Prenatal Androgen Excess Impairs Sexual Behavior in Adult Female Mice: Perspective on Sexual Dysfunction in PCOS

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders worldwide, affecting 5-20% of reproductive aged women [1]. PCOS is characterised by androgen excess, oligo- or anovulation, and polycystic ovarian morphology [1]. PCOS patients also experience sexual dysfunction, including decreased sexual desire, increased sexual dissatisfaction and gender dysphoria [2-4]. The origins of PCOS-related sexual difficulties remain unidentified, but may be related to impaired central mechanisms regulating sexual behaviours. Prenatally androgenized (PNA) mice recapitulate the PCOS phenotype and exhibit alterations in the neuronal network regulating reproductive function [5], providing a powerful, pathology-based model to unravel the biological origins of sexual dysfunction in PCOS. Here, we aimed to determine whether female sexual behaviours are impaired in the PNA mouse model of PCOS. To model PCOS, female dams received injections of dihydrotestosterone (PNA) or oil vehicle (VEH) daily from gestational day 16-18. Adult female offspring were ovariectomized and implanted with a silastic capsule of estradiol to examine the female-typical sexual behaviour: lordosis as well as partner preference. We also examined a potential masculinisation of the brain by replacing the estradiol implant by a testosterone implant then testing the female for male-like sexual behaviours. PNA females exhibited significantly reduced lordosis behaviour compared to VEH females (p<0.01). In contrast, partner preference and male-like sexual behaviour were not different between PNA and VEH females. In addition, using Open-field test and elevated-plus maze, we observed no effect of prenatal androgen exposure on locomotion and anxiety. These results highlight, for the first time, that prenatal exposure to the non-aromatisable androgen, DHT, impairs female receptivity only without masculinisation. These findings support the use of the PNA mouse model of PCOS to identify the neuronal targets of prenatal androgen action and to determine the mechanisms by which prenatal androgen excess impairs lordosis. Taken together, this study introduce a novel perspective on the origins of sexual dysfunction in women with PCOS and indicate the need for further investigation into the mechanisms of androgen excess on the female brain and sexual function. [1] Lizneva D et al, Fertil Steril. 2016;106:6-15. [2] Fliegner M et al, Geburtshilfe Frauenheilkd. 2019;79:498-509.[3] Kowalczyk R et al, Acta Obstet Gynecol Scand. 2012;91:710-4.[4] Mansson M et al, Eur J Obstet Gynecol Reprod Biol. 2011;155:161-5. [5] Ruddenklau A, Campbell RE. Endocrinology. 2019 Oct 1;160(10):2230-2242.