SAT607 Targeted Modulation Of Kisspeptin Neurons Improves Hyperandrogenism And Hyperactive LH Secretion In A Pre-clinical PCOS-like Mouse Model: Implications For Novel Therapeutics In PCOS Women

Abstract

Abstract Disclosure: E. Coutinho: Employee; Self; Crinetics. L.A. Esparza: None. A.S. Kauffman: Consulting Fee; Self; Crinetics. Polycystic ovary syndrome (PCOS), a common reproductive disorder in women, is characterized by hyperandrogenemia, chronic anovulation, and/or cystic ovarian follicles. Another common hallmark of PCOS is LH hyper-pulsatility, believed to be driven by hyperactive GnRH neurons, but the reason for the increased GnRH secretion still remains unclear. We previously developed a PCOS-like mouse model using chronic letrozole (LET; aromatase inhibitor) and reported that LET females demonstrated multiple PCOS-like phenotypes, including polycystic ovaries, anovulation, hyperandrogenemia, enlarged ovaries, and hyperactive LH pulse secretion. Given the proposed role of hypothalamic arcuate kisspeptin neurons as the GnRH pulse generator, we determined that LET females have markedly elevated Kiss1 and Tac2 expression and increased Kiss1 neuronal activation in the arcuate nucleus, correlating with their hyper-pulsatile LH secretion. Thus, in the LET PCOS-like condition, and perhaps in PCOS women, increased hypothalamic kisspeptin and NKB neuron activity may be fundamental contributors to the hyperactive LH secretion and downstream hyperandrogenemia. We next tested this possibility using chemogenetics in transgenic PCOS-like mice to acutely and chronically suppress kisspeptin neuron activity. Acute inhibition of kisspeptin neurons successfully lowered abnormally high, rapid in vivo LH pulse secretion in PCOS-like females. Likewise, chronic in vivo suppression of endogenous kisspeptin neuron activity for several weeks dramatically lowered both circulating LH and T levels, and reduced ovarian weights, in females previously displaying a PCOS-like phenotype, with a trend towards improvement of overweight phenotype. These data support the hypothesis that overactive kisspeptin neurons may be one possible driver of neuroendocrine PCOS-like phenotypes. Importantly, these findings suggest that modulation of kisspeptin neurons may be a viable, novel therapeutic target to treat hyperandrogenism and hyperactive LH pulsatility in PCOS women. Indeed, although identical studies have not yet been done in humans, our findings complement recent clinical investigations using NKB receptor antagonists or dynorphin analogs to lower LH pulse secretion in PCOS women and other PCOS-like animal models. Presentation: Saturday, June 17, 2023