UC San Diego

It is well known that the brain undergoes changes in a sexually dimorphic manner during fetal development. Here, we postulate that sex differences are present in another neuroendocrine tissue, the pituitary gland. We tested the hypothesis that androgens mediate sex differences in gonadotropin gene expression during fetal development of the anterior pituitary gland. We compared gonadotropin gene expression in fetal male and female mice treated with either an androgen receptor agonist or antagonist from embryonic day 15.5-17.5. Multiple gonadotrope-derived genes were expressed at significantly higher levels in females compared to males, including luteinizing hormone beta (Lhb), follicle-stimulating hormone beta (Fshb) and gonadotropin-releasing hormone receptor (Gnrhr). Treatment with flutamide, testosterone, or dihydrotestosterone eliminated the sex difference in gene expression. Specifically, flutamide relieved the suppression in male gene expression to the level observed in females. In contrast, testosterone and dihydrotestosterone attenuated female gene expression to male levels. Having determined that male and female fetal pituitary glands contain an equivalent number of gonadotrope cells, we focused on understanding the mechanism underlying sex-dependent transcriptional regulation within this cell type. Fetuses either lacking GnRH or GnRH receptor showed no sex difference in expression of Lhb, Fshb, or Gnrhr, suggesting that GnRH signaling is important for expression in a sex-dependent manner. Collectively, our data demonstrate that there is a sex difference in gonadotropin gene expression during fetal development which is regulated by androgens. Furthermore, we postulate that hypothalamic drive to the pituitary is greater in female fetuses and blunted in males during fetal development.