Testosterone inhibits spermatogonial differentiation in juvenile spermatogonial depletion mice

The juvenile spermatogonial depletion (jsd) mutation results in spermatogon ial arrest after the first wave of spermatogenesis. In homozygous jsd mice in a hybrid background (C3HxB6) that were identified with microsatellite ma rkers, the percentage of tubules showing differentiating germ cells [tubule differentiation index (TDI)] rapidly decreased after 7 weeks of age with a correlative increase in the intratesticular testosterone (ITT) levels. Tre atment with a GnRH antagonist, Cetrorelix, suppressed ITT and stimulated sp ermatogonial differentiation at the end of treatment. When treated mice wer e killed 5-13.3 weeks after the end of treatment, the ITT progressively inc reased, and the TDI progressively declined, but there was a transient appea rance of tubules with mature spermatids. To delineate the role of testoster one (T) in spermatogonial arrest, we gave 7.6-week-old jsd mice exogenous T and/or the androgen receptor antagonist flutamide with or without GnRH ant agonist for 4 weeks. Flutamide alone moderately stimulated spermatogonial d ifferentiation (TDI = 30%). GnRH antagonist increased the TDI to 73%, and t he addition of flutamide to the GnRH antagonist treatment further increased it to 95%. When T was combined with GnRH antagonist treatment, ITT was inc reased, and the TDI was reduced to 7%. Addition of flutamide to this combin ation reversed the T inhibition of GnRH antagonist stimulation of spermatog onial differentiation to a TDI of 57%. ITT levels showed a good negative co rrelation to the TDI obtained with various treatments, but no such correlat ion was observed for FSH or LH levels. The results indicate that T inhibits the ability of spermatogonia to differentiate in jsd mice through an andro gen receptor mediated process.