Estimated Number of Lifetime Ovulatory Years and Its Determinants in Relation to Levels of Circulating Inflammatory Biomarkers

Reproductive events, such as ovulation, trigger an inflammatory cascade. Few studies have examined their long-term influence on inflammatory profiles. We included 3,393 premenopausal and 3,915 postmenopausal women with intact ovaries/uterus from the Nurses' Health studies (Nurses' Health Study (1989-1990) and Nurses' Health Study II (1996-1999)) in an analysis of the association between lifetime ovulatory years (LOY) and levels of inflammatory biomarkers. We estimated LOY as age at menopause (age at blood collection for premenopausal women) minus age at menarche, subtracting years of oral contraceptive (OC) use and 1 year per pregnancy. After adjustment for other inflammation-related factors (e.g., body mass index, exercise, diet), every 5-year increase in LOY was associated with lower C-reactive protein (CRP) levels in both premenopausal (difference = -11.5%, 95% confidence interval: -15.0, -8.0; P < 0.0001) and postmenopausal (difference = -7.2%, 95% confidence interval: -10.0, -4.3; P < 0.0001) women. Older age at menopause (P = 0.007), earlier menarche (P = 0.007), and shorter duration of OC use (P = 0.002) were associated with lower CRP levels in postmenopausal women, whereas duration of OC use was positively associated with CRP levels in premenopausal women (P < 0.0001). LOY was modestly inversely associated with interleukin 6 in postmenopausal women (P = 0.03). Notably, the associations of CRP with LOY were similar in magnitude to associations with exercise and a healthy diet, though weaker than the association with body mass index. Although many reproductive events induce acute inflammation, increased LOY was associated with lower chronic systemic inflammation even after menopause.