Serum Sex Hormones and the Risk of Fracture across the Menopausal Transition: Study of Women’s Health Across the Nation

Cauley JA1, Ruppert K1, Lian Y1, Finkelstein JS2, Karvonen-Gutierrez CA3, Harlow SD3, Lo JC4, Burnett-Bowie SM2, Karlamangla A5, Greendale GA5.

J Clin Endocrinol Metab. 2019 Jan 23. doi: 10.1210/jc.2018-02047. [Epub ahead of print]

Abstract
CONTEXT:
Sex steroid hormones have been linked to fractures in older women.

OBJECTIVE:
To test the hypothesis that hormones measured over the menopausal transition predict fractures.

SETTING:
7 US clinical centers.

SUBJECTS AND MEASUREMENTS:
2960 women (average age 46.4 ± 2.7 years) who had at least two repeat hormone measures and prospective information on fractures. Fasting serum was collected annually for hormone assays. Estradiol (E2) was measured with a modified direct immunoassay. Follicle-stimulating hormone (FSH) and sex hormone binding globulin (SHBG) were measured with 2 site chemiluminescence immunoassays. Hormones were lagged (visit year -1) and transformed using log base 2. Incident fractures were ascertained at each annual visit. All medications including hormone therapy (HT) were time varying covariates. Discrete survival methods were used.

RESULTS:
508 (17.1%) women experienced an incident fracture over an average follow-up of 8.8 ± 4.4 years. Women who experienced an incident fracture were more likely to be White, report high alcohol intake and diabetes and less likely to report premenopausal status at baseline. A woman whose log E2 was twice that of another had a 10% lower risk of fracture independent of covariates, relative risk (95% confidence intervals) = 0.90 (0.82, 0.98). Neither FSH or SHBG were associated with fractures.

CONCLUSIONS:
Serum E2 levels may help to identify women at higher risk of fractures over the menopausal transition. However, hormone assays must be standardized across laboratories for clinical implementation and further work is needed to define E2 thresholds.

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