Early menarche, nulliparity and the risk for premature and early natural menopause

STUDY QUESTION: Are parity and the timing of menarche associated with premature and early natural menopause? SUMMARY ANSWER: Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40-44 years), a risk that is amplified for nulliparous women. WHAT IS KNOWN ALREADY: Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power. STUDY DESIGN, SIZE, DURATION: This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). PARTICIPANTS/MATERIALS, SETTING, METHODS: Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40-44 years), 45-49 years, 50-51 years, 52-53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation. MAIN RESULTS AND THE ROLE OF CHANCE: The median age at FMP was 50 years (interquartile range 48-53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12-13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53-2.12) and early menopause (1.31, 1.19-1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84-2.77) and early menopause (1.32, 1.09-1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04-7.87) and 2-fold increased risk of early menopause (2.16, 1.48-3.15) compared with women who had menarche at ≥12 years and two or more children. LIMITATIONS, REASONS FOR CAUTION: Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause. STUDY FUNDING/COMPETING INTEREST(S): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.