On July 9, 2002, the National Institutes of Health announced that the Data and Safety Monitoring Board (DSMB) of the Women’s Health Initiative (WHI) had halted that portion of the study comparing combination treatment with an estrogen and a progestin (conjugated equine estrogens, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d) to placebo in healthy postmenopausal women with a uterus. The Board concluded that the risks of combined use of hormone therapy (HT) outweighed the benefits and stopped the study 3 years early, after a mean follow-up of 5.2 years. A total of 16,608 women between the ages of 50 and 79 (averaging over 61) had been randomized to combination HT or placebo.

Several members of the American Society for Reproductive Medicine have reviewed the data and offer these preliminary comments and observations in an effort to help physicians and their patients:

Data presented indicate increased relative risks for invasive breast cancer and for cardiovascular disease:

Invasive breast cancer relative risk 1.26 (95% confidence interval, CI, 1.00-1.59)
Coronary heart disease risk 1.29 (95% CI 1.02-1.63)
Stroke risk 1.41 (95% CI 1.07-1.85)
Pulmonary embolism risk 2.13 (95% CI 1.39-3.25)

Data also indicate decreased relative risks for both colorectal cancer and hip fracture:

Colorectal cancer risk 0.63 (95% CI, 0.43-0.92)
Hip fracture risk 0.66 (95% CI, 0.45-0.98)

These relative risks translate into small but real actual risks for individual patients utilizing combined HT: For every 10,000 women taking combined HT there will be 8 additional cases of breast cancer, 7 more heart attacks, 8 more strokes, and 18 more thromboembolic events per year. There will also be 6 fewer cases of colorectal cancer and 5 fewer hip fractures per year. Stated differently, the risk of invasive breast cancer in any individual taking combined HT is 0.08% (less than 1%) per year, and the risk did not appear until after 4 years of use. Risks for thromboembolic events were greatest in the first 2 years of use. The reduced risk of colorectal cancer did not appear until after 3 years of use.

The appearance of increased risk for invasive but not in situ breast cancer after only 4 years of use may suggest that combined HT does not increase the risk of new breast cancers but rather accelerates the development of incipient breast cancers already present. Whether this is the case will need to be examined in future investigations.

Because the DSMB did not stop the other portion of the HT trial, that comparing conjugated estrogens alone to placebo in women with previous hysterectomies, it is reasonable to assume that to date estrogen alone may be safer than combination HT, at least as administered in the WHI study.

The full report of this study will appear in the July 17,2002, issue of the Journal of the American Medical Association (JAMA) and is also available on the JAMA website at http://jama.ama-assn.org/.

The data emerging from this methodologically sound randomized controlled trial appear incontrovertible. However, as is true for all studies, generalizability may be limited. Moreover, the data are entirely consistent with observations from earlier retrospective analyses and from smaller prospective trials. They indicate that there are real but small risks associated with use of combined HT and that the benefits and the risks need to be carefully considered by each individual patient with her physician. Data from the WHI make it clear that the risks to the population at large, with millions of women treated with combined HT for many years, make this an important public health care issue, but it is important to remember that the risks to each woman are very small indeed.

Some physicians have commented to the press that these data indicate that combined HT 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 HT 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 HT to women. The data will no doubt lead to altered usage of estrogen but for the present, we suggest the following for consideration:

Women currently taking estrogen should not panic. They should seek the counsel of their physician to weigh the benefits and the risks of continued therapy.

It is important to remember that the study only tested combined HT with one dose of combination estrogen-progestin. Results of this study should not be interpreted, however, as relating solely to the combined HT preparation employed in this study. Presumably the risks of conjugated estrogen alone are smaller, but, for women with a uterus, use of this regimen will increase the risk of endometrial cancer greatly.

Women at risk for osteoporosis who wish to discontinue estrogen should be evaluated and consider use of alternative therapies, including bisphosphonates and selective estrogen receptor modulators.

Women at risk for cardiovascular disease who wish to discontinue estrogen should consider dietary and lifestyle changes (i.e., weight loss, regular exercise, and smoking cessation) as well as use of drugs to lower cholesterol and high blood pressure.
Women who present with symptoms of estrogen deficiency may use 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 clearly demonstrated that short-term use of estrogen is not associated with any increased risk of breast cancer. Estrogens clearly can improve quality of life in perimenopausal women, many of whom may be younger than the average age studied in the WHI trial. Given what is known about metabolism of sex steroids, it is possible, but unproven, that transdermal estrogen may have less risk in this regard. Physicians may wish to consider use of alternative therapies in symptomatic women who do not wish to take estrogen or who have only mild symptoms. 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 patches (which are not approved for this indication by the FDA); and some other alternative therapies have been shown to have some efficacy.
Women wishing to discontinue estrogen may be less apt to develop symptoms of estrogen deficiency if the estrogen is tapered gradually over 1 to 2 months. Symptoms of dyspareunia may be improved by the use of vaginal lubricants, use of the estrogen-containing vaginal ring, or estrogen vaginal cream.
HT should not be initiated or continued for the purpose of reducing cardiovascular risk.
What constitutes “long term” therapy will need to be reconsidered in the months and years ahead.

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