Early menopause, defined as the cessation of menstruation before age 45, is experienced by approximately 10% of women (Jacobsen et al., 2003; Broekmans et al., 2009; Shuster et al., 2010). Early menopause is associated with an increased risk of premature mortality, cardiovascular disease and other chronic conditions (van Der Voort et al., 2003; Miller, 2012; Wellons et al., 2012; Bleil et al., 2013; Torrealday and Pal, 2015). Genetic factors alone do not explain the development of early menopause, and recent studies suggests that modifiable lifestyle factors may also influence risk, including physical activity (Aydin et al., 2005; Ortega-Ceballos et al., 2006; Dratva et al., 2007; Dorjgochoo et al., 2008; Nagata et al., 2012; Emaus et al., 2013; Gold et al., 2013).In premenopausal women, physical activity may influence ovarian function by altering production of estrogens and other steroid hormones via the hypothalamic–pituitary–ovarian axis (Tworoger et al., 2007). Intense physical activity can disrupt regular ovarian cycles, leading to luteal phase insufficiency, anovulation and amenorrhea; these may be associated with a lower risk of early menopause as they are associated with a lower frequency of ovulation and a slower rate of exhaustion of the follicle pool (Gudmundsdottir et al., 2009). Most prior research of physical activity and menopause has primarily addressed a potential relation with menopausal timing more generally. Prospective studies have yielded inconsistent findings. Only two studies of physical activity and early menopause specifically have been conducted; both were based on small sample sizes and observed point estimates consistent with a strong inverse association, but the results were not statistically significant. It thus remains unclear whether physical activity may be importantly related to risk of early menopause.We evaluated the relation of physical activity at multiple ages with risk of early menopause in the prospective Nurses’ Health Study II (NHSII).Materials and Methods
Participants
The NHSII cohort includes of 116 429 female US registered nurses aged 25–42 years in 1989. Participants completed questionnaires assessing lifestyle factors and medical conditions every two years thereafter. Follow-up rates for each questionnaire cycle were least 89%. The study protocol was approved by the Institutional Review Board at Brigham, Women Hospital in Boston, MA and the Harvard TH Chan School of Public Health.Assessment of physical activity
In study questionnaires in 1989, 1991, 1997, 2001, 2005 and 2009, women reported the average time per week during the past year spent on recreational activities. In 1989, activities included walking, jogging, running, bicycling (including on a stationary machine), racquet sports, lap swimming, calisthenics and other aerobic activities. In later years, activities were expanded to include weight training, low intensity exercises like yoga and high intensity activities like lawn mowing. Response options ranged from 0 minutes to ≥11 h/week. In 1997, women also reported the average amount of time per week spent on moderate and strenuous recreational activities at three ages: grades 7–8 (ages 12–13), grades 9–12 (ages 14–17) and ages 18–22, 23–30 and 30–34. Response options ranged from none to ≥11 h/week. To incorporate the frequency, duration and intensity of activity, we multiplied hours per week of each activity by its metabolic equivalent (MET) score, with one MET equal to 1 kcal/kg/h or the energy expended by sitting quietly (Ainsworth et al., 2000), and then summed values for all activities to create total MET hours/week.Assessment of early menopause
In 1989 and on each subsequent biennial questionnaire, women were asked if their menstrual periods had ceased permanently, and if so, at what age, and whether cessation was related to surgery, radiation or chemotherapy or occurred naturally. Information regarding use of hormone therapy (HT) was collected as well. Age at menopause was defined as age after 12 consecutive months of amenorrhea. A small number of women reported being postmenopausal on one questionnaire and then subsequently reported being premenopausal. For these women, we defined age at menopause as age after which periods were absent for 12 months or more, and then confirmed that this status persisted for at least three consecutive questionnaires.Eligibility for the current analysis was limited to women who were premenopausal and reported physical activity at the baseline 1989 questionnaire (n = 107 275). Women were followed for incidence of menopause until June 2011. We defined cases as those women who reported natural menopause before age 45.
Covariate assessment
Information on race, ethnicity, age, education, height and age at menarche was collected at baseline. Information on parity, oral contraceptive (OC) use, HT use and smoking was collected biennially since baseline. Current weight and body mass index (BMI; weight (kg)/height (m)2) were also assessed biennially. Information on diet was collected using semi-quantitative food frequency questionnaires (FFQ) in 1991 and every 4 years thereafter (Willet et al., 1985). Additional information on dietary supplement use, including vitamin D and calcium, was collected on main NHSII questionnaires. Nutrient intake was adjusted for total energy using the residual method (Willett, 2012).Statistical analysis
We divided women into categories of total MET hours/week and then compared the distribution of covariates at baseline with physical activity in age-adjusted general linear models. We evaluated the relation of category of physical activity with incidence of early menopause using Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Women contributed person-time in months from the date of return of the baseline questionnaire (1989) until menopause, hysterectomy, oophorectomy, diagnosis of cancer (other than non-melanoma skin cancer), death, loss to follow-up, age 45 or June 2011, whichever came first.We modeled total physical activity participation in adulthood in three ways: (1) MET h/week at baseline (1989) only; (2) updating MET h/week data every 4 years; (3) cumulatively averaging MET h/week, updated every 4 years; this method uses the mean MET h/week from all prior physical activity assessments as a measure of long-term physical activity (Eliassen et al., 2010). In addition, we evaluated associations of early menopause with the cumulative average of time spent walking, as walking was the most common activity reported by participants. Risk associated with moderate and strenuous activity in adolescence, early and middle adulthood was also assessed.In addition to models adjusting for age, we built a multivariate model controlling for time-varying factors including age, pack-years of smoking, parity, breastfeeding duration, alcohol intake, percentage of total calories from vegetable protein, and vitamin D from dairy intake, as well as age at menarche (time invariant); these covariates were selected a priori based on previous studies of early menopause in our population (Purdue-Smithe et al., 2017, Boutot et al., 2018, Whitcomb et al., 2018). We created a second multivariate model additionally controlling for BMI (time-varying), given that adiposity could be a confounder or intermediate in the pathway; BMI and physical activity are closely related, and prior research in the same population found that underweight women are at increased risk for early menopause (Szegda et al., 2017). To test for linear trend, we assigned the median activity level of each category to all women in that category and used median values in regression models.We conducted several sensitivity analyses. We stratified analyses to evaluate whether hazard ratio estimates were comparable across categories of BMI, smoking status and current OC use, using likelihood ratio tests to compare models with and without multiplicative interaction terms. Finally, because HT use may contribute to misclassification of menopause status, we ran additional models censoring at first use of HT. Statistical analyses were conducted with SAS v9.3 software (SAS Institute Inc, Cary, NC).Results
During 20 years of follow-up, 2786 members of the analytic cohort experienced incident early menopause. Overall, women reporting higher physical activity were somewhat younger, had lower BMI at baseline and recalled BMI at age 18, and lower parity compared to those reporting lower activity overall (Table I). Greater physical activity was associated with slightly longer duration of OCs use, and higher intake of alcohol, vegetable protein and vitamin D.
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