Cumulative Endogenous Estrogen Exposure Is Associated With Postmenopausal Fracture Risk: The Women's Health Initiative Study

We aimed to evaluate the relationship between cumulative endogenous estrogen exposure and fracture risk in 150,682 postmenopausal women (aged 50 to 79 years at baseline) who participated in the Women's Health Initiative. We hypothesized that characteristics indicating lower cumulative endogenous estrogen exposure would be associated with increased fracture risk. We determined ages at menarche and menopause as well as history of irregular menses from baseline questionnaires and calculated years of endogenous estrogen exposure from ages at menarche and menopause. Incident clinical fractures were self-reported over an average 16.7 years of follow-up. We used multivariable proportional hazards models to assess the associations between the estrogen-related variables and incidence of any clinical fracture. In fully adjusted models, those with the fewest years of endogenous estrogen exposure (<30) had an 11% higher risk of developing central body fractures and a 9% higher risk of lower extremity fractures than women with 36 to 40 years of endogenous estrogen exposure (the reference category). In contrast, women with the most years of endogenous estrogen exposure (more than 45 years) had a 9% lower risk of lower extremity fractures than the reference category. Women with irregular (not monthly) menstrual cycles were 7% to 8% more likely to experience lower extremity fractures than women with regular monthly cycles. Our findings support the hypothesis that characteristics signifying lower cumulative endogenous estrogen exposure are associated with higher fracture risk.