Women's Health Initiative Study

South Med J. 2002;95(9) 

In This Article

After the Women's Health Initiative -- What to Tell Our Patients

The shock caused by the release of the principal results of the Women's Health Initiative (WHI)[1] is now fading, and we must come to grips with how to integrate this new information into our practices. We will be helped in the future by the WHI releasing a series of papers discussing each of its findings in more detail, and by several of the large professional societies (such as the American College of Obstetricians and Gynecologists) establishing expert committees to draw up practice guidelines incorporating the WHI information.

The scope of the WHI was impressive; designed to be the first prospective, randomized, controlled clinical trial of hormone replacement therapy (HRT), it aimed to recruit more than 16,000 women and do follow-up on them for 8.5 years. The next-biggest studies in women's health have involved several thousand women, lasted 4 to 5 years, and cost dramatically less. Practically, this means that the WHI is not just one more study in a long line of menopause studies; rather, the WHI is the only sizeable, randomized, controlled trial that has ever been done in this field. Its results will be regarded as definitive, and it is highly unlikely that any study will be done in the future to challenge or change its findings.

What are the key WHI findings? A 37% reduction in colon cancer in HRT users was found, confirming a dozen previous epidemiologic studies that uniformly found about a 40% reduction in the incidence of colon cancer in both current and past users of HRT. The WHI found a 34% decrease in hip fractures among HRT users, the first study to show that HRT decreased that most important osteoporosis endpoint. A 2.11-fold increase in deep venous thromboses was observed, in the low range of the twofold to threefold increase seen in previous studies of estrogen, HRT, or selective estrogen-receptor modulator (SERM) administration. The WHI was stopped prematurely when a 26% increase in invasive breast cancer achieved statistical significance. This finding was surprising, since a recent comprehensive review of previous epidemiologic studies had concluded that no convincing link between breast cancer and HRT was present.[2] The big WHI surprises were the 29% increase in heart attacks and the 41% increase in strokes that were seen. For many years, epidemiologic studies indicated that HRT decreased these events by half; however, the Heart and Estrogen/Progestin Replacement Study (HERS) trial (and its extension, HERS II) was the first prospective, randomized, controlled trial of HRT and heart disease.[3,4] It examined women with established heart disease and found no benefit of HRT use. Previous epidemiologic trials of stroke patients suggested that HRT provided a benefit, but a definitive, prospective trial of the use of estrogen alone for secondary prevention, the Women's Estrogen for Stroke Trial (WEST), failed to find a benefit of hormone therapy.[5] We must conclude that much of our previous "knowledge" of HRT was erroneous, due to artifacts inherent in epidemiologic studies.

In talking to patients, the main challenge will be accurately conveying the numeric risks they face. By any standards, a 0.08% increased risk of breast cancer for each year of HRT use is extremely low. After 10 years of use, the cumulative 0.8% increase in risk is still low, but it has become a reasonable fraction of the 8% to 12% total risk of breast cancer diagnosis. Nationally, with millions of women taking HRT, many thousands will presumably have HRT-associated disease; the risk for any one woman is extremely low, however, and she may decide that the benefits she personally obtains in symptom relief outweigh this risk. Grouping all of the WHI endpoints, 30 more bad outcomes than good outcomes per 10,000 women each year were noted, a surplus risk of 0.3% yearly. After 4 years of HRT, the risk becomes 1.2% -- still low, but not as discountable.

A major problem is that HRT is the only potent therapy for vasomotor symptoms and genital atrophy in menopausal women, a particularly important consideration for women with severe symptoms. Although these problems have been shown to improve when patients use some non-HRT hormones (progestins, androgens), nonhormonal prescription drugs (eg, fluoxetine, clonidine hydrochloride), and herbs (eg, black cohash), women with significant symptoms are seldom satisfied with those treatments. Similarly, some women have mood changes at menopause that are only relieved with HRT; also, HRT may help a long list of other problems (forgetfulness, cognition, libido, skin thickness, etc).

A reasonable course of action now would be to discuss this information with patients and to carefully document their being informed of these risks. Some patients will elect to quit HRT altogether. Patients taking HRT for prevention will need to reassess their treatment; few patients will get benefits from HRT that they could not get with other therapy. In addition to increased adherence to dietary/lifestyle modifications, women concerned with osteoporosis might be better served by taking SERMs (eg, raloxifene hydrochloride) or bisphosphonates (alendronate sodium, risedronate sodium); either seems to give the same approximate fracture prevention as HRT. Some evidence indicates that raloxifene hydrochloride lowers the risk of breast cancer.[6] Women focused on heart disease and stroke prevention should similarly work on life-style, blood pressure, and lipid issues, and HRT should be dropped.

The challenging decision, however, will come regarding women taking HRT to treat vasomotor symptoms and other symptoms of menopause, for which no truly equivalent therapies are available. Some patients will elect to continue HRT, deciding that their quality-of-life improvement outweighs the 0.3% yearly risk of a bad event. Many will try to discontinue the HRT as soon as possible after their symptoms are "over," but little, if any, evidence indicates that menopausal symptoms will be prevented or diminished by a course of HRT; rather, they will occur after HRT is stopped. Still, most women who took HRT in the past did so for a relatively brief time, usually measured in months, giving support to this approach. The efficacy of other maneuvers to minimize HRT's impact is entirely speculative but includes using estrogen-progestin medications other than those studied in the WHI, minimizing their dosages, using alternate delivery routes (patches, creams), and, in particular, adding occasional (every 2 to 4 months) progestin administration to the estrogen treatment.

Ken Muse, MD
University of Kentucky
Division of Reproductive Endocrinology
Department of Obstetrics and Gynecology
800 Rose St
Lexington, KY 40536-0084

  1. Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy menopausal women. principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333

  2. Bush TL, Whiteman M, Flaws JA: Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001; 98:498-508

  3. Hulley SB, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605-613

  4. Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Follow-up Study (HERS II). JAMA 2002; 288:49-57

  5. Viscoli CM, Brass LM, Kernan WN, et al: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345:1243-1249

  6. Cauley JA, Norton L, Lippman ME, et al: Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treat 2001; 65:125-134

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