Pharmacological Antagonism of the Kisspeptin-Neurokinin System Improved Adverse Metabolic Traits in a PCOS Mouse Model

Abstract

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine condition affecting up to 20% of reproductively aged women worldwide. Owing to an ambiguous etiology and complicated pathophysiology, current PCOS treatments remain purely symptomatic. Aberrations in androgen receptor driven neuroendocrine pathways are reportedly involved in the pathogenesis of PCOS. A clinical trial, focusing on the androgen regulated kisspeptin-neurokinin B-dynorphin system, treated women with PCOS with a neurokinin B receptor (neurokinin 3 receptor, NK3R) antagonist and reported improvements in LH secretion, LH pulses and testosterone levels. Aim: To investigate if pharmacological antagonism of NK3R can ameliorate PCOS traits in a mouse model. Method: Reproductive and metabolic features of PCOS were evaluated in control and dihydrotestosterone (DHT)-induced PCOS mice, treated +/-NK3R antagonist (MLE4901) for 28 days at a dose of 25mg/kg/day. Results: PCOS-like mice were acyclic and exhibited ovulatory dysfunction, which were not rescued by NK3R antagonist treatment. Compared to control mice, the PCOS-like mice displayed a significant increase in total body weight and inguinal, parametrial, mesenteric, retroperitoneal, and brown fat pad weights (all P[Formula: see text]0.01). NK3R antagonism partially reversed the total body weight and fat pad weight gains (all P[Formula: see text]0.01) in all white fat depots of PCOS-like mice. PCOS-like mice also displayed adipocyte hypertrophy and increased leptin levels compared to control mice (both P[Formula: see text]0.01), which were improved with NK3R antagonism treatment (P[Formula: see text]0.01 and P[Formula: see text]0.05, respectively). Moreover, DHT exposure significantly reduced the respiratory exchange ratio (RER) (P[Formula: see text]0.01), whereas NK3R antagonism significantly increased RER compared to control mice (P[Formula: see text]0.01), suggesting a metabolic shift in the PCOS-like mice treated with the NKR3 antagonist. Conclusion: These findings show that pharmacological antagonism of the kisspeptin-neurokinin system may be a beneficial treatment for adverse metabolic features of PCOS. This study also reveals important new insights into neuroendocrine androgen actions in the pathogenesis of PCOS.