To date, research on estrogen replacement therapy (ERT) and a potential increased risk of ovarian cancer has yielded conflicting results. Now, research published in the July 17, 2002 issue of the Journal of the American Medical Association (JAMA) suggests that ERT, but not hormone therapies that combine estrogen with progestin, increases a woman’s risk of developing ovarian cancer.

About the study

Researchers at the National Cancer Institute studied 44,241 women who had participated in the Breast Cancer Detection Demonstration Project—a breast cancer screening program conducted between 1973 and 1980. For this second study, the women were followed up from 1979 to 1998. Women were excluded from this study if they had a history of breast or ovarian cancers or had undergone surgery to remove their ovaries (oophorectomy).

Between 1979 and 1986, the women were interviewed by telephone about their age at first use of female hormones and duration of use. But these questions did not distinguish between estrogen-only (ERT) and estrogen-progestin combinations (HRT). The women were also asked about menopausal status, gynecologic surgeries (such as hysterectomy and oophorectomy), and other risk factors for ovarian cancer. Between 1987 and 1989, the women were mailed a questionnaire asking about ERT and HRT use and diagnoses of ovarian cancer, since the last interview. Questionnaires were mailed again between 1993 and 1995 and between 1995 and 1998. It wasn’t until the last questionnaire in 1995-98, that women were asked if they had a family history of ovarian cancer.

Researchers compared the number of ovarian cancer cases among women who took ERT and HRT with the number of cases among those who did not. Cases of ovarian cancer were confirmed through medical records and death certificates.

The findings

Compared with women who never took hormone replacement therapies, those who took estrogen only (ERT) were 60% more likely to develop ovarian cancer. This risk seemed to increase the longer the women took ERT. For example, ERT use for 10 to 19 years increased the risk of ovarian cancer by 80%, and 20 or more years of use increased risk by 300%. On the other hand, women taking estrogen-progestin combinations (HRT) did not seem to be at increased risk for ovarian cancer.

In calculating these statistics, the researchers accounted for age, oral contraceptive use, and whether or not women entered menopause naturally or via hysterectomy—all factors that could affect a woman’s risk of developing ovarian cancer.

The majority of women taking ERT in this study had undergone hysterectomy, because research has shown that women who still have a uterus (that is, have not had a hysterectomy) are at increased risk for endometrial cancer if they take ERT. Women who have not undergone hysterectomy are prescribed HRT (combined estrogen and progestin) instead, which essentially eliminates the increased risk of endometrial cancer from ERT. However, the July 17, 2002 issue of JAMA also reports that a major study of HRT in postmenopausal women was stopped three years early due to evidence that HRT may increase the risk of breast cancer, heart disease, stroke, and blood clots. See: "HRT study stopped early because risks seem to outweigh benefits"

Although these results are interesting and they raise concern about the safety of ERT, this study has its limitations. For example, information on family history of ovarian cancer was only included on the last questionnaire in 1995-98, when not all women were still available to answer. For this reason, the impact of family history on ovarian cancer risk in this study remains uncertain. In addition, during the earlier years of this study, ERT contained higher doses of estrogen than today’s ERT preparations. It is difficult to discern the difference in risk associated with the different dosage levels, because women don’t necessarily remember what dosages they were prescribed at various times over a 20-year period. Therefore, the effect of longer-term use of lower-dose ERT on ovarian cancer risk is still unclear.

How does this affect you?

Should you rethink your decision to take ERT? Yes, and you should talk it over with your health care provider. This study suggests that women who take ERT may be at increased risk for ovarian cancer, especially if they take it for 10 years or more. More research is needed, however, to better understand the risk of ovarian cancer associated with long-term use of the lower-dose ERT prescribed today.

Remember long-term ERT should only be given to women who have undergone hysterectomy. Even though this study did not find an increased risk of ovarian cancer among women taking HRT, another study in the same issue of JAMA did find increased risk of breast cancer, heart disease, stroke, and blood clots among HRT users. If you are taking HRT, you should read "HRT study stopped early because risks seem to outweigh benefits."