Cytokine Modulation by Follicle-Stimulating Hormone

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.