Current issues of ACP Journal Club are published in Annals of Internal Medicine


Review: Postmenopausal hormone replacement therapy is associated with increased invasive ovarian cancer, especially after long-term use

ACP J Club. 1999 Jan-Feb;130:23. doi:10.7326/ACPJC-1999-130-1-023

Source Citation

Garg PP, Kerlikowske K, Subak L, Grady D. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol. 1998 Sep;92:472-9.



Does postmenopausal hormone replacement therapy (HRT) increase the risk for invasive epithelial ovarian carcinoma?

Data sources

Studies were identified with MEDLINE (1966 to June 1997) using the terms ovarian neoplasms, ovarian cancer, estrogen replacement therapy, estrogens, hormone replacement therapy, post-menopausal estrogens, post-menopausal hormones, non-contraceptive estrogens, and non-contraceptive hormones. Bibliographies of relevant papers were scanned, and experts were contacted.

Study selection

Studies were selected if they assessed the association between HRT and the development of invasive or borderline ovarian cancer, if case-patients (women with ovarian cancer) were matched with control-women on the basis of age, if the results were adjusted for age, if data distinguished between postmenopausal and premenopausal hormone use, and if women with bilateral salpingo-oophorectomy were excluded.

Data extraction

Data were extracted on study design, source of control-women, tumor histology, use of HRT (unopposed estrogen or estrogen combined with progestin), duration of HRT (< 1, 1 to 5, 6 to 10, or > 10 y), and cancer type (ovarian cancer, borderline ovarian tumors, or both).

Main results

11 articles, which included data from 21 studies, met the inclusion criteria. 10 studies evaluated invasive ovarian cancer (4392 women with ovarian cancer). Using meta-analysis techniques, the studies showed that ever-use of HRT and use > 10 years were associated with an increased risk for invasive ovarian cancer (Table). Population-based and hospital-based studies yielded similar results. Invasive or borderline ovarian cancer was associated only with ever-use of HRT (Table).


Hormone replacement therapy, especially long-term use, may be associated with an increased risk for invasive epithelial ovarian cancer.

Source of funding: In part, Robert Wood Johnson Foundation.

For correspondence: Dr. K. Kerlikowske, San Francisco Veterans Affairs Medical Center, 4150 Clement Street (111A1), San Francisco, CA 94121, USA. FAX 415-386-4044.

Table. Relative risk (RR) for the association between hormone replacement therapy (HRT) and ovarian cancer in postmenopausal women

Ovarian cancer Studies Duration of HRT RR (95% CI)
Invasive All (n = 10) Ever use 1.15 (1.05 to 1.27)
Invasive All (n = 6) > 10 y 1.27 (1.00 to 1.61)
Invasive All case-control (n = 9) Ever use 1.16 (1.03 to 1.29)
Invasive Hospital-based (n = 6) Ever use 1.15 (1.00 to 1.33)
Invasive or borderline All (n = 12) Ever use 1.14 (1.04 to 1.24)


Evaluation of preventive HRT has focused on osteoporosis prevention, cardiovascular disease, and breast cancer risk (1). Re-analysis of data from 51 epidemiologic studies of women with breast cancer supported the position that breast cancer risk is slightly increased in women who use long-term HRT (2).

Any potential increased risk for ovarian cancer with long-term HRT would be of concern because screening and therapy for ovarian cancer is less effective than that for breast cancer. This analysis by Garg and colleagues of 11 articles (21 studies) may be limited by publication bias (although the authors were contacted to identify unpublished studies) and surveillance bias. It also does not prove any causal relation between ovarian cancer and HRT. It is important to note that HRT has been associated with a reduction in all-cause mortality in cohort studies. Its overall protective benefit, although somewhat attenuated, is still present after 10 years of use (3). These positive findings may, however, result from the fact that healthier women use HRT and not because of HRT use itself.

This study piques our interest in examining other serious conditions in women that may be modified by long-term HRT, such as the recent finding of a reduction in risk for colon cancer (4). Clinicians should discuss the preventive benefits and potential harms of HRT with postmenopausal women.

Holly L. Thacker, MD
Cleveland Clinic FoundationCleveland, Ohio, USA


1. Col NS, Eckman MH, Karas RH, et al. Patient specific decisions about hormone replacement therapy in postmenopausal women. JAMA. 1997;277:1140-7.

2. Breast cancer in hormone replacement therapy. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997; 350:1047-59.

3. Grodstein F, Stampfer NJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769-75.

4. Grodstein F, Martinez E, Platze A, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med. 1998;128:705-12.