Hormone therapy: continuing discussion and debate – Editorials
Barbara S. Apgar
On July 9, 2002, the Data and Safety Monitoring Board of the Women’s Health Initiative (WHI) announced the abrupt termination of the continuous hormone replacement therapy (now referred to as hormone therapy, or HT) portion of the WHI trials sponsored by the National Institutes of Health. Confusion and disbelief were common reactions to the announcement–patients seemed to focus on terms such as “harm” and “alternatives,” while clinicians focused on “relative” versus “absolute” risk. No clear directions for counseling strategies were proposed after the announcement was made.
The continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) regimen that was used in the WHI trial is one of the most commonly studied HT regimens and has been strategically marketed as beneficial for multiple conditions in postmenopausal women.
The WHI trial, a large-scale study of preventive and treatment therapies for postmenopausal women, was designed to assess the long-term risk/benefit ratio of continuous estrogen replacement therapy (ERT) and combination HT. The combination clinical trial and observational study, which was scheduled to conclude in 2005, enrolled 161,809 women between 1993 and 1998. A total of 16,608 women were randomized to combination HT versus placebo. (1) Before the publication of the WHI data, (2) there was a paucity of definitive studies addressing the issue of benefit or harm from HT. Observational studies showed that women who used HT lived longer and with fewer health problems than those who did not use HT. Perhaps HT was the real reason for the longevity and good health of those women, or perhaps the women using HT were simply healthier than their counterparts.
For more than a decade, it was generally thought that HT reduced cardiovascular risk in healthy postmenopausal women. (3) However, the Heart and Estrogen/Progestin Replacement Study (HERS I) in 19984 and HERS II in 20025 demonstrated that HT did not prevent or reduce the risk of fatal myocardial infarction in postmenopausal women with preexisting coronary heart disease (CHD). Therefore, the American Heart Association stated that initiation or continuance of HT for secondary prevention of CHD is not recommended. (6)
What did the WHI trial demonstrate? (2) It showed that estrogen is effective in reducing menopausal symptoms such as vasomotor events, vaginal dryness and, perhaps, mood swings at the time of the menopausal transition. There was an increased absolute risk for nonfatal stroke only (8 per 10,000 women per year), a twofold increase in absolute risk of venous thromboembolism (18 per 10,000 women per year), and an increased absolute risk of CHD events, including nonfatal myocardial infarction, among HT users (7 per 10,000 women per year). Overall, there was no apparent cardiovascular protection in HT users.
An increased absolute risk of breast cancer (8 per 10,000 women per year) was demonstrated in women who used HT for more than 5.2 years. Although the risk of endometrial cancer significantly increased in estrogen-only users, the addition of a progestogen significantly decreased that risk. On the benefit side, the WHI demonstrated an absolute benefit for reduced incidence of osteoporotic hip fractures (5 per 10,000 women per year) and colon cancer (6 per 10,000 women per year).
In a systematic review developed for the U.S. Preventive Services Task Force (USPSTF) and funded by the Agency for Healthcare Research and Quality (AHRQ), benefits and harms of HT were assessed, outcome rates were calculated, and meta-analyses were performed when appropriate. (7) Despite conflicting results, the overall message is that the long-term harm of HT outweighs the benefits. It appears that the increased relative risk of HT versus placebo or the potential harms of increased risk of venous thromboembolism, breast cancer, stroke, and myocardial infarction associated with continuous HT outweigh the benefits of reduced incidence of colon cancer and osteoporotic hip fractures. For some outcomes, such as breast cancer and cholecystitis, the risk increases over time. For outcomes such as venous thromboembolism and myocardial infarction, the risk is greatest in the first years of use. The North American Menopause Society (www.menopause.org) Advisory Panel suggests using the following points of discussion when counseling women about HT, with the understanding that the lowest effective dosage for the shortest duration should be used:
1. Each woman considering the use of HT should undergo a risk-profile analysis and be educated to understand the risks and benefits of HT use. The terms “long-” and “short-term” therapy should be abandoned, because the risk profile of the individual patient should guide the duration of benefit.
2. Relief of menopausal symptoms (e.g., vasomotor events, vaginal dryness) is the primary indication for use of HT.
3. Although various HT regimens are approved by the U.S. Food and Drug Administration for the prevention of postmenopausal osteoporosis, alternative therapies such as bisphosphonates should be considered.
4. Use of HT for primary and secondary prevention of CHD should be abandoned. Although it is unclear whether estrogen alone is beneficial in this regard, it should not be used for this indication.
5. There have been no definitive studies on alternative routes of administering HT, and it should not be assumed that regimens other than CEE and MPA are less harmful.
6. Data are lacking on the optimal method of discontinuing HT.
7. Although the Advisory Panel could not agree on the extended use of HT, it was suggested that it may be acceptable under the following circumstances, provided informed consent is obtained and there is strict follow-up: in women for whom symptom relief outweighs the risks, women with symptoms who are at risk for osteoporosis, and women with significant osteoporosis risk who are unable to tolerate alternative therapies for that condition.
So what should we tell our patients? HT has a limited place and is recommended based on risk assessment. The unopposed CEE arm of the WHI trial is continuing to study postmenopausal women who have had hysterectomies. A new chapter on menopause has been written–and the discussion and debate on HT will undoubtedly continue for quite some time.
(1.) Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 1998; 19:61-109.
(2.) Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
(3.) Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-41.
(4.) Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
(5.) Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66.
(6.) Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 104:499-503.
(7.) Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002;288:872-87.
Barbara S. Apgar, M.D., M.S., is a clinical professor of family medicine at the University of Michigan Medical School in Ann Arbor and associate editor of American Family Physician.
David G. Weismiller, M.D., Sc.M., is assistant professor of family medicine and director of the Women’s Health Fellowship at the Brody School of Medicine at East Carolina University, Greenville, N.C.
Address correspondence to Barbara S. Apgar, M.D., M.S., 883 Sciomeadow Dr., Ann Arbor, MI 48104. Reprints are not available from the authors.
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