Association of oral contraceptives and tubal ligation with risk of early natural menopause.

STUDY QUESTION: What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? SUMMARY ANSWER: We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. WHAT IS KNOWN ALREADY: OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. STUDY DESIGN, SIZE, DURATION: We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses' Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. MAIN RESULTS AND THE ROLE OF CHANCE: Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). LIMITATIONS, REASONS FOR CAUTION: Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. STUDY FUNDING/COMPETING INTEREST(S): The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Adult adiposity and risk of early menopause.

STUDY QUESTION: Is adult adiposity associated with early menopause? SUMMARY ANSWER: Overall and abdominal adiposity were non-linearly associated with odds for early natural menopause with elevated odds observed among women who were underweight in early or mid-adulthood compared to lean-normal weight women. WHAT IS KNOWN ALREADY: High and low adiposity have been associated with reproductive function and may potentially impact timing of menopause. It is unclear whether various aspects of adiposity are associated with risk of early menopause. STUDY DESIGN, SIZE, DURATION: Prospective cohort study that examined data from 78 759 premenopausal women from the Nurses' Health Study II who were followed from 1989 to 2011 for incidence of early natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were aged 25-42 years and premenopausal at baseline in 1989, when information on menopausal status, height and weight was reported via questionnaire. Information on menopausal status, type of menopause (natural, surgical, radiation/chemotherapy), hormone therapy use and weight was updated every two years along with information on smoking, physical activity and other behavioral and health-related factors. Multivariable logistic regression was used to estimate odds ratios for early menopause, defined as natural menopause before age 45 years, by aspects of adiposity. MAIN RESULTS AND THE ROLE OF CHANCE: Early natural menopause was reported by 2804 participants. Body mass index (BMI) was non-linearly associated with risk for early menopause. Compared to women with BMI = 18.5-22.4 kg/m2, those with BMI < 18.5 kg/m2 had a significant 30% higher odds of early menopause (95% confidence interval (CI) = 1.08, 1.57), while women with BMIs between 25.0-29.9 kg/m2 had significant 21-30% lower odds. Odds were not higher in women with BMI ≥ 35.0 kg/m2 in fully adjusted analysis. Non-linear associations with higher odds in underweight women were also observed for age 18 and age 35 BMI, though lower odds for overweight women was only observed for age 35 BMI. Odds were highest among women with age 18 BMI < 18.5 kg/m2 reporting severe weight cycling. LIMITATIONS, REASONS FOR CAUTION: Though weight and early menopause status were self-reported, validation studies conducted among Nurses' Health Study participants suggest that self-reported weight is highly correlated with directly measured weight, and prospective self-reported menopausal status is highly reproducible. It is possible that underweight women may have been misclassified with an earlier age at menopause if being underweight led to amenorrhea. WIDER IMPLICATIONS OF THE FINDINGS: In one of the few studies to prospectively examine a variety of adiposity measures and risk for early menopause, our findings that women who were underweight in early or mid-adulthood had elevated risk for early menopause can assist in efforts to better understand the etiology of early menopause. Additional prospective research is needed to understand how low adiposity may physiologically impact timing of menopause. STUDY FUNDING/COMPETING INTEREST(S): This study was conducted with funding from NIH UM1CA176726 and R01HD078517. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.