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.

Keywords: cohort; early menopause; epidemiology; menopause; natural menopause; oral contraceptives; ovarian function; prospective; reproductive factors; tubal ligation.

Figure 1.

Flowchart of participant selection, from the Nurses’ Health Study II (NHSII), 1989–2017. Of the 116 429 participants at baseline in 1989, a total of 106 633 were included in the analytic sample and followed-up to 2017 for incident early natural menopause (n=2579). NHSII, Nurses’ Health Study II.

Figure 2.

Associations of oral contraceptive use at ages 13–42 years with early natural menopause, NHSII, 1989–2017 (n = 106 633).^aReference group for each Hazard Ratio (HR) is no oral contraceptive use at each age. ^bAdjusted for age at menarche (≤9, 10, 11, 12, 13, 14, 15, 16, ≥17 years), smoking (never, past 1–14, 15–24, 25+ years, current 1–14, 15–24, 25+ years), alcohol (0, 1 to <10, 10 to <30, ≥30 g/d), BMI (<18.5, 18.5–24.9, 25.0–29.9, ≥30 kg/m²), vitamin D from dairy (quintiles), vitamin D supplement use (0, >0 to <600, ≥600 IU/d), parity (0, 1, 2, 3, 4+), total cumulative breastfeeding, 0 to <1, 1–3, >3–6, >6–12, >12–18, >18–24, >24–36, ≥36 months, parous but breastfeeding data missing), infertility because of ovulatory disorder (no, yes), menstrual cycle length in 1993 (≤25, 26–31, 32–39, ≥40 days), tubal ligation (no, yes), and duration of oral contraceptive use (category medians).