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: 10446232
• 负责人: Jennifer Wright Bea
• 金额: $ 80.73万
• 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/10446232
• 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; Buffaloes; Cancer Prevention Intervention; Case-Control Studies; Clinical; Clinical Trials; Computer software; Conjugated Equine Estrogens; Data; Development; Dual-Energy X-Ray Absorptiometry; 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; Measures; Mediating; Mediator of activation protein; Medroxyprogesterone 17-Acetate; Menopause; Modeling; Obesity; Observational Study; Osteoporosis; Ovarian; Participant; Pharmaceutical Preparations; Pilot Projects; Postmenopause; Pre-Clinical Model; Premenopause; Prevention; Preventive therapy; Process; Race; Randomized; Reporting; Resources; Risk Factors; Role; Safety; Sampling; Scanning; Serum; Source; Testing; Therapeutic; Therapy trial; Time; Tissue Banks; Translations; Visceral; Woman; Women' s Health; adjudicate; arm; base; 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).

抽象的 有强烈而一致的证据表明肥胖与绝经后乳房之间存在关联 癌症;但是，确切的机制尚不清楚。卵泡刺激马酮（FSH）随着 更年期，伴随着肥胖的增加，尤其是内脏脂肪组织（VAT）。最近的 临床前数据表明，FSH可能会促进肥胖的有害转移，而与雌激素无关（E2）。 此外，现在已知FSH受体在乳腺肿瘤中表达。迄今为止，还没有很大的 规模对这些FSH辅助乳腺癌协会的人类投资。使用女性健康 倡议（WHI），一项对绝经后妇女的长期国家流行病学研究，我们将测试 假设FSH在横截面和纵向上都在绝经后促进肥胖。大的 WHI参与者的子集完成了重复的双能X射线绝对图（DXA）扫描，因此 具有可用的肥胖度测量值（包括对增值税的新颖测量）和来自 随机马酮治疗试验（n = 1400）和观察性研究（OS; n = 1499）。第二，使用一个 病例对照设计，我们将检验以下假设：较高的基线FSH水平与增加的风险增加 使用调整后的癌症事件数据跨越> 25年的随访（n = 785例； n = 2510） 非案例）。此外，我们将确定肥胖是否介导FSH-胸癌风险关联。 对于所有分析，我们将考虑使用外源HT（共轭的马雌激素±甲状腺羟孕酮） 乙酸盐或报告的HT在OS中使用），内源性雌激素（E2）和脂肪衍生的激素 或间接调节FSH（例如瘦素）。我们的研究是FSH的首次全面流行病学研究 和肥胖以测量和研究乳腺癌诊断前几年的FSH水平以评估 FSH在乳腺癌中的潜在作用。这项研究包括丰富的骑马和身体组成数据 使立即翻译到更精确的乳腺癌预防干预措施与新的乳腺癌干预措施 管道中的药物或目前用于其他癌症和骨质疏松症的药物，例如FSH和FSH 受体调节剂，上游GNRH拮抗剂（例如Goserelin）和Estetrol（E4）。