Association between Laparoscopically Confirmed Endometriosis and Risk of Early Natural Menopause

Importance: Early natural menopause (ENM) has been associated with reduced reproductive span, cardiovascular disease risk, and early mortality. The potential adverse implications of endometrioma surgery for ovarian reserve are known, yet the association of endometriosis with menopausal timing remains understudied. Objective: To investigate the association between endometriosis and risk for ENM. Design, Setting, and Participants: This large, population-based cohort study analyzed data from the Nurses' Health Study II cohort questionnaires from the 1989 to 2015 questionnaire cycles. The sample included premenopausal women aged 25 to 42 years at baseline or enrollment in 1989. Cumulative follow-up rate was greater than 90%, and participants continued follow-up until the onset of ENM, age 45 years, hysterectomy, oophorectomy, cancer diagnosis, death, loss to follow-up, or end of follow-up in May 2017, whichever occurred first. Data analyses were conducted from October 26, 2020, to April 27, 2021. Exposures: Endometriosis diagnosis status was queried in the biennial questionnaires, with participants reporting physician diagnosis and whether the diagnosis was laparoscopically confirmed. Main Outcomes and Measures: Natural menopause before age 45 years. Menopause status was assessed every 2 years. Results: The study included 106633 premenopausal women with a mean (SD) age of 34.8 (4.3) years at baseline, of whom 3921 reported a laparoscopically confirmed endometriosis diagnosis. During 1 508 462 person-years of follow-up, 6640 participants reported being diagnosed with endometriosis, 99993 never reported endometriosis, and 2542 reported experiencing ENM. In the age- and calendar time-adjusted model, laparoscopically confirmed endometriosis was associated with a 50% greater risk for ENM (hazard ratio [HR], 1.51; 95% CI, 1.30-1.74). A similar risk was observed after adjusting for race and ethnicity and time-varying anthropometric and behavioral factors (HR, 1.46; 95% CI, 1.26-1.69). With additional adjustment for reproductive factors, the HR of ENM was attenuated but significant (HR, 1.28; 95% CI, 1.10-1.48). A greater risk of ENM was observed among women who were nulliparous after stratifying by parity (nulliparous vs parous: HR, 1.46 [95% CI, 1.15-1.86] vs 1.14 [95% CI, 0.94-1.39]; P for heterogeneity =.05) or who never used oral contraceptives when stratifying by oral contraceptive use (never vs ever: HR, 2.03 [95% CI, 1.34-3.06] vs 1.20 [95% CI, 1.02-1.42]; P for heterogeneity =.02). No significant differences were observed in the association between endometriosis and ENM when stratifying by body mass index (calculated as weight in kilograms divided by height in meters squared; <25 vs ≥25: HR, 1.20 [95% CI, 0.99-1.45] vs 1.43 [95% CI, 1.11-1.83; P for heterogeneity =.34), cigarette smoking status (never vs ever: HR, 1.36 [95% CI, 1.13-1.65] vs 1.11 [95% CI, 0.87-1.42]; P for heterogeneity =.57), or history of infertility attributed to ovulatory disorder (no vs yes: HR, 1.28 [95% CI, 1.08-1.51] vs 1.28 [95% CI, 0.90-1.82]; P for heterogeneity =.86). Conclusions and Relevance: This cohort study found a risk for ENM in women with laparoscopically confirmed endometriosis. These women compared with those without endometriosis may be at a higher risk for shortened reproductive duration, particularly those who were nulliparous or never used oral contraceptives..