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 有强有力且一致的证据表明肥胖与绝经后乳房之间存在关联 癌症;然而，确切的机制尚不清楚。促卵泡激素 (FSH) 随 更年期，伴随肥胖增加，特别是内脏脂肪组织（VAT）。最近的 临床前数据表明，FSH 可能会导致肥胖的有害变化，而与雌激素 (E2) 无关。 此外，现在已知 FSH 受体在乳腺肿瘤中表达。迄今为止，还没有发生过大规模的—— 对这些 FSH-肥胖-乳腺癌关联进行大规模人体研究。利用女性健康 倡议（WHI）是一项针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 在横向和纵向上驱动绝经后肥胖。大的 WHI 参与者子集完成了重复双能 X 射线吸收测定 (DXA) 扫描，因此 拥有可用的稳健的肥胖测量方法（包括一种新的增值税测量方法）和来自 随机激素治疗试验 (N=1400) 和观察性研究 (OS; N=1499)。其次，使用 病例对照设计，我们将检验以下假设：较高的基线 FSH 水平与增加的风险相关 使用超过 25 年随访的判定癌症发病率数据（N=785 例；N=2510 非个案）。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 的使用（结合马雌激素 ± 甲羟孕酮 醋酸盐或报道的 OS 中使用的 HT）、内源性雌激素 (E2) 和脂肪源性激素，这些激素直接 或间接调节 FSH（例如瘦素）。我们的研究是首次对 FSH 进行全面的流行病学调查 和肥胖症来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。这项研究包含丰富的激素和身体成分数据，将 能够立即转化为与新的癌症预防措施相一致的更精确的乳腺癌预防干预措施 正在研发或目前用于治疗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（例如戈舍瑞林）和雌四醇 (E4)。