Role of FSH in postmenopausal obesity and breast cancer

FSH 在绝经后肥胖和乳腺癌中的作用

• 批准号: 10580054
• 负责人: Jennifer Wright Bea
• 金额: $ 73.8万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580054
• 关键词: Accounting; Adipose tissue; Age; Ancillary Study; Attention; Automobile Driving; Bilateral oophorectomy; Binding; Biological Markers; Body Composition; Body Weight; Body fat; Body mass index; Breast; Breast Cancer Prevention; Breast Cancer Risk Factor; Cancer Prevention Intervention; Case/Control Studies; Clinical; Clinical Trials; Computer software; Conjugated Equine Estrogens; Data; Development; Dual-Energy X-Ray Absorptiometry; Endocrinology; Estradiol; Estrogen receptor positive; Estrogens; Ethnic Origin; Feedback; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Future; Goals; Gonadotropin Releasing Hormone Inhibitor; Goserelin; Growth Factor; Hormonal; Hormones; Human; Hysterectomy; Image; Incidence; Inflammatory; Investigation; Joints; Leptin; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Marketing; Measures; Mediating; Mediator; Medroxyprogesterone 17-Acetate; Menopause; Modeling; Obesity; Observational Study; Osteoporosis; Ovarian; Participant; Pharmaceutical Preparations; Pilot Projects; Postmenopause; Pre-Clinical Model; Premenopause; Prevention; Preventive therapy; Process; Production; Race; Randomized; Reporting; Resources; Risk Factors; Role; Safety; Sampling; Scanning; Serum; Source; Testing; Therapeutic; Therapy trial; Time; Translations; Visceral; Woman; Women' s Health; adjudication; arm; bone; breast cancer diagnosis; breast tumorigenesis; cancer subtypes; case control; cohort; design; druggable target; epidemiology study; experience; follow-up; hormone therapy; improved; innovation; insight; interest; large datasets; malignant breast neoplasm; novel; obesity development; phase 3 testing; pre-clinical; receptor; research clinical testing; subcutaneous; waist circumference

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).

摘要 有强有力和一致的证据表明肥胖和绝经后乳腺癌之间存在关联 癌症;然而，确切的机制尚不清楚。卵泡刺激素（FSH）增加， 绝经期，伴随肥胖增加，特别是内脏脂肪组织（VAT）。最近 临床前数据表明，FSH可能独立于雌激素（E2）而驱动肥胖的有害转变。 此外，目前已知FSH受体在乳腺肿瘤中表达。到目前为止，还没有大的- 这些FSH-肥胖症-乳腺癌关联的大规模人类调查。利用妇女的健康 倡议（WHI），一项长期的全国流行病学研究绝经后妇女，我们将测试 FSH在横截面和纵向上驱动绝经后肥胖的假设。大 WHI参与者的子集完成了重复的双能X线吸收测定法（DXA）扫描，因此 具有可用的肥胖的稳健措施（包括一种新的VAT措施）和来自 随机激素治疗试验（N=1400）和观察性研究（OS; N=1499）。第二，使用 采用病例对照设计，我们将检验基线FSH水平较高与以下风险增加相关的假设： 使用判定的癌症发病率数据，随访时间>25年（N=785例; N=2510例 非案件）。此外，我们将确定肥胖是否介导FSH-乳腺癌风险关联。 对于所有分析，我们将考虑外源性HT使用（结合马雌激素±甲羟孕酮 醋酸盐或报告的HT在OS中的使用）、内源性雌激素（E2）和脂肪源性激素， 或间接调节FSH（例如瘦素）。我们的研究是第一次全面的FSH流行病学调查 和肥胖，以测量和研究乳腺癌诊断前几年的FSH水平， FSH在乳腺癌中的潜在作用这项研究，其中包括丰富的激素和身体成分的数据将 能够立即转化为更精确的乳腺癌预防干预措施， 正在开发或目前用于其他癌症和骨质疏松症的药物，如FSH和FSH 受体调节剂、上游GnRH拮抗剂（例如戈舍瑞林）和雌四醇（E4）。