Elucidating the effect of prenatal androgen excess on male reproductive function

The in utero nutritional and hormonal environment is critical in shaping the developing male and female reproductive systems. Elevated in utero androgen exposure has been correlated with the manifestation of abnormal reproductive phenotypes in both males and females. Exposure to elevated prenatal androgens in female offspring is strongly linked to the development of polycystic ovary syndrome (PCOS) later in life. It is less clear whether male offspring also exposed to elevated in utero androgen levels exhibit similar reproductive abnormalities in adulthood. Our group and others have identified significant anatomical changes to the neuronal network regulating gonadotropin-releasing hormone (GnRH) neurons, the neuronal cell type that underlies fertility, in female offspring exposed to elevated maternal androgens. Clinical studies have recently demonstrated that the male relatives of PCOS women manifest alterations in certain reproductive hormonal levels. Therefore, this present study aimed to investigate whether exposure to elevated prenatal androgens is also detrimental to overall GnRH neuronal function and downstream reproductive function in males. It was hypothesised that adult males exposed to elevated prenatal androgens (PNAM) during late prenatal development (embryonic days 16, 17 and 18) would manifest impaired reproductive function and similar neuroendocrine deficits as previously reported in prenatally androgenised (PNA) female mice (a PCOS model). PNAM mice (n = 10) in comparison to vehicle (VEH) control male mice (n = 10) did not manifest alterations in luteinising hormone (LH) pulse frequency, daily sperm production (DSP), or plasma testosterone and Anti-Müllerian hormone (AMH) levels (p = 0.13, 0.20, 1.00, 0.14). Additionally, testicular messenger ribonucleic acid (mRNA) expression of Amh and its receptors (Amhr2, Acrv1, Bmpr1a and Bmpr1b) was not different between PNAM and VEH control mice (p = 0.11, 0.57, 0.84, 0.67, 0.18). Confocal imaging of GnRH neurons revealed that PNAM mice manifest similar levels of GABAergic input to the GnRH neuronal soma and primary dendrite as VEH controls (p = 0.82, 0.50). Likewise, androgen receptor (AR) expression in hypothalamic and limbic nuclei related to male reproductive function, sexual behaviour and aggression was also similar in PNAM mice compared to VEH control mice. In summary, no significant differences were identified at any level of the adult reproductive axis in males exposed to elevated prenatal androgens. Therefore, we can conclude that, unlike in females, exposure to elevated prenatal androgens does not elicit anatomical or functional changes in neuronal systems important in steroid hormone signalling and reproductive function in males