Targeting central and peripheral kisspeptin/KISS1R signaling: a novel perspective on PMOS pathogenesis and therapy

Polyendocrine metabolic ovarian syndrome (PMOS), formerly recognized as polycystic ovary syndrome (PCOS), is characterized by well-understood symptoms. However, current clinical management predominantly targets symptom relief, with effective targeted therapies remaining elusive due to the unclear origins of the syndrome. This review synthesizes current research and posits the hypothesis that dysfunction in central and peripheral kisspeptin/KISS1R may contribute to the pathogenesis of PMOS. Potential mechanisms include overactivity of hypothalamic KNDy neurons or peripheral KISS1R deficiency. In ovarian granulosa cells, KISS1R deficiency may impair cell function and energy metabolism, while such deficiency in hepatocytes can lead to hepatic steatosis. These disruptions could hinder follicular development and ovulation, as well as precipitate metabolic disorders in PMOS patients. Accordingly, two potential therapeutic strategies for PMOS are proposed: (1) Central inhibition via NK3R antagonists to suppress hypothalamic KNDy neuron activity, thereby decreasing kisspeptin/GnRH/LH secretion; (2) Activation of peripheral KISS1R in ovarian granulosa cells and hepatocytes to enhance cell survival, regulate cytokine and sex steroid secretion, and provide feedback to central kisspeptin/GnRH/LH release. This strategy aims to lower basal serum LH levels, mitigate hyperandrogenism and hyperinsulinemia, and induce LH surges and ovulation. Furthermore, KISS1R on peripheral adipocytes and androgen receptors on kisspeptin neurons in the hypothalamus may also play roles in metabolic disorders and PMOS pathogenesis through kisspeptin signaling. By analyzing PMOS pathogenesis from this novel perspective and proposing therapies aimed at central kisspeptin neurons and peripheral KISS1R, new strategies for PMOS treatment may be identified.