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Hormone Replacement Therapy: Trials, Turmoil, Trust
by Arline Kaplan
Geriatric Times September/October 2002 Vol. III Issue 5
Since the recent publication of three studies linking hormone replacement therapy (HRT) to increased risk of breast cancer, cardiovascular disease and ovarian cancer, many clinicians are reassessing their HRT recommendations while seeking to calm their patients' fears.
Approximately 38% of postmenopausal women in the United States use hormone replacement therapy (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 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). Consequently, when the Women's Health Initiative (WHI) clinical trial investigating combination HRT was halted three years ahead of schedule and the reasons why were explained in a major media blitz, patients began deluging their physicians with phone calls. In the days following the announcement, Charles Moniak, M.D., an obstetrician/gynecologist with a private practice in Fountain Valley and Newport Beach, Calif., told Geriatric Times that he received 10 to 20 calls per day from patients concerned about the WHI study findings. He was not alone.
The WHI, a 15-year project sponsored by the National Institutes of Health, is studying two types of hormone replacement therapy. One is the use of estrogen alone in women who have had a hysterectomy, and the second is combination treatment with an estrogen and a progestin (conjugated equine estrogens 0.625 mg/day and medroxyprogesterone acetate, 2.5 mg/day).
The 16,608 study participants in the combination HRT study were healthy, active postmenopausal women who had an intact uterus and who ranged in age from 50 years to 79 years (mean age 63.3 years) at the time of initial screening. The volunteers came from varied backgrounds and circumstances and about 16% were minorities. The trial examined the effect of estrogen plus progestin on the prevention of heart disease and hip fractures and any changes associated with the risk for breast and colon cancer, Marcia Stefanick, Ph.D., reported at a press conference during which the study results were released. Stefanick is principal investigator for the WHI and associate professor of medicine at Stanford University's Center for Research in Disease Prevention.
But on May 31, the Data Safety Monitoring Board (DSMB) of WHI recommended terminating the study early after a mean follow-up of 5.2 years. Study participants were asked to stop taking the pills but 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 the same 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 group, more women had adverse effects from HRT therapy than benefited from it.
"These findings are the first confirmation from a rigorous clinical trial that taking estrogen plus progestin increases the risk of breast cancer," he said.
He explained that women on the estrogen plus progestin therapy (n=8,506) had a 26% higher incidence of breast cancer than those taking a placebo (n=8,102). The increased risk did not appear until four years into the study. Women who had the hormone therapy before entering the study were more likely to develop breast cancer, indicating that the estrogen plus progestin treatment may have a cumulative effect. Otherwise, the increased risk applied to all women, regardless of age, ethnicity and family history of breast cancer.
With regard to endometrial cancer, combination HRT did not increase the risk, he added.
The study findings, Rossouw said, also showed a 22% increase in total cardiovascular disease (29% increase in heart attacks and a 41% increase in strokes) as well as a doubling of the rate of blood clots in the lungs and legs.
Estimated hazard ratios (nominal 95% confidence intervals) were invasive breast cancer, 1.26 (1.00-1.59) with 290 cases; coronary heart disease, 1.29 (1.02-1.63) with 286 cases; stroke, 1.41 (1.07-1.85) with 212 cases; and pulmonary embolism, 2.13 (1.39 to 3.25) with 101 cases (Writing Group for the Women's Health Initiative, 2002).
Women also gained some benefits from the combination HRT; there was a 34% reduction in hip fractures and 24% reduction for total fractures, as well as a 37% reduction in the risk of colorectal cancer that emerged after three years of hormone use. Hazard ratios were hip fracture, 0.66 (0.45-0.98) with 106 cases; and colorectal cancer, 0.63 (0.43-0.92) with 112 cases.
While acknowledging that the data from the WHI "are bound to sound frightening to women," Rossouw said the percent of women who experienced adverse effects from the estrogen plus progestin therapy was small, and therefore the risk to individual women in the trial was small.
The way the study was reported caused much alarm, said Moniak, who is both a practicing physician and assistant clinical professor of obstetrics and gynecology at the University of California, Irvine. He explained that 48 women got breast cancer on hormones, but that is per 10,000 women. There were 40 women per 10,000 who were not on hormones who got breast cancer, so the difference was less than 1 per 1,000.
We "can call it a 26% increase risk or we can call it a minimal increase risk depending upon how you want to play with the numbers," he said. An unmentioned factor is that generally "women who get breast cancer on hormones have a lower stage of disease and a better survival rate."
Moniak generally exercises some caution with study findings and believes in the credibility of clinical observation and experience.
"It's going to be hard to prove how well HRT helps osteoporosis in three to five years, because it is a long-term effect. Same with Alzheimer's disease," he said. "It is rare that we see bad heart disease in a woman who has been taking hormones for a long period of time. We know there is more to the story."
Other Studies
Just two weeks prior to the publication of the WHI study, JAMA published two reports of the Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). This open-label observational follow-up of 2.7 years involved 2,321 women (Grady et al., 2002; Hulley et al., 2002). The original HERS study was a randomized, blinded, placebo-controlled trial of 4.1 years' duration (Hulley et al., 1998). Both trials looked at the effect of a combination of HRT (0.625 mg of conjugated estrogens plus 2.5 mg medroxyprogesterone acetate daily) on coronary and noncoronary diseases in postmenopausal women who were 79 years of age or younger at baseline and who had coronary artery disease but no prior hysterectomy. In both studies coronary heart disease (CHD) events included heart attack, coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke, transient ischemic attack or peripheral artery disease.
In the initial HERS trial, researchers reported an increase in CHD events among women taking HRT during the first year of treatment compared with those on placebo (Hulley et al., 1998). But in years three to five, they found fewer CHD events occurred in the HRT group, raising the question of whether longer follow-up might show significant benefit. Even with additional years of observations (6.8 years of study on average), the HERS II trial results indicated that combination hormone treatment does not provide a cardiovascular benefit in older women with CHD (Grady et al., 2002).
Combination treatment in HERS II was also found to increase the rates of venous thromboembolism and biliary tract surgery and did not produce favorable trends in overall rates of fracture or death (Hulley et al., 2002).
The investigators found cancer was 19% more common in the hormone therapy group, but the finding was not statistically significant.
Another recently published large prospective study exploring the potential association between menopausal HRT and ovarian cancer found that women who used estrogen-only replacement therapy, particularly for 10 or more years, were at significantly increased risk for ovarian cancer (Lacey et al., 2002).
"We observed significant associations between ERT [estrogen replacement therapy] use and incident ovarian cancer in this prospective study of 44,241 postmenopausal US women who provided multiple exposure assessments over approximately 20 years," the researchers noted. Use of estrogen-progestin replacement therapy (EPRT) only was "not associated with ovarian cancer in our data, but our results were based on only 18 women with EPRT-only use who developed ovarian cancer. Although our analysis captured HRT use through 1998, few women developed ovarian cancer after EPRT-only use for more than four years."
What Next?
In light of the latest research 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 Women's Health Initiative trial and considering regulatory issues such as labeling, FDA spokesperson Susan Cruzan told GT. She pointed out that Prempro, the combination HRT drug used in the WHI, was never indicated for prevention of cardiovascular events, and the 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 ASRM's Web site <www.asrm.org>. 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 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," Issac Schiff, M.D., told GT. Schiff is task force chair and chair of the medical advisory board for Managing Menopause.
The task force, Schiff said, will be involved in a research review, covering not only the WHI findings and HERS II, but also the studies that have preceded them. 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 beneficial, then maybe all 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 increases 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 hormone replacement therapy, 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 to lower 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, b-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 a trial annually 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 the 50 years may be wise 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 (SERMs) that exhibit estrogen-agonist effects on bone and on lipoproteins and estrogen-antagonist effects on the breast and endometrium.
Mosca is on the executive committee for a trial exploring the use of SERMs in the prevention of heart disease. Called the Raloxifene Use for The Heart (RUTH) trial, the study involves 10,101 women from 26 countries. It is testing whether the SERM raloxifene (Evista) is efficacious in preventing cardiovascular disease and breast cancer.
"We hope to have results … within five years. So, I think the jury is still out about SERMs preventing heart disease," Mosca said. "Preliminary studies from randomized clinical trials, such as the MORE [Multiple Outcomes of Raloxifene Evaluation] study have not shown any increase in cardiovascular risk with SERMs. In fact, there was a reduction in the risk of cardiovascular disease, among the highest-risk women. One of the things we need to be clear with our patients about is that SERMs are not HRT, and women are confused about that."
In her practice, Mosca sees many women who like to take soy to relieve menopausal symptoms. Soy may potentially be a weak SERM, she said, but we do not have enough quality control or data on soy yet to recommend it to our patients.
Moniak believes that patients need to discuss their concerns with their physicians and to understand that there are many studies going on.
"Research is always ongoing. Every week we are inundated in our journals with all these different studies. It is not that they finally did the study, and now they finally know the truth. This [WHI study] is one more piece of the puzzle. If there is good trust between patients and doctors, then we can help patients get through this."
References
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