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.

Monitoring reproductive aging in a 5-year prospective study: aggregate and individual changes in steroid hormones and menstrual cycle lengths with age.

OBJECTIVE: We describe a 5-year prospective study of reproductive aging, and present analyses of steroid hormone and menstrual cycle changes with age. DESIGN: Participants were college-educated white women, primarily of northern European ancestry, recruited from the Tremin Research Program on Women's Health (n = 156, 25-58 years). In each of 5 consecutive years, they collected daily urine specimens for 6 months and recorded menstrual bleeds for all months. Urine specimens were assayed for estrone-3-glucuronide (E1G) and pregnanediol-3-glucuronide (PDG), urinary metabolites of estradiol and progesterone. Using multilevel models, we estimated hormone and cycle-length trajectories for individual women and within- and between-woman variance by age. RESULTS: At the aggregate level, PDG declined beginning in the 30s, E1G increased into the 40s before declining, and cycle length became more variable with age. Individual-level models revealed substantial hormonal variation across women, in both absolute levels and rates of change. Most women showed declining E1G by the late 40s, declining PDG in the 30s, and increasing mean cycle length in the 40s. Hormonal variation decreased with age; cycle length variation decreased and then increased. Within individual women, cycle lengths were highly variable while hormone levels were more stable. Women differed more from each other in hormone levels than for cycle lengths. CONCLUSIONS: Aggregate-level analyses show general changes in steroid hormones and cycle length but cannot show variation within and across women. Individuals' cycle lengths were too variable to predict hormone levels. Clinicians should obtain more data on individual women's hormonal patterns when determining fertility or menopause treatments.