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

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.

• Authors: Caroline Decourt, Yugo Watanabe, Maggie C Evans, Megan A Inglis, Lorryn C Fisher, Christine L Jasoni, Rebecca E Campbell, Greg M Anderson
• Journal: Endocrinology (Endocrinology) Vol. 164 Issue 6 (04 17 2023) ISSN: 1945-7170 [Electronic] United States
• PMID: 37191144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• Androgens
• Kisspeptins
• Letrozole
• Receptors, Androgen
• Kiss1 protein, mouse
• AR protein, mouse

Topics

• Animals
• Female
• Mice
• Androgens (metabolism)
• Disease Models, Animal
• Hyperandrogenism (metabolism)
• Kisspeptins (genetics, metabolism)
• Letrozole
• Neurons (metabolism)
• Polycystic Ovary Syndrome (chemically induced, genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)