Estrogen Replacement Therapy & Ova Ca Mortality

Estrogen Replacement Therapy and Ovarian Cancer Mortality in a Large Prospective Study of US Women

Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ

JAMA. 2001;285:1460-1465

This paper reports on the relation between long-term use of estrogen replacement therapy (ERT) and ovarian cancer mortality, including 14 years of follow-up data and 944 ovarian cancer deaths. Participants were 211,581 women from the United States and Puerto Rico enrolled in the American Cancer Society's Cancer Prevention Study in 1982. Past and current use of ERT was obtained from the baseline questionnaire as were other health-related data.

Twenty-two percent of women in the study population had used ERT. Among ever users, 24% were users at baseline and 76% were former users. Mean duration of estrogen use before enrollment was 6.4 years among baseline users and 3.8 years among former users. Compared with never users, women who ever took estrogens were more likely to be white, have used oral contraceptives, be former smokers, and have had a tubal ligation. They were also more educated, had fewer children, and were thinner.

A positive association was observed between ever use of postmenopausal estrogens and ovarian cancer mortality (RR = 1.23; 95% CI 1.06-1.43). The increased risk was mainly observed among women who were estrogen users at baseline (RR = 1.51; 95% CI, 1.16-1.96).

Risk was increased, but not significantly, among former users (RR = 1.16; 95% CI 0.99-1.37). Estrogen use of 10 or more years was associated with increased risk among both baseline (RR = 2.20; 95% CI, 1.53-3.17) and former users (RR = 1.59; 95% CI, 1.13-2.25). Short duration of use (< 10 years) was associated with small and statistically nonsignificant increases in risk.

Annual age-adjusted ovarian cancer death rates per 100,000 women were 64.4 for baseline users, 38.3 for former users, both with 10 or more years of use, and 26.4 for never users. Risk of ovarian cancer among women who took estrogen for 10 or more years was independent of oral contraceptive use and parity. Risk of ovarian cancer among ERT users decreased with length of time since last use.


Clinical commentary

This large prospective study supports the hypothesis that ERT increases the risk of fatal ovarian cancer. The association was related to both duration and recency of hormone use. Women who used postmenopausal estrogens for 10 or more years were at increased risk of fatal ovarian cancer. Estrogen use for less than 10 years was not associated with increased risk. The mechanisms underlying an association between postmenopausal estrogens and ovarian cancer have not been established.

However, the lifetime risk of ovarian cancer is low (1.7%), and any increase in risk of ovarian cancer mortality related to long-term estrogen use must be considered in the context of the overall balance of potential risks and benefits.

There are several limitations to the current study, including the fact that data were not available on type of hormone replacement therapy; the majority of baseline users in 1982 were likely to have been taking unopposed estrogens. The impact of sequential or combined estrogen and progesterone therapy on ovarian cancer risk is unknown. Additional studies are needed to confirm the results of this study and to examine whether effects are similar for unopposed and combined therapies.

Clinicians may need to include ovarian cancer among the health risks of long-term estrogen use.

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