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Review: Long-term estrogen therapy increases the risk for breast and endometrial cancer but decreases the risk for coronary heart disease and hip fracture in postmenopausal women in primary prevention trials

ACP J Club. 1993 May-June;118:65. doi:10.7326/ACPJC-1993-118-3-065

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Source Citation

Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992 Dec 15;117:1016-37.



To compare the risks and benefits of long-term hormone therapy for asymptomatic postmenopausal women. Data were used to develop clinical guidelines.

Data sources

English-language studies published after 1970 were identified using MEDLINE, manual literature searches, bibliographies of relevant papers, and consultations.

Study selection

Case-control, cross-sectional, cohort, and randomized controlled studies that compared women who used postmenopausal hormones with nonusers for the risk for endometrial (n = 35 studies) or breast cancer (n = 39), coronary heart disease (CHD) (n = 32), hip fracture (n = 11), or stroke (n = 15). Studies were excluded if they had combined end points; lacked confidence intervals; or used inappropriate participants, controls, or comparison groups.

Data extraction

The estimated relative risk was taken from each study and a weighted pooled relative risk (PRR) was calculated. Mortality and incidence data were collected, and lifetime probabilities for developing disease and for life expectancy were calculated.

Main results

Compared with nonusers, the PRR for endometrial cancer in women who had used short-term estrogen was 2.3 (95% CI 2.1 to 2.5), and in women who had used long-term estrogen, the PRR was 8.2 (CI 6.3 to 10.8). The risk for endometrial cancer increased with increasing dose and duration of use. The addition of progestin to estrogen appeared to prevent the increase in endometrial cancer risk. No clear evidence was found that breast cancer was associated with short-term estrogen therapy alone (PRR 1.01, CI 0.97 to 1.05) or with progestin. Breast cancer may be associated with long-term estrogen use (PRR 1.25, CI 1.04 to 1.51). Estrogen use reduced the risk for CHD by 35% (PRR 0.65, CI 0.59 to 0.71). Estrogen, alone or in combination with progestin, reduced the risk for osteoporotic hip fracture by 25% (PRR 0.75, CI 0.68 to 0.84). The calculated life expectancy of a 50-year-old white woman with long-term estrogen use was 83.7 years and was 82.8 years for a nonuser.


For asymptomatic women on long-term postmenopausal estrogen therapy, the risk for breast and endometrial cancer is increased and the risk for coronary heart disease and hip fracture is decreased. Progestin use lowers the increased risk for endometrial cancer.

Sources of funding: American College of Physicians*; Merck/Society for Epidemiologic Research Clinical Epidemiology Fellowship Program; Henry J. Kaiser Family Foundation.

For article reprint: Ms. L.J. White, Director, Scientific Policy, American College of Physicians, Independence Mall West, Sixth Street at Race, Philadelphia, PA 19106-1572, USA. FAX 215-351-2869.

*Information supplied by author.


Grady and colleagues have comprehensively and carefully weighed the quantitative risks and benefits associated with postmenopausal hormone therapy in 50-year-old women. To quote an example, long-term estrogen therapy would afford an estimated average protective effect against CHD of 35% and hip fracture of 25%, while increasing the risk for breast cancer by 25% and for endometrial cancer by up to eightfold. Because CHD is 100 times more common than endometrial cancer, the overall result is an increase in life expectancy. Similarly, the authors weigh the risks and benefits of hormone therapy using estrogen alone or combined with progesterone for women at increased risk for various diseases, and for both white and black women.

Historically, prescribing behavior for postmenopausal hormones has waxed and waned with each new revelation about their risks and benefits. In the 1970s, concern about the substantially increased risk for endometrial cancer related to estrogen replacement therapy peaked and prescriptions declined. Subsequently, a small resurgence in the use of estrogen therapy reflected the findings that such therapy reduced the risk for CHD and osteoporotic hip fractures in women and that the addition of a progestin to the hormone regimen prevented the development of endometrial cancer. The meta-analytic approach used may allow us to stabilize our thinking and our prescribing of postmenopausal hormones while we await the results of more definitive randomized clinical trials. Clinical guidelines for counseling postmenopausal women about preventive hormone therapy were developed by the American College of Physicians (1) in conjunction with this meta-analysis. The need for more definitive trials is underscored by the many assumptions the authors make in consolidating the existing data. In the meantime, application of the authors' quantitative results to specific clinical situations provides a rationale for deciding for whom to initiate therapy and what type of therapy to use.

Roberta B. Ness, MD, MPH
University of PennsylvaniaPhiladelphia, Pennsylvania, USA


1. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med. 1992;117:1038-41.