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AS649 - Role of FSH in postmenopausal obesity and breast cancer

AS649 - Role of FSH in postmenopausal obesity and breast cancer

[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Jennifer W. Bea (jbea@uacc.arizona.edu)

Introduction/Intent

There is strong and consistent evidence of an association between obesity and post-menopausal breast cancer. In spite of these consistent epidemiologic associations, the exact mechanisms by which they are associated are not clear. The menopausal transition is most often characterized by decreased circulating estrogen levels and weight gain and/or changes in adipose distribution. However, hormone therapy (HT), including estrogen, does not favorably alter body composition long-term, nor does it reverse the increased risk of postmenopausal breast cancer. Follicle stimulating hormone (FSH) also increases with the menopausal transition and has emerged as a potential novel factor associated with decreased thermogenesis and increased adiposity in animal models. Therefore, we hypothesize that FSH may play an estrogen-independent role in breast cancer risk via its influence on the development of postmenopausal obesity. To date, there have been no large-scale epidemiologic investigations of these associations. Our study will first evaluate the association of FSH and multiple measures of total and abdominal adiposity in a large sample of postmenopausal women from the Women’s Health Initiative (WHI), a long-term national epidemiologic study. The sample will include 1733 postmenopausal women randomized in WHI HT trials, with repeat DXA scans over 6 years follow-up and 685 postmenopausal women in the observational study (OS) with repeat scans over 20 years follow-up. Additionally, in this sample, we will assess the dynamics of FSH levels in relation to adipose derived regulatory hormones of estrogen, activin and leptin, prior to breast cancer diagnosis, given the importance of feedback and feedforward regulation of FSH. Second, we will compare FSH levels in women who develop breast cancer (N=759 with DXA) to those women who remained breast cancer free (N=2333 non-cases in HT and OS sample above). Finally, we will analyze associations of germline polymorphisms in FSHR and FSHB and serum FSH levels and test for a causal association of FSH on adiposity in a Mendelian randomization framework, hypothesizing that genetic instruments for FSH levels are causally related to postmenopausal adiposity. Our study includes a novel measure of visceral adiposity derived from full body dual xray absorptiometry (DXA) as well as BMI, waist circumference and DXA-derived fat mass and percent body fat, as well as stored blood samples and GWAS data in WHI. To our knowledge, our study is the first 
comprehensive epidemiologic investigation of FSH and obesity, including both cross-sectional and longitudinal designs, and the first to measure and study FSH levels in the years prior to breast cancer diagnosis for study of the potential role of FSH in breast cancer development. Further, we will derive a mechanistic understanding of the influence of the menopausal hormonal milieu, hormone therapy, and genetics on body composition and breast cancer risk. These pieces of information in combination will enable novel and more precise future intervention targeting for breast cancer prevention.

Specific Aims

Significant gain of fat occurs with menopausal transition and is associated with increased risk of post-menopausal breast cancer. However, Women’s Health Initiative (WHI) studies have demonstrated that neither post-menopausal adiposity nor obesity-associated breast cancer risk are countered by hormone therapy (HT), which suggests that hormonal changes unrelated to estrogen, but specific to menopause, may be driving adiposity and associated breast cancer risk. The fact that estrogen alone did not increase breast cancer risk, while estrogen plus progesterone did, is not sufficient evidence to fully understand the effects of HT on breast cancer risk. Further, not all postmenopausal women could safely receive estrogen alone. Thus, a greater understanding of postmenopausal endocrinology related to adiposity and breast cancer risk is needed.

Recent pre-clinical research suggest that high follicle stimulating hormone (FSH) levels in post-menopausal women may drive adiposity and be associated with breast cancer risk. High FSH levels, a hallmark of menopause due to loss of ovarian feedback inhibition by follicular inhibin and estrogen (E2), can lower thermogenesis and drive an increase in adiposity. Interestingly, adipose-derived factors of leptin and activin, known to be elevated in obese individuals, can induce FSH secretion. Therefore, positive adipose feed forward cycles may help support post-menopausal FSH expression under circumstances where estrogen is insufficient to counter this effect (i.e. post-menopausal women). While links between obesity and adiposederived factors, such as leptin, and breast cancer have been identified, a possible role for FSH in mediating post-menopausal changes in body composition and/or cancer risk has not been evaluated in epidemiologic studies. We therefore propose to fill this important knowledge gap by querying associations of FSH and counter-regulatory hormones, with changes in body composition and breast cancer risk. 

A large subset of participants in the WHI HT trials (estrogen vs placebo and estrogen plus progestin vs placebo) completed body composition assessment by dual-energy X-ray absorptiometry (DXA) scans at baseline, year 1, and year 3, blood draw at baseline and year 1 (N=1733), and GWAS analyses (N=896). This provides a unique opportunity to tease apart the contributions of endogenous and exogenous hormones to body composition within the context of a randomized trial. A case-control design in the DXA cohort will enable examination of invasive breast cancer incidence (N=759 cases) relative to body composition and the hormonal milieu. Further, heritable differences in germline FSH-related polymorphisms will enhance our mechanistic understanding of FSH and adiposity. Race/ethnicity in the DXA cohort were enhanced and hysterectomy/bilateral oophorectomy status are well documented, therefore their influence on postmenopausal FSH levels and adiposity will also be explored. Lastly, we will conduct a parallel comparison of FSH associations free-living postmenopausal women enrolled in the WHI Observational Study (OS) with repeat DXA at years 3, 8, and 20 years (Buffalo, NY subset, N=685) and FSH at baseline and years 3, 8, and 20, which will further enhance generalizability and provide insight on late life influence of FSH on adiposity trajectory which is associated with several adverse chronic diseases contributing to high U.S. morbidity and mortality.
  1. Determine the dynamics of FSH and body composition, as well as FSH and adipose derived counter-regulatory hormones in post-menopausal women. We will examine the more precise imaging-basedadiposity measures (DXA total body fat, visceral, VAT, and subcutaneous adipose tissue, SAT) as well as standard anthropometric measures and use gold-standard assays for circulating biomarkers.
    • Using a cross-sectional design, evaluate the independent association of FSH on each body composition measure at baseline. Hypothesis: FSH predicts body composition, independent of E2.
    • Examine whether FSH predicts future body composition. Hypothesis: Higher and increasing FSH are associated with higher and increasing VAT and total adiposity long-term.
      • i. Baseline and 1 year change in FSH to predict body composition at year 3 (HT trials)
      • ii. Baseline FSH and change over 20 years, with repeat measures at year 3, 8, and 20, to predict 20 year trajectory of body composition (OS).
    • Characterize relationships between biomarkers of FSH, estrogen, leptin, and activin at baseline and year 1 in the HT trial sample and baseline, year 3, 8, and 20 in the OS sample. Hypothesis: The relationship between FSH, estrogen, leptin, and activin varies by trial arm and time.
  2. Evaluate the association between baseline FSH and invasive breast cancer incidence; determine if the relationships are mediated by adiposity and differential according to adiposity measurement. Hypothesis: FSH strongly correlates with breast cancer risk; abdominal adiposity mediates the association.
We will secondarily explore associations of germline polymorphisms in FSHR and FSHB and serum FSH levels; test for a causal association of FSH on adiposity in a Mendelian randomization framework. Hypothesis: Genetic instruments for FSH levels are causally related to post-menopausal adiposity. We will explore the 
effects of hysterectomy and bilateral oophorectomy, as well as race/ethnicity and age.