Age at Natural Menopause in Women Exposed to Diethylstilbestrol in Utero

Abstract

TM1-O-03 Introduction: A woman's age at natural menopause is related to several important health outcomes, including breast cancer, cardiovascular disease, and overall mortality. Age at menopause may be affected by the size of the original pool of follicles formed during gestation, suggesting that in utero factors could be important in determining menopausal age. Diethylstilbestrol (DES), a nonsteroidal estrogen widely prescribed during the 1950s and 1960s to prevent miscarriage, has been related to numerous reproductive tract abnormalities and adverse health outcomes among prenatally exposed daughters but has not been studied previously in relation to age at menopause. Methods: We analyzed age at natural menopause in 4 combined cohorts of 4210 women exposed to DES in utero, and a comparable group of 1829 nonexposed women, all of whom had exposure status documented by prenatal medical records. The original cohorts were first identified in the 1970s from several different geographic regions in the United States. Women were recontacted by mail questionnaire in 1994, 1997, and 2001. Questions were asked about the occurrence of natural or surgical menopause, hormone replacement therapy, and other risk factors. Survival analysis methods, including Cox proportional hazards modeling, were used to estimate the risk of natural menopause in DES-exposed versus unexposed women. Results: DES-exposed women were approximately 50% more likely to be naturally menopausal than unexposed women at any given age (hazard ratio [HR] = 1.48; 95% CI, 1.28–1.71), controlling for year of birth and original cohort. Adjustment for a broad range of other confounders had little effect on the results. On average, DES-exposed women reached menopause 11 months earlier than unexposed women, which, in our data, was approximately the same effect size as having ever smoked. In a subset of women with information on the total cumulative dose of DES, dose-response effects were found, with a twofold increased risk of menopause among women exposed to >10,000 mg during pregnancy. Interpretation: Women who were exposed to DES in utero tend to reach natural menopause at an earlier age than unexposed women. The causal mechanism for this association is unclear but may be related to a reduction in the size of the original follicle pool, more rapid depletion of follicles, or changes in steroid hormone synthesis and metabolism. Age at natural menopause has been previously related to several exposures, including smoking and parity, but this study is the first to suggest that an in utero exposure may affect reproductive lifespan.