Weighing the Risks and Benefits of Postmenopausal Hormone Therapy

As women reach menopause and beyond, more than 80 percent will experience symptoms such as hot flashes, night sweats, sleep disturbance and vaginal dryness.[1] Estrogen, with or without progestin, is the most effective treatment for many of these symptoms.[2] However, recent findings from the Women’s Health Initiative study have raised questions about whether the risks of hormone therapy outweigh the benefits. In the wake of these findings, women and their doctors have been left to make difficult individual decisions.

Elsa Smith, a breast cancer survivor from Richland, Washington, relied on estrogen to manage postmenopausal mood swings, her most bothersome symptom. She recalls that deciding to stop taking estrogen after her breast cancer diagnosis was “one of the toughest things I did.”

So, what do women need to consider when deciding whether to take postmenopausal hormones? And for women who cannot take hormone therapy, or who choose not to take it, what are other options for managing menopausal symptoms?

The Women’s Health Initiative

First, some background on The Women’s Health Initiative. The Women’s Health Initiative (WHI) was funded by the National Institutes of Health (NIH) in order to address the most common health problems affecting postmenopausal women: cardiovascular disease (including heart disease and strokes), cancer and bone health. An important component of the WHI was the evaluation of potential approaches to disease prevention, including postmenopausal hormone therapy, dietary modification and calcium and vitamin D supplementation. Previous studies had suggested that these approaches might be beneficial, but only very large clinical trials, such as those conducted within the WHI, could provide definitive answers.

The WHI studies of postmenopausal hormone therapy involved a total of 27,347 women. One study evaluated estrogen alone in 10,739 women without a uterus, and a second study evaluated estrogen plus progestin in 16,608 women with a uterus. Only women without a uterus were given estrogen alone because estrogen alone increases the risk of uterine cancer. The studies enrolled women between the ages of 50 and 79. In each study, women were randomly assigned to receive either hormone therapy or a placebo (a sugar pill). The primary purpose of these studies was to evaluate the effect of hormone therapy on a woman’s risk of heart disease and stroke, bone fractures and breast and colorectal cancers.[3] Although information about menopausal symptoms among WHI subjects has been published,[4] assessing the effect of hormone therapy on menopausal symptoms was not the primary purpose of the study.

The first major headlines from the WHI hormone studies appeared in July 2002: WHI scientists reported that they were stopping the study of estrogen plus progestin earlier than planned because there had been more cases of heart disease, breast cancer, stroke and blood clots among women taking estrogen plus progestin than among women taking placebo.[5] Women taking estrogen plus progestin had fewer fractures and were less likely to develop colorectal cancer, but these benefits were thought to be outweighed by the risks.

The study of estrogen alone was not stopped in 2002 because the balance of risks and benefits was still uncertain at that time. In March 2004, however, the NIH decided to stop that study as well because there was no evidence of an overall benefit of hormone therapy.[6] Women taking estrogen alone were more likely to have strokes and less likely to have fractures than women taking the placebo. In contrast to the study of estrogen plus progestin, women taking estrogen alone did not have an increased risk of heart disease or breast cancer.

The average age of the women participating in WHI was 63 years, and a majority was more than 10 years beyond menopause. Since these women were older and had fewer menopausal symptoms than most women who take hormone therapy, it’s possible that the WHI results should not be applied to younger women who take hormone therapy closer to the time of menopause. It’s also important to note that each of the WHI studies assessed only one type and dose of hormone therapy. But until data about younger women, lower doses of hormones or different hormone formulations are available, the results of WHI offer the best available information about how hormone therapy affects the risk of developing chronic conditions such as heart disease and cancer.[7]

Why Were the WHI Results So Unexpected?

Before WHI, several studies had suggested that hormone therapy would reduce the risk of heart disease.[8] Most of these studies, however, were “observational.” In an observational study, scientists do not control the medications that women take. Rather, they observe what happens to women after the women themselves decide whether or not to take hormones. A limitation of this type of study is that the women who decide to take hormones are likely to be different from women who do not take hormones, and these differences may affect the study results. Researchers attempt to account for differences between groups when they analyze the data, but some differences may be difficult to identify or measure.

In a clinical trial such as the WHI, researchers assign study subjects to a particular treatment group. Clinical trials generally offer the most convincing evidence about the effects of a treatment, but they’re very expensive. In addition, they are only ethical when there is some initial evidence that the benefits of the treatment are likely to outweigh the risks. While some of the WHI results confirmed what the previous observational studies had reported (for example, a decreased risk of fracture in women taking hormones), many of the risks were quite different from what the observational studies had suggested they would be. These differences may be a reflection of both the type of study design (observational vs. clinical trial), as well as the ages of the women who were enrolled in the two types of studies.

The Response

After release of the WHI findings, there was a quick and dramatic decline in the use of postmenopausal hormone therapy. A study of over 169,000 women between the ages of 40 and 80 years, enrolled at five managed care organizations, evaluated hormone therapy use before and after the WHI reports of July 2002.[9] Before July 2002, approximately 15 percent of the women in this population were using estrogen plus progestin and 13 percent were using estrogen alone. By December 2002, only 8 percent of women were using estrogen plus progestin and 9 percent were using estrogen alone. Similarly, a study of national prescription data estimated that roughly 57 million prescriptions for hormone therapy would be filled in 2003, down from 91 million in 2001.[10]

Some women who stopped using postmenopausal hormones in the wake of WHI found it necessary to resume use. Among 377 women who were enrolled in a managed care organization and reported that they had tried to discontinue hormone use, 97 women (26 percent) chose to go back on hormone therapy. Women who developed troublesome symptoms after discontinuing hormone therapy were more likely to resume use.[11]

Hormone Therapy for Prevention of Chronic Disease:

Not Recommended

In May 2005, in response to findings from WHI and other studies, the United States Preventive Services Task Force (USPSTF) issued revised recommendations regarding postmenopausal hormone use.[12] It recommended against use of both estrogen plus progestin and estrogen alone for prevention of chronic diseases such as heart disease, cancer and osteoporosis, noting that the risks appear to outweigh the benefits. In making its recommendations, the USPSTF did not consider use of hormones for management of menopausal symptoms.

Hormone Therapy for Management of Menopausal Symptoms:

Benefits May Outweigh Risks for Some Women

While recommendations are clear that postmenopausal hormone therapy is generally not the best option for prevention of chronic disease, an important remaining issue is relief of menopausal symptoms. For some women, symptoms such as frequent hot flashes can cause a great deal of discomfort and disruption of daily life.

So how should women balance the increased risk of conditions such as strokes against relief from menopausal symptoms? This depends on a number of factors, including the severity of menopausal symptoms, but use of hormone therapy for relief of symptoms is most likely to be appropriate for younger women who are at low risk for other conditions and plan to use hormone therapy for a short time.[13] Ultimately, every woman needs to be assessed on an individual basis, and longer term use will sometimes be appropriate.

If vaginal dryness is the only symptom requiring treatment,use of a local estrogen treatment such as an estrogen-containing vaginal cream may be appropriate.[13] If a woman chooses to use hormone therapy, she should reassess her need for it with her doctor at least once a year.[14] Symptom management needs often change over time.

A statement issued by the Food and Drug Administration in September 2004 advises, “If you choose to use hormones for treating symptoms of menopause, use them at the lowest dose that helps for the shortest time needed.” [15]

Options for Osteoporosis

Aside from relief of menopausal symptoms, one of the most consistently reported benefits of postmenopausal hormone therapy is a reduced risk of bone fracture. For most women, however, it appears that this benefit will be outweighed by increased risks of other conditions. Steps women can take to prevent osteoporosis without taking hormone therapy include eating a diet rich in calcium and vitamin D, doing weight-bearing exercises, avoiding tobacco or excessive alcohol intake, and talking with their doctor about bone health, bone density screening and osteoporosis treatment options.

Elsa Smith was concerned about her risk of osteoporosis when she stopped taking estrogen, and she has taken other medication to replace the benefits of estrogen for the past two years: “I am very small boned, and osteoporosis is in my family. I’ve been careful about that.” Several prescription medications are available to prevent or treat osteoporosis, and women may wish to discuss these medications with their doctors.

For women who are at high risk for osteoporosis but who are not able to use other treatments, postmenopausal hormone therapy may be an appropriate choice for preventing or treating osteoporosis.[13] This will need to be determined on an individual basis.
Relief of Menopausal Symptoms in Women with Breast Cancer

Women with breast cancer are especially in need of guidance about relief of menopausal symptoms. While many breast cancer survivors experience menopausal symptoms as a result of their age or their cancer treatment, few are given estrogen because of the concern that it might increase the risk of breast cancer recurrence.

Two recent studies of menopausal hormone therapy in breast cancer survivors were stopped early because one of the studies reported that women taking hormones were more likely to have a breast cancer recurrence.[16],[17] While these studies, along with WHI, suggest that estrogen plus progestin poses a greater breast cancer risk than estrogen alone, there is currently too little information available to weigh the risks and benefits of estrogen alone in breast cancer survivors.[18]

In Elsa Smith’s case, she is clear about the fact that she would have liked to stay on estrogen. “For me, the benefits in my life outweighed everything else. I felt so much better with it.” However, she ultimately made the decision to stop taking estrogen in light of her breast cancer diagnosis.

Other medications that may provide relief from hot flashes include certain antidepressant medications such Effexor® (venlafaxine hydrochloride) and Paxil® (paroxetine hydrochloride). Neurontin® (gabapentin), a drug used to treat seizures, also appears have a beneficial effect on hot flashes.[19]

Many breast cancer survivors are interested in alternative approaches to menopausal symptom management, such as herbs. A survey of women in Wisconsin found that women with breast cancer were several times more likely than other women to report using alternative therapies for menopausal symptoms. The most frequently reported alternative therapies were soy, vitamin E and herbal remedies.[20] Currently, however, there is little information about the safety and efficacy of most of these approaches. “I’ve been very careful about what I put in my body,” says Elsa Smith, who’s avoided most over-the-counter remedies. “I’ve stayed on vitamin E. I think it played a big part in my healing process. And I eat a healthy diet.”

Finally, women may wish to take simple steps such as wearing layers of clothing that can be removed during a hot flash, or avoiding common triggers of hot flashes, such as a spicy foods, caffeine, alcohol and stress. For vaginal dryness, an over-the-counter vaginal lubricant may help.

What Does the Future Hold?

Important unanswered questions remain about the use of postmenopausal hormones. Specifically, there is interest in knowing whether the results of WHI apply to younger women who use menopausal hormones close to the time of menopause and whether lower doses of hormones will minimize risks while still relieving menopausal symptoms. To address some of these issues, a clinical trial has been funded by the Kronos Foundation to assess hormone therapy among women 42 to 58 years of age, who are within three years of their final menstrual period.[21] In women taking oral estrogen, the dose will be lower than the dose used in WHI. The main goal of the study is to evaluate the effect of hormone therapy on markers of cardiovascular disease.

Studies are also underway to test alternative approaches to symptom management in postmenopausal women. The National Center for Complementary and Alternative Medicine, part of NIH, is funding clinical studies of black cohosh, other botanicals, and acupuncture.[22]

As studies continue to answer questions about the most appropriate use of estrogen and about the risks and benefits of alternatives to estrogen, a recent NIH conference on the management of menopausal symptoms offered the reminder that menopause is a natural part of a woman’s life.[2] The conference report, prepared by an independent group of health professionals and members of the public, describes menopause as a “normal, healthy phase of women’s lives” that doesn’t necessarily require medical treatment. But the report also notes that safe and effective treatment of menopausal symptoms should be available to women who need it.

The decision about whether or not to take postmenopausal hormone therapy requires individualized consideration of the risks and benefits. Recent research findings have given us tools to make more informed decisions about postmenopausal hormone therapy, and research currently underway will address important remaining questions.

References:


[1]Gracia CR, Freeman EW. Acute consequences of the menopausal transition: the rise of common menopausal symptoms. Endocrinol Metab Clin N Am. 2004;33:675-689.

[2] NIH State of the Science Panel. National Institutes of Health State-of-the-Science Conference Statement: Management of Menopause-Related Symptoms. Ann Intern Med. 2005; 142:1003-1013.

[3] The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials. 1998; 19:61-109.

[4] Barnabei VM, Cochrane BB, Aragaki AK et al. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol. 2005; 105:1063-73.

[5]Rossouw JE, Anderson GL, Prentice RL 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

[6]Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004; 291:1701-1712.

[7]Hormone therapy. Executive Summary. Obstet Gynecol. 2004; 104:1S-4S.

[8]Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Annals of Internal Medicine. 1992. 117:1016-1037.

[9]Buist DSM, Newton KM, Miglioretti DL et al. Hormone therapy prescribing patterns in the United States. Obstet Gynecol. 2004; 104:1042-1050.

[10]Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004; 291:47-53.

[11]Grady D, Ettinger B, Tosteson ANA, Pressman A, Macer JL. Predictors of difficulty when discontinuing postmenopausal hormone therapy. Obstet Gynecol. 2003; 102:1233-1239.

[12]U.S. Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med. 2005:142:855-860.

[13]North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of the North American Menopause Society. Menopause. 2004;11:589-600.

[14]Peterson HB, Thacker SB, Corso PS, Marchbanks PA, Koplan JP. Hormone therapy: making decisions in the face of uncertainty. Arch Intern Med. 2004;164:2308-2312.

[15] FDA News: September is National Menopause Awareness Month! September 29, 2004. http://www.fda.gov/bbs/topics/news/2004/NEW01121.html (accessed January 29, 2008)

[16] Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer – is it safe?), a randomised comparison: trial stopped. Lancet. 2004; 363:453-455.

[17] von Schoultz E, Rutqvist E. Menopausal hormone therapy after breast cancer: The Stockholm Randomized Trial. J Natl Cancer Instit. 2005; 97:533-535.

[18] Chlebowski RT, Anderson GL. Prosgestins and recurrence in breast cancer survivors. J Natl Cancer Instit. 2005; 97:471-472.

[19]Molina JR, Barton DL, Loprinzi CL. Chemotherapy-induced ovarian failure: manifestations and management. Drug Safety. 2005; 28:401-416.

[20] Harris PF, Remington PL, Trentham-Dietz A, Allen CI, Newcomb PA. Prevalence and treatment of menopausal symptoms among breast cancer survivors. J Pain Symptom Manage. 2002; 23:501-509.

[21] Harmon SM, Brinton EA, Cedars M et al. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric. 2005; 8:3-12.

[22]National Center for Complementary and Alternative Medicine. Do CAM Therapies Help Menopausal Symptoms? Available at: http://nccam.nih.gov/health/menopauseandcam/ (accessed January 29, 2008).

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