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Direct Effect of Progestogen on Gene Expression in the Testis during Gonadotropin Withdrawal and Early Suppression of Spermatogenesis

Division of Reproductive and Developmental Sciences (M.J.W., D.T.B., R.A.A.), Medical Research Council Human Reproductive Sciences Unit (R.A.L.B.), Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; and Family Planning and Well Woman Services (I.W.), Lothian Health, Edinburgh EH4 1NL, United Kingdom

Address all correspondence and requests for reprints to: Professor R. A. Anderson, Centre for Reproductive Biology, The Queen’s Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: richard.anderson{at}ed.ac.uk.

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-reductase type 1 compared with both controls and the CT group. Inhibin- 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-reduction and disruption of spermiation as important components of the testicular response to gonadotropin withdrawal.

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