Prenatal Testosterone Masculinizes Synaptic Input to Gonadotropin-Releasing Hormone Neurons in Sheep1

Abstract

In sheep, the control of tonic and surge GnRH secretion is sexually differentiated by testosterone in utero. However, GnRH neurons are not sexually dimorphic with respect to number, distribution, or gross morphology. Therefore, this study tested the hypothesis that prenatal steroids influence synaptic input to GnRH neurons. We compared the number of synapses on GnRH neurons from male, female, and androgenized female lambs (n = 5 each). Androgenized females were exposed to testosterone during mid-gestation. Yearling lambs were perfused, and GnRH neurons were visualized using the LR-1 antibody. Five to seven GnRH neurons from the rostral preoptic area in each animal were viewed at the ultrastructural level. Afferent synapses and glial ensheathment on each neuron were counted in a single section through the plane of the nucleus. GnRH neurons from females received approximately twice as many contacts (3.6 +/- 0.7 synapses/100 microm plasma membrane) as those from male lambs (1.6 +/- 0.3; p < 0.05), similar to previous reports in rats. In addition, the number of synapses on GnRH neurons from androgenized female lambs (1.5 +/- 0.5) was similar to that from male lambs, suggesting that prenatal steroids give rise to sex differences in synaptic input to GnRH neurons.

Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: Implications for a common fertility disorder

“…In GnRH neurons specifically, removal of endogenous androgens by castration reduced spine number on these cells in males (47). Additionally, in female sheep, prenatal androgenization reduced synaptic contacts with GnRH neurons to levels seen in males (48). Although the direction of change in that study was in the opposite direction to what might be predicted from the present work, neurochemical phenotype of those synapses was not determined; thus, it remains possible that a relative increase in GABAergic connections occurred.…”

Endocrine Traits of Polycystic Ovary Syndrome in Prenatally Androgenized Female Sprague-Dawley Rats

“…However, the mechanism of prenatal aR activation and program hyperactivity of the gnRH pulse generator in adulthood is unclear. Prenatal androgenization of female sheep was found to reduce synaptic contacts to gnRH neurons to lower levels that those observed in males [29], which suggests that the effects of androgens on gnRH pulsation may be mediated by alterations in synaptic connectivity. Sullivan and Moenter [19], however, provided evidence that aR activation may produce specific alterations in the drive from gamma-aminobutyric acid-releasing neurons to gnRH neurons, perhaps by altering synaptic connectivity between the two neuronal phenotypes.…”

The role of glia in the hypothalamus: implications for gonadal steroid feedback and reproductive neuroendocrine output

“…Sex differences in the differentiation of astroglia may impact on the organization of the neuronal network that regulates the activity and secretion of GnRH neurons. Exposure of the fetal brain of guinea pigs (Connolly & Resko 1994), rats (Foecking et al 2005), mice (Sullivan & Moenter 2004), pigs (Elsaesser & Parvizi 1979), sheep (Fabre-Nys & Venier 1991, Herbosa et al 1996, Kim et al 1999, Robinson 2006, and rhesus monkeys (Dumesic et al 1997) to testosterone results in modifications in the number and function of synaptic inputs to GnRH neurons. Differences in the morphology of glial cell processes associated with GnRH neurons have been observed in parallel to the synaptic changes (Chen et al 1990, Kim et al 1999, Sullivan & Moenter 2004.…”

“…Exposure of the fetal brain of guinea pigs (Connolly & Resko 1994), rats (Foecking et al 2005), mice (Sullivan & Moenter 2004), pigs (Elsaesser & Parvizi 1979), sheep (Fabre-Nys & Venier 1991, Herbosa et al 1996, Kim et al 1999, Robinson 2006, and rhesus monkeys (Dumesic et al 1997) to testosterone results in modifications in the number and function of synaptic inputs to GnRH neurons. Differences in the morphology of glial cell processes associated with GnRH neurons have been observed in parallel to the synaptic changes (Chen et al 1990, Kim et al 1999, Sullivan & Moenter 2004. The GnRH neuronal network in female animals that have been exposed in utero to testosterone has an impaired, male-like response to the estrogen-stimulated GnRH surge (Sharma et al 2002, Birch et al 2003.…”