Direct effect of progestogen on gene expression in the testis during gonadotropin withdrawal and early suppression of spermatogenesis

Context: Testicular production of steroids and gametes is under gonadotropin support, but there is little information as to the molecular mechanisms by which these are regulated in the human. The testicular response to gonadotropin withdrawal is important for the development of effective contraceptive methods. Objective: Our objective was investigation of expression of genes in the normal human testis reflecting steroidogenesis, Sertoli cell function, and spermatogenesis after short-term gonadotropin withdrawal and the effects of activating testicular progesterone receptors. Design and Setting: We conducted a randomized controlled trial at a research institute. Patients: Thirty healthy men participated. Interventions: Subjects were randomized to no treatment or gonadotropin suppression by GnRH antagonist (cetrorelix) with testosterone (CT group) or with additional administration of the gestogen desogestrel (CTD group) for 4 wk before testicular biopsy. Gene expression was quantified by RT-PCR. Results: Both treatment groups showed similar suppression of gonadotropins and sperm production and markedly reduced expression of steroidogenic enzymes. Addition of progestogen in the CTD group resulted in reduced expression of 5 alpha-reductase type 1 compared with both controls and the CT group. Inhibin-alpha and the spermatocyte marker acrosin-binding protein were significantly lower in the CTD but not CT groups, compared with controls, but did not differ between treated groups. Men who showed greater falls in sperm production also showed reduced expression of these three genes but not of the spermatid marker protamine 1. Conclusions: These data provide evidence for direct progestogenic effects on the testis and highlight steroid 5 alpha-reduction and disruption of spermiation as important components of the testicular response to gonadotropin withdrawal.