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Hormone Replacement Therapy: Trials, Turmoil, Trust
by Arline Kaplan
Geriatric Times September/October 2002 Vol. III Issue 5
Approximately 38% of postmenopausal women in the United States use hormone replacement therapy (HRT) (Keating et al., 1999), with one national survey showing that 20% continue use for five years or more (Brett and Madans, 1997). In 2000, 46.8 million prescriptions were written for Premarin (conjugated estrogens), and 22.3 million prescriptions were written for Prempro (conjugated estrogens plus medroxyprogesterone acetate) (Kreling et al., 2001).
To answer questions about the risks and benefits of HRT, the Women's Health Initiative (WHI), a 15-year project sponsored by the National Institutes of Health, was studying the use of estrogen alone in women who have had a hysterectomy and combination treatment with an estrogen and a progestin (conjugated equine estrogens 0.625 mg/day and medroxyprogesterone acetate, 2.5 mg/day) in healthy postmenopausal women who have an intact uterus.
On May 31, the Data Safety Monitoring Board of WHI recommended terminating the combination study early after a mean follow-up of 5.2 years. Study participants were asked to stop taking the pills but to keep getting yearly mammograms and WHI clinic exams to help investigators track what happens when combination HRT is stopped. Study findings were published in JAMA (Writing Group for the Women's Health Initiative Investigators, 2002).
At a press conference, Jacques Rossouw, M.D., acting director of the WHI, explained that while there was no difference in the number of deaths between the estrogen plus progestin therapy and placebo groups, more women had adverse effects than benefits from HRT.
"These findings are the first confirmation from a rigorous clinical trial that taking estrogen plus progestin increases the risk of breast cancer," he said.
In light of these findings, physicians and their respective specialty associations, as well as government health agencies, have begun considering their next steps.
The U.S. Food and Drug Administration's Division of Reproductive and Urologic Drug Products is reviewing the data of the WHI trial and considering regulatory issues such as labeling, FDA spokesperson Susan Cruzan told Geriatric Times. She pointed out that Prempro was never indicated for prevention of cardiovascular events and that its labeling already mentions breast cancer and cardiovascular risks. Should the division feel the need for outside guidance, Cruzan said, it most likely would seek assistance from the Advisory Committee on Reproductive and Urologic Drugs.
After reviewing the data from the WHI study, some members of the American Society of Reproductive Medicine (ASRM) prepared a preliminary guidance document to help physicians and their patients. It is posted on the ASRM's Web site
. The guidance group warned against abandoning combination HRT: Some physicians have commented to the press that these data indicate that combined HRT is dangerous and should not be provided to any women. We disagree strongly with these upsetting and careless opinions. Estrogen remains the most effective treatment for vasomotor and other symptoms of estrogen deficiency appearing at the time of menopause. These symptoms can be incapacitating to some women; moreover, for many women only estrogen provides relief. The benefit of HRT on vasomotor and genitourinary symptoms was not considered in evaluating the global risks and benefits in this study. It should be remembered that managing these symptoms is the primary reason for providing HRT to women.
The ASRM guidance group suggested treating women who present with symptoms of estrogen deficiency with estrogen for "short-term relief of symptoms as long as they are counseled about the risks, especially those related to thromboembolic events, and are followed regularly. This study [WHI] clearly demonstrated that short-term use of estrogen is not associated with any increased risk of breast cancer."
For women wishing to discontinue HRT, the guidance group suggested physicians advise them to taper off gradually over one to two months. Additionally, "symptoms of dyspareunia may be improved by the use of vaginal lubricants, use of the estrogen-containing vaginal ring, or estrogen vaginal cream," they said.
For physicians whose female patients are symptomatic but do not want to take estrogen or who have only mild symptoms, the ASRM group suggested consideration of alternative therapies:
Many of these symptoms have been shown to respond to selective serotonergic reuptake inhibitors (SSRIs); hot flashes may be reduced in some women in response to clonidine [Catapres] patches (which are not approved for this indication by the FDA); and some other alternative therapies have been shown to have some efficacy.
In response to the WHI findings, the American College of Obstetricians and Gynecologists (ACOG) formed a special Task Force on Hormone Replacement Therapy to make clinical practice recommendations. The task force includes a multispecialty panel of medical experts.
"There has been a lot of conflicting information from very good studies and well-intentioned studies, and the purpose of the task force is to create some guidelines, so that practicing obstetricians and gynecologists can better inform their patients," Isaac Schiff, M.D., told GT. Schiff is task force chair and chair of the medical advisory board for ACOG's Managing Menopause.
The task force, Schiff said, will be involved in a research review, covering not only the WHI findings, but also previous studies (Table). One example is the Nurses' Health Study, which suggested the risk for major coronary events was lower among current users of hormones compared to women who never used them (Grodstein et al., 2000).
"The Women's Health Initiative answered some very specific areas, but there are other parts of medicine that our patients have questions about that the WHI, at least at this time, doesn't have answers for," said Schiff, who is chief of the Vincent Memorial Obstetrics and Gynecology Service at Massachusetts General Hospital in Boston. "[The] Women's Health Initiative, which was a superb study, was really dealing with heart disease, breast cancer, colon cancer and osteoporosis, but it hasn't published [information] … dealing with symptoms such as hot flashes and vaginal dryness, which is what brings a lot of women in to see their ob/gyns."
There is also interest in the other hormone study of the WHI, Schiff said.
The Data Safety Monitoring Board for WHI recommended that the study of estrogen alone versus placebo continue as planned, since the balance of risks and benefits for women in the estrogen alone study is still uncertain. To date in that trial, women on estrogen have not shown an increased risk of breast cancer compared to those on placebo.
Schiff said that if estrogens are shown to be beneficial, then maybe the negative information that came out of the combination study was because of the progesterone effect.
Early evidence from studies of unopposed estrogen suggested it lowered risk of cardiovascular disease while a secondary prevention trial and observational studies showed combination therapy increased the risk of coronary heart disease. A recent JAMA editorial said this outcome difference "may reflect prothrombotic and proinflammatory effects of progestins that outweigh any effects of estrogens on atherogenesis and vasodilation" (Fletcher and Colditz, 2002).
Along with other associations, the American Heart Association's Science Advisory and Coordinating Committee is in the process of updating its recommendations with regard to HRT, according to committee chair Lori Mosca, M.D., Ph.D., M.P.H. Mosca is associate professor of medicine at Columbia University and head of the first joint program in preventive cardiology for New York Presbyterian Hospital (Columbia and Cornell Universities).
"At first pass," Mosca told GT, "these studies sound confusing, but this is exciting information. We found the answer years ahead of schedule. We now know we have to direct our efforts toward developing more tissue-specific estrogen, and physicians can really take comfort in knowing that randomized clinical trials do provide us with definitive information."
Based on the new information, Mosca said she "would recommend that combination hormone replacement therapy not be used to prevent heart disease or stroke in postmenopausal women. There is important research that is ongoing regarding the effects of estrogen alone, but until there is clear evidence that this or other forms of hormone replacement therapy show benefits, I would not recommend that women use these for the purposes of preventing heart disease or stroke either."
The most important take-home message for physicians, Mosca said, is that we have many established methods for lowering heart disease risk in women, such as lowering cholesterol, blood pressure control, avoiding smoking, regular physical activity and a heart-healthy diet. In addition, for women who are at high risk for heart disease or who have existing cardiovascular disease, the use of aspirin, statins, ß-blockers and angiotensin-converting enzyme inhibitors may be prudent.
For women experiencing menopausal symptoms, Mosca indicated HRT might be "worth a small, absolute increase in the risk for heart disease and breast cancer." But since the risk for these complications increased with duration, she "would recommend that HRT be used for the shortest period of time necessary and optimally for no more than three or four years after natural menopause."
Mosca recommended that women 50 years and older should have an annual trial of coming off HRT. Additionally, for women who have had premature menopause and have been on estrogen for long periods of time, she said discontinuing estrogen therapy around the age of 50 years may be prudent to consider.
While HRT has been effective for preventing osteoporosis and fracture, Mosca said there are other options. These include bisphosphonate drugs like alendronate (Fosamax) that slow bone loss and selective estrogen receptor modulators that exhibit estrogen-agonist effects on bone and on lipoproteins and estrogen-antagonist effects on the breast and endometrium.
Schiff told GT that HRT research is a "moving target" and that more information will be forthcoming as other studies are completed. In the final analysis, he said, "Physicians need to take the time to speak with their patients."
References
Brett KM, Madans JH (1997), Use of postmenopausal hormone replacement therapy: estimates from a nationally representative cohort study. Am J Epidemiol 145(6):536-545.
Fletcher SW, Colditz GA (2002), Failure of estrogen plus progestin therapy for prevention. JAMA 288(3):366-368 [comment].
Grodstein F, Manson JE, Colditz GA et al. (2000), A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 133(12):933-941 [see comments].
Keating NL, Cleary PD, Rossi AS et al. (1999), Use of hormone replacement therapy by postmenopausal women in the United States. Ann Intern Med 130(7)545-553 [see comments].
Kreling DH, Mott DA, Wiederholt JB et al. (2001), Prescription Drug Trends: a Chartbook Update. Menlo Park, Calif.: Kaiser Family Foundation.
Writing Group for the Women's Health Initiative Investigators (2002), Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288(3):321-333 [see comment].
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