Cytokine Modulation by Follicle-Stimulating Hormone

描述(申请人提供)：绝经过渡涉及循环卵巢类固醇的急剧减少和循环下丘脑促性腺激素的急剧增加。雌激素丢失对与衰老和更年期相关的健康问题的生物学后果，如骨质疏松症和心血管疾病，已经进行了广泛的研究。1结果是雌二醇对炎性细胞因子合成的紧张性抑制作用消失。这些细胞因子，包括白介素1B(IL-1B)、白介素6(IL-6)和肿瘤坏死因子-α(TNFa)，促进了骨吸收和动脉粥样硬化病变的发展。虽然雌二醇对绝经后健康的根本影响是毋庸置疑的，但促性腺激素浓度增加的潜在影响，特别是卵泡刺激素(FSH)，却较少受到关注。本项目将研究FSH可能影响骨骼和血管健康的潜在机制，即通过刺激IL-1B、IL-6和TNFa的分泌和抑制这些细胞因子受体的脱落。这些机制将使用从绝经前和围绝经期妇女的外周血液中分离出来的白细胞来研究。此外，这些机制的生物学意义将通过比较血浆FSH、细胞因子和细胞因子受体浓度与循环中的骨转换标志物(N-端肽和骨钙素)、双能X射线吸收测量仪测量的骨密度和血管健康指数(超声测量的颈动脉内膜-中层厚度和脉搏波速度)进行比较。更好地了解FSH在围绝经期和绝经后健康中的调节机制可能会导致针对FSH调节的新疗法，这种疗法可以缓解绝经后健康问题，而不会伴随类固醇激素替代疗法的风险。

DESCRIPTION (provided by applicant): The menopausal transition involves dramatic decreases in circulating ovarian steroids and dramatic increases in circulating hypothalamic gonadotropins. The biological consequences of estrogen loss on health problems associated with aging and menopause, such as osteoporosis and cardiovascular disease, have been studied extensively. 1 consequence is that tonic inhibition of inflammatory cytokine synthesis by estradiol is lost. These cytokines, including interleukin-1B (IL-1B), interleukin-6 (IL-6) and tumor necrosis factor-a (TNFa), contribute to bone resorption and development of atherogenic lesions. Although the fundamental influence of estradiol on post-menopausal health is unquestioned, the potential influence of increased gonadotropin concentrations, particularly follicle-stimulating hormone (FSH), has received less attention. This project will investigate potential mechanisms by which FSH may affect skeletal and vascular health, namely by stimulating IL-1B, IL-6 and TNFa secretion and inhibiting the shedding of receptors for these cytokines. These mechanisms will be studied using leukocytes isolated from the peripheral blood of pre-and peri-menopausal women. In addition, the biological significance of these mechanisms will be assessed by comparing plasma FSH, cytokine and cytokine receptor concentrations with circulating markers of bone turnover (N-telopeptide and osteocalcin), bone densities measured by dual energy X-ray absorptionmetry, and indices of vascular health (carotid intimal-medial thickness and pulse wave velocity measured by ultrasound). A better understanding of FSH-mediated mechanisms in peri-and postmenopausal health may lead to new therapies directed at modulation of FSH that can alleviate menopausal health problems without the attendant risks associated with steroid hormone replacement therapy.