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

Abstract

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

Association of oral contraceptives and tubal ligation with antimüllerian hormone

“…35 More recent studies found no significant effect of duration of OC use on AMH levels. 18,23,24 We recently examined the association of OC use and risk of early menopause in the full NHSII cohort 36 and, although we observed a significant trend of increasing risk associated with longer duration of OC use in our age-adjusted models (P for trend ¼ 0.003), results were substantially attenuated and nonsignificant in our fully adjusted models (P for trend ¼ 0.71). In our AMH analysis, the pattern of attenuation was similar to our early menopause analysis, although our final AMH model remained significant.…”

The relation of number of childbirths with age at natural menopause: a population study of 310 147 women in Norway

“…Also, oral contraceptive use has been assumed to reduce the recruitment and atresia of oocytes, and thereby delay menopause. However, recent studies report modest influence of oral contraceptive use on age at menopause, and these findings also challenge the ‘oocyte sparing’ hypothesis ( Roman Lay et al , 2020 ; Langton et al , 2021 ).…”

“…Thus, we did not make adjustment for variables that have unknown relation with either number of childbirths or age at menopause, such as physical activity and alcohol consumption. The use of hormonal contraceptives may influence women’s number of childbirths, and possibly the age at menopause ( Roman Lay et al , 2020 ; Langton et al , 2021 ). Adjustment for oral contraceptive use did not alter the associations of number of childbirths with age at menopause in our study.…”

Association of lifetime lactation and age at natural menopause: a prospective cohort study

“…Alternatively, there may be a complex interrelationship between reproductive factors like lifetime lactation and oral contraceptive use that have yet to be fully disentangled in studies to date. 53 Additional research on the biological processes impacting menopause before versus after 45 years and on the interrelationship between lifetime lactation and other reproductive factors are needed to better understand these paradoxes.…”

“…This suggests that early menopause may have an underlying pathology that is distinct from the causes of variation in timing of menopause after 44 years, which could be differentially affected by reproductive factors. Alternatively, there may be a complex interrelationship between reproductive factors like lifetime lactation and oral contraceptive use that have yet to be fully disentangled in studies to date 53 . Additional research on the biological processes impacting menopause before versus after 45 years and on the interrelationship between lifetime lactation and other reproductive factors are needed to better understand these paradoxes.…”