Total and unopposed estrogen exposure across stages of the transition to menopause.

Detailed characterization of estrogen dynamics during the transition to menopause is an important step toward understanding its potential implications for reproductive cancers developing in the transition years. We conducted a 5-year prospective study of endogenous levels of total and unopposed estrogen. Participants (n=108; ages 25-58 years) collected daily urine specimens for 6 months in each of 5 consecutive years. Specimens were assayed for estrone-3-glucuronide (E1G) and pregnanediol-3-glucuronide. Linear mixed-effects models were used to estimate exposure to total and unopposed estrogen by age and reproductive stage. Reproductive stage was estimated using menstrual cycle length variance. E1G mean area under the curve and mean E1G 5th and 95th percentiles represented total estrogen exposure. An algorithm identifying days of above-baseline E1G that coincided with the days of baseline pregnanediol-3-glucuronide was used to identify days of unopposed estrogen. Mean E1G area under the curve increased with age in the pretransition and early transition and decreased in the late transition. Ninety-fifth percentile E1G levels did not decline until after menopause, whereas 5th percentile levels declined from the early transition to the postmenopause. The number of days of unopposed estrogen was significantly higher during the transition compared with the pretransition. Given the length of time women spend in the transition, they are exposed to more total and unopposed estrogen than has been previously appreciated. Coupled with epidemiologic evidence on lifetime exposure to estrogen, these results suggest that variation in the amount of time spent in the transition may be an important risk factor for reproductive cancers.