Maternal androgen excess significantly impairs sexual behavior in male and female mouse offspring: Perspective for a biological origin of sexual dysfunction in PCOS

Abstract

IntroductionPolycystic ovary syndrome (PCOS) is the most common infertility disorder worldwide, typically characterised by high circulating androgen levels, oligo- or anovulation, and polycystic ovarian morphology. Sexual dysfunction, including decreased sexual desire and increased sexual dissatisfaction, is also reported by women with PCOS. The origins of these sexual difficulties remain largely unidentified. To investigate potential biological origins of sexual dysfunction in PCOS patients, we asked whether the well-characterized, prenatally androgenized (PNA) mouse model of PCOS exhibits modified sex behaviours and whether central brain circuits associated with female sex behaviour are differentially regulated. As a male equivalent of PCOS is reported in the brothers of women with PCOS, we also investigated the impact of maternal androgen excess on the sex behaviour of male siblings.MethodsAdult male and female offspring of dams exposed to dihydrotestosterone (PNAM/PNAF) or an oil vehicle (VEH) from gestational days 16 to 18 were tested for a suite of sex-specific behaviours. ResultsPNAM showed a reduction in their mounting capabilities, however, most of PNAM where able to reach ejaculation by the end of the test similar to the VEH control males. In contrast, PNAF exhibited a significant impairment in the female-typical sexual behaviour, lordosis. Interestingly, while neuronal activation was largely similar between PNAF and VEH females, impaired lordosis behaviour in PNAF was unexpectedly associated with decreased neuronal activation in the dorsomedial hypothalamic nucleus (DMH). ConclusionTaken together, these data link prenatal androgen exposure that drives a PCOS-like phenotype with altered sexual behaviours in both sexes.

Validation of a new Custom Polyclonal Progesterone Receptor Antibody for Immunohistochemistry in the Female Mouse Brain

“…For estradiol treatment, a 5-mm-long Silastic capsule (inner diameter: 1.57 mm; outer diameter: 2.41 mm) containing crystalline 17β-estradiol (E2758, Sigma-Aldrich, USA), diluted 1:1 with cholesterol (C8667, Sigma Aldrich), was inserted subcutaneously at the nape of the neck at the same time as ovariectomy, as previously described [ 44 ]. This is a routinely used method of exogenously elevating circulating E2 levels in mice [ 44-46 ]. Brain tissue from OVX mice was collected 3 weeks after ovariectomy and OVX + E2 mice 6 weeks after ovariectomy.…”

Role of Anti-Müllerian Hormone in the Central Regulation of Fertility

“…However, two recent studies utilized robust preclinical animal models to investigate the underlying neural circuitry and found that female mice, prenatally exposed to either excess AMH (PAMH) or androgens (PNA), exhibit impaired sexual behavior and sexual partner preference throughout their reproductive age. 8 58 These studies shed light on the impact of prenatal hormone exposure on sexual function in PCOS-like animal models, providing insights into the potential neural mechanisms underlying sexual dysfunction in PCOS. Noteworthy, in the PAMH females, sexual dysfunction has been linked to a significant reduction in the number of neurons expressing neuronal nitric oxide synthase (nNOS) and progesterone receptor in the ventromedial nucleus of the hypothalamus (VMH).…”