Deletion of Androgen Receptors From Kisspeptin Neurons Prevents PCOS Features in a Letrozole Mouse Model

• Published in: Endocrinology (Philadelphia) 2023-06, Vol.164 (6), p.1
• Main Authors: Decourt, Caroline, Watanabe, Yugo, Evans, Maggie C, Inglis, Megan A, Fisher, Lorryn C, Jasoni, Christine L, Campbell, Rebecca E, Anderson, Greg M
• Format: Article
• Language: English
• Subjects: Analysis; Androgen receptors; Androgens; Androgens - metabolism; Animal models; Animals; Body weight; Body weight gain; Deletion; Disease Models, Animal; Endocrinology; Estrus cycle; Female; Females; Hyperandrogenism - metabolism; Hypotheses; Infertility; Insulin; Kiss1 protein; Kisspeptins - genetics; Kisspeptins - metabolism; Letrozole; Liquid oxygen; Metabolic disorders; Metabolism; Mice; mRNA; Negative feedback; Neurons; Neurons - metabolism; Ovaries; Pathogenesis; Polycystic ovary syndrome; Polycystic Ovary Syndrome - chemically induced; Polycystic Ovary Syndrome - genetics; Polycystic Ovary Syndrome - metabolism; Receptors; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA; Stein-Leventhal syndrome
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqad077

Abstract Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility and is a heterogenous condition associated with a range of reproductive and metabolic impairments. While its etiology remains unclear, hyperandrogenism and impaired steroid negative feedback have been identified as key factors underpinning the development of PCOS-like features both clinically and in animal models. We tested the hypothesis that androgen signaling in kisspeptin-expressing neurons, which are key drivers of the neuroendocrine reproductive axis, is critically involved in PCOS pathogenesis. To this end, we used a previously validated letrozole (LET)-induced hyperandrogenic mouse model of PCOS in conjunction with Cre-lox technology to generate female mice exhibiting kisspeptin-specific deletion of androgen receptor (KARKO mice) to test whether LET-treated KARKO females are protected from the development of reproductive and metabolic PCOS-like features. LET-treated mice exhibited hyperandrogenism, and KARKO mice exhibited a significant reduction in the coexpression of kisspeptin and androgen receptor mRNA compared to controls. In support of our hypothesis, LET-treated KARKO mice exhibited improved estrous cyclicity, ovarian morphology, and insulin sensitivity in comparison to LET-treated control females. However, KARKO mice were not fully protected from the effects of LET-induced hyperandrogenism and still exhibited reduced corpora lutea numbers and increased body weight gain. These data indicate that increased androgen signaling in kisspeptin-expressing neurons plays a critical role in PCOS pathogenesis but highlight that other mechanisms are also involved.