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Insulin serves as a link between the metabolic and reproductive systems, communicating energy availability to the hypothalamus and enabling reproductive mechanisms. Adult Suffolk ewes prenatally exposed to testosterone (T) display an array of reproductive and metabolic dysfunctions similar to those seen in women with polycystic ovarian syndrome (PCOS), including insulin resistance. Moreover, prenatal T treatment alters neuropeptide expression in KNDy (co-expressing kisspeptin, neurokinin B/dynorphin) and agouti-related peptide (AgRP) neurons in the arcuate nucleus, two populations that play key roles in the control of reproduction and metabolism, respectively. In this study, we determined whether prenatal T treatment also altered insulin receptors in KNDy and AgRP neurons, as well as in preoptic area (POA) kisspeptin, pro-opiomelanocortin (POMC), and gonadotropin-releasing hormone (GnRH) neurons of the adult sheep brain. Immunofluorescent detection of the beta subunit of insulin receptor (IRβ) revealed that KNDy, AgRP and POMC neurons, but not GnRH or POA kisspeptin neurons, colocalize IRβ in control females. Moreover, prenatal T treatment decreased the percentage of KNDy and AgRP neurons that colocalized IRβ, consistent with reduced insulin sensitivity. Administration of the anti-androgen drug, Flutamide, during prenatal T treatment, prevented the reduction in IRβ colocalization in AgRP, but not in KNDy neurons, suggesting that these effects are programmed by androgenic and oestrogenic actions, respectively. These findings provide novel insight into the effects of prenatal T treatment on hypothalamic insulin sensitivity and raise the possibility that decreased insulin receptors, specifically within KNDy and AgRP neurons, may contribute to the PCOS-like phenotype of this animal model., Competing Interests: The authors have no no conflicts of interest to declare., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesised to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep, with higher numbers of tyrosine hydroxylase (TH)-immunoreactive (-ir) cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30-90 or 60-90 resulted in increased numbers of VTA TH-ir cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T-treated ewes, which was primarily accounted for by greater numbers of TH-ir cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T-treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels within dopamine cells. Sex differences were also noted in numbers of TH-ir cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH-ir cells in the substantia nigra, suggesting that this sex difference is organised independently of prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T., (© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Experimental elevation of maternal testosterone (T) from 30 to 90 days of gestation leads to intrauterine growth retardation (IUGR) and increased prepubertal growth rate in female lambs. This study tested the hypothesis that prenatal T treatment during mid-gestation alters the trajectory of the fetal insulin-like growth factor (IGF)–insulin-like growth factor binding protein (IGFBP) system to promote IUGR and subsequent postnatal catch-up growth in female lambs. Plasma IGF-I and IGFBPs were measured by radioimmunoassay and Western ligand blot, respectively, on 65, 90 and 140 days (d) of gestation, at birth, ∼5 months (prepubertal, the catch-up growth period), and ∼9.5 months (postpubertal). Northern blot analysis was used to measure hepatic mRNA content of IGF system components during fetal stages. At fetal 65 d, plasma protein and hepatic mRNA content of IGFBP-1, an inhibitor of IGF bioactivity, was elevated in prenatal T-treated fetuses although body weight did not differ. There was a transient increase in plasma IGF-I and IGFBP-3 concentrations at fetal 90 d in prenatal T-treated fetuses. Hepatic IGF-I mRNA and plasma IGFBP-3 content were reduced by 140 d when body weight was reduced in prenatal T-treated fetuses. Plasma IGFBP-2 content was significantly reduced in prenatal T-treated newborns, but by 4 months these females had significantly higher circulating IGF-I and IGFBP-3 concentrations and faster growth rates than control females. After puberty, plasma IGF-I remained elevated in prenatal T-treated females. These findings provide evidence that prenatal T excess programmes the developmental trajectory of the IGF/IGFBP system in female sheep to reduce IGF bioavailability during IUGR and increase IGF bioavailability during prepubertal catch-up growth. [ABSTRACT FROM AUTHOR]