For Menopausal Women, Risk of Blood Clots Depends on Form of Therapy, Research Suggests Overcoming the Icky Factor By TARA PARKER-POPE In a twist in the debate about the safety of menopause hormones, new research suggests the real problem may not be the hormone itself, but the fact that it's typically swallowed as a pill. This week, the medical journal Circulation offers some of the strongest evidence yet that the risks of hormones are dramatically reduced when the drugs are absorbed through the skin in patches and gels rather than taken as pills. The study by French researchers showed that one of the most serious risks associated with hormone use -- blood clots -- could be virtually eliminated if women switch to a skin-delivery system like the patch. It's estimated that more than four million U.S. women use menopause hormones to relieve hot flashes and other symptoms. Although hormone drugs come in pills, patches, creams, gels and rings, the vast majority of U.S. women use the pill form. DIFFERENT RISKS? Among the 881 women studied in the Circulation report, researchers found that women who took hormone pills were four times as likely to suffer a serious blood clot. Women who used hormone patches or gels were at no higher risk for blood clots than women who didn't take hormones at all. The research, collected from a continuing study called ESTHER (which stands for Estrogen and Thromboembolism Risk), was funded primarily by French government health agencies but also received some support from drug companies that make patch treatments. The women studied were taking either estrogen only or an estrogen-and-progestin combination. Although hormone patches are popular among European women, the sticky, tan or clear patches aren't widely used in the U.S. The most popular brands include Climara, made by Berlex of Wayne, N.J., and Vivelle-Dot from Novogyne, a joint venture of Novartis and Noven Pharmaceuticals. Estrogen gels and creams, which are rubbed on the arms and legs, also aren't big-sellers. Part of the reason is that doctors here are simply more accustomed to prescribing hormones in pill form. Another issue is that the patches, typically worn on the abdomen or buttocks and changed once or twice a week, can irritate the skin, get dirty or collect lint around the edges. For some women, the bigger issue is that they don't want such a visible reminder of their menopause treatment. "Many women think a pill is just easier," says Alan M. Altman, assistant clinical professor of gynecology at Harvard Medical School, who says more than 80% of his own patients use the patch. "When you wear a patch, some women feel there is a tattoo on them that says 'I'm post-menopausal.' " He has received consulting fees from hormone makers, including patch makers. USING THE PATCH Pros and cons of taking menopause hormones through the skin rather than in pill form: Lowers the risk of blood clots. May cause fewer side effects. Less likely to lower cholesterol. Can irritate skin and collect lint. Patch is visible on abdomen or buttocks. But the latest research adds to the evidence that patch or other skin-delivered therapy can dramatically reduce some of the most serious risks of menopause hormones. The Circulation study also noted that blood-clot risk varied depending on the type of progestin used, although the highest-risk types studied aren't typically used by women in the U.S. Even so, the fact that women in France had different risks depending on the type of progestin and delivery system they used signals that far more research is needed to understand the differences in the various hormones now prescribed to women. A spokesman for Wyeth, maker of the best-selling pills Premarin and Prempro, couldn't be reached for comment on the study, which came out on a holiday. However, the company has said in the past that the main advantage of Premarin and Prempro compared with new drugs is that they are the most-studied hormones available to women. While the evidence is strong that hormone patches lower blood-clot risks, doctors warned that the new data don't address other risks and benefits of hormones. Several studies show that while menopause hormones relieve hot flashes and protect women's bones, they also may slightly increase risk for stroke and breast cancer. But clearly one of the most common health risks associated with hormones are blood clots, which can block blood vessels and cut off the blood supply to important organs. In the most serious cases a clot causes pulmonary embolism, which occurs when a blood clot travels to the lungs from another part of the body. The reason hormones delivered through the skin by patch, gel or cream may cause fewer blood clots, doctors say, is that the drug doesn't have to pass through a woman's liver and instead enters the blood stream directly, much like her own natural hormones do. When a woman swallows a hormone pill, the drug must first be metabolized by the liver before it enters the blood stream. This "first pass" through the liver triggers some unwelcome side effects, stimulating the liver to produce too many triglycerides and blood-clotting factors, among other issues. The lower clotting risk of patch therapy hasn't been shown with birth control pills, likely because contraceptives use far higher doses of estrogen. The differences in clotting risks between menopause hormone patches and pills has prompted questions about the results of another major study, the Women's Health Initiative. That much-discussed study was halted in 2002 after older women taking the combination hormone drug Prempro were found to be at higher risk for heart attacks, blood clots and strokes. Although the big concern about the WHI is that it studied older women long past menopause, another criticism is that it studied only conjugated equine estrogen pills, the most popular hormone used today, which is derived from the urine of pregnant horses. Hormone patches use 17-beta estradiol, which is a chemical match to the dominant estrogen found in premenopausal women. Harvard professor JoAnn E. Manson, a WHI researcher who co-authored an editorial about the Circulation study, says the new data suggest that the balance of risks and benefits shown in the WHI might have been dramatically different if patches were studied instead. In the WHI estrogen and progestin study, at least 44% of the adverse events were related to blood clots, suggesting that a woman who uses a patch instead of a pill can eliminate nearly half the risks associated with the drugs, says Dr. Manson. "If you're talking about women who are recently menopausal, the patch could be enough to very dramatically change the benefit-risk ratio," says Dr. Manson, who doesn't receive funding from any hormone makers. While earlier studies have also shown that blood-clot risk is lower with hormone patches compared with pills, most experts say the message hasn't gotten to many doctors or women themselves. Part of the problem is that blood-clot data tend to get published in cardiology journals that may not be read by internal medicine doctors or gynecologists who typically prescribe hormone drugs. Another problem is that no large clinical trials comparing oral, patch and other forms of hormone drugs have been conducted. Even the data from the Circulation study isn't considered conclusive because it's based on observational evidence, rather than a clinical trial where a specific treatment is studied against a placebo. And it is too soon to say definitively that hormone patches are better than pills in every way. Because oral estrogens pass through the liver, they actually do a better job of raising a woman's good cholesterol, lowering her bad cholesterol and lowering blood sugar, suggesting there could be differences in heart and diabetes risk among pill and patch users. "I very much would like to believe the patch is safer, but in order to know that we need better data," says Susan Hendrix, a WHI researcher and professor of obstetrics and gynecology at Wayne State University Medical School in Detroit. "Look at the numbers of women who need these therapies. ... I think there's a public outcry for the need for this kind of research." More answers about the differences in risks and benefits of various hormone drugs and delivery systems will come from the Kronos Early Estrogen Prevention Study, or KEEPS, which is now recruiting women who are within three years of menopause. Women in the KEEPS study (www.keepstudy.org1) will be given different forms and types of estrogen and progestin, including patches and pills. The study, at eight major medical centers, is funded by a nonprofit institute in Phoenix. "Whether hormone therapy is in vogue or out of vogue, there will be many women with impaired quality of life who will be seeking treatment for menopause symptoms," says Dr. Manson. "We need to push for more research for women so they will have clear answers to these questions."