FSH Signaling in Osteoporosis and Alzheimer's Disease.

PURPOSE OF REVIEW: The female sex is itself a major risk factor for both osteoporosis and Alzheimer’s disease (AD), two age–related, chronic conditions that rise sharply during the menopausal transition. Although estrogen deficiency has traditionally been viewed as the primary cause of female predominance of postmenopausal bone loss and cognitive decline, emerging evidence suggests that rising follicle–stimulating hormone (FSH) levels, particularly during late perimenopause and beyond, play an independent and critical role. This Review will summarize the direct effect of FSH on the skeleton and brain. RECENT FINDINGS: Large epidemiologic studies have shown that elevated serum FSH levels correlate with negative skeletal consequences, even after adjustment for estrogen. Pre–clinical studies demonstrate that FSH directly activates osteoclasts to promote bone resorption and suppresses osteoblastogenesis. Findings in Alzheimer’s disease mouse models likewise reveal that FSH binds to neuronal FSH receptors in AD–prone brain regions and accelerates amyloid and tau pathology. Population studies support these mechanistic insights by linking rising FSH levels to cognitive decline. This corpus of evidence has not only reframed FSH as an aging hormone that affects both the skeleton and brain, but also reveals a new therapeutic avenue that includes the development of FSH blocking antibodies to address multiple age–related diseases that disproportionately affect postmenopausal women.