7985 Insights into the Menopausal Transition: A Comparative Analysis of Hypothalamic Reproductive Aging in Women and a Mouse Model of Menopause

Abstract Disclosure: J.C. Bloom: None. S.A. Pereira: None. E. Torres Jimenez: None. D.C. Page: None. V.M. Navarro: None. Menopause onset is the major determinant of reproductive lifespan in women and is characterized by the decline in estrogen production from the ovary. While much of our current understanding of the menopause transition in humans comes from a series of observational longitudinal studies initiated in the 1980s and 1990s, the mechanisms by which reproductive aging impacts healthy brain aging remains a profoundly under-studied aspect of women’s health. The hypothalamus, a hub of homeostatic and temperature regulation, is highly sensitive to changes in sex steroid levels. Recently, activation of the neurokinin 3 receptor (NK3R) by neurokinin B (NKB) has been linked to the onset of vasomotor symptoms (VMS) during menopausal transition. NKB is secreted by hypothalamic Kisspeptin, NKB, Dynorphin (KNDy) neurons in response to decreasing estradiol levels. Here, we present a comparative study of the expression trajectories of the KNDy genes (KISS1, TAC3, PDYN, respectively) and NK3R (TACR3) in hypothalamic samples of humans across menopause and a mouse model of peri- and post-menopause (short- and long-term ovariectomy (OVX), respectively). RNA-sequencing data of human and mouse hypothalamic samples revealed a high correlation in the expression profile of the KNDy/NK3R genes between both species. Further investigation has revealed a highly conserved pool of genes in human and mouse hypothalami that correlate with TACR3 upon decline of circulating sex steroids. Thus, by examining conserved gene expression patterns across this critical reproductive period, we have been able to identify novel candidate targets involved in menopausal transition which may serve to better elucidate the biology of menopause-associated conditions affecting the brain, such as VMS and cognitive decline. Presentation: 6/2/2024