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Deletion of Androgen Receptors From Kisspeptin Neurons Prevents PCOS Features in a Letrozole Mouse Model.
- Source :
-
Endocrinology [Endocrinology] 2023 Apr 17; Vol. 164 (6). - Publication Year :
- 2023
-
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.<br /> (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
- Subjects :
- Animals
Female
Mice
Androgens metabolism
Disease Models, Animal
Kisspeptins genetics
Kisspeptins metabolism
Letrozole
Neurons metabolism
Receptors, Androgen genetics
Receptors, Androgen metabolism
Hyperandrogenism metabolism
Polycystic Ovary Syndrome chemically induced
Polycystic Ovary Syndrome genetics
Polycystic Ovary Syndrome metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 164
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 37191144
- Full Text :
- https://doi.org/10.1210/endocr/bqad077