Effect of Fetal Pituitary-Testes Suppression on Brain Sexual Differentiation and Reproductive Function in Male Sheep

Abstract

We previously demonstrated that treating fetal lambs on gestational day 62 with the long-acting gonadotrophin-releasing hormone (GnRH) antagonist degarelix (DG) suppresses pituitary-testicular function during midgestation. The objective of this study was to investigate whether impaired gonadotrophic drive during this fetal period has enduring effects on sexual differentiation and reproductive function in adult male sheep. We assessed the effects of prenatal administration of DG, with or without testosterone (T) replacement, on various sexually dimorphic behavioral traits in adult rams, including sexual partner preferences, as well as neuroendocrine responsiveness and testicular function. Our findings revealed that DG treatment had no effect on genital differentiation or somatic growth. There were some indications that DG treatment suppressed juvenile play behavior and adult sexual motivation; however, male-typical sexual differentiation of reproductive behavior, sexual partner preference, and gonadotropin feedback remained unaffected and appeared to be fully masculinized and defeminized. DG-treated rams showed an increased LH response to GnRH stimulation and a decreased T response to human chorionic gonadotropin stimulation, suggesting impaired Leydig cell function and reduced T feedback. Both effects were reversed by cotreatment with T propionate. DG treatment also suppressed the expression of CYP17 messenger RNA, a key enzyme for T biosynthesis. Despite the mild hypogonadism induced by DG treatment, ejaculate volume, sperm motility, and sperm morphology were not affected. In summary, these results suggest that blocking GnRH during midgestation does not have enduring effects on brain sexual differentiation but does negatively affect the testes' capacity to synthesize T.