Role of FSH in postmenopausal obesity and breast cancer

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ABSTRACT There is strong and consistent evidence for an association between obesity and post-menopausal breast cancer; however, the exact mechanisms are not clear. Follicle stimulating hormone (FSH) increases with menopause, concomitant with increased adiposity, particularly visceral adipose tissue (VAT). Recent preclinical data suggests that FSH may drive the deleterious shift in adiposity, independent of estrogen (E2). Further, FSH receptors are now known to be expressed in breast tumors. To date, there have been no large- scale human investigations of these FSH-adiposity-breast cancer associations. Using the Women's Health Initiative (WHI), a long-term national epidemiologic study of postmenopausal women, we will test the hypothesis that FSH drives adiposity postmenopausally, both cross-sectionally and longitudinally. Large subsets of WHI participants completed repeat dual energy x-ray absorptiometry (DXA) scans, and therefore have available robust measures of adiposity (including a novel measure of VAT) and banked serum from the randomized hormone therapy trials (N=1400) and the observational study (OS; N=1499). Second, using a case-control design, we will test the hypothesis that higher baseline FSH levels associate with increased risk of breast cancer using adjudicated cancer incidence data spanning >25 years follow-up (N=785 cases; N=2510 non-cases). Further, we will determine whether adiposity mediates the FSH-breast cancer risk associations. For all analyses, we will account for exogenous HT use (conjugated equine estrogen ± medroxyprogesterone acetate or reported HT use in the OS), endogenous estrogen (E2), and adipose-derived hormones that directly or indirectly regulate FSH (e.g. leptin). Our study is the first comprehensive epidemiologic investigation of FSH and obesity to measure and study FSH levels in the years prior to breast cancer diagnosis to assess the potential role of FSH in breast cancer. This study, which includes rich hormone and body composition data will enable immediate translation to more precise breast cancer prevention interventions aligned with new medications in the pipeline or currently in use for other cancers and osteoporosis, such as FSH and FSH receptor modulators, upstream GnRH antagonists (e.g. goserelin), and estetrol (E4).