Is To Cull Good From Bad

Interested in reading more?

Become a Member of