Testosterone inhibits spermatogonial differentiation in juvenile spermatogonial depletion mice.
The juvenile spermatogonial depletion (jsd) mutation results in spermatogonial arrest after the first wave of spermatogenesis. In homozygous jsd mice in a hybrid background (C3HxB6) that were identified with microsatellite markers, 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. Treatment with a GnRH antagonist, Cetrorelix, suppressed ITT and stimulated spermatogonial differentiation at the end of treatment. When treated mice were killed 5-13.3 weeks after the end of treatment, the ITT progressively increased, and the TDI progressively declined, but there was a transient appearance of tubules with mature spermatids. To delineate the role of testosterone (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 antagonist for 4 weeks. Flutamide alone moderately stimulated spermatogonial differentiation (TDI = 30%). GnRH antagonist increased the TDI to 73%, and the addition of flutamide to the GnRH antagonist treatment further increased it to 95%. When T was combined with GnRH antagonist treatment, ITT was increased, and the TDI was reduced to 7%. Addition of flutamide to this combination reversed the T inhibition of GnRH antagonist stimulation of spermatogonial differentiation to a TDI of 57%. ITT levels showed a good negative correlation to the TDI obtained with various treatments, but no such correlation was observed for FSH or LH levels. The results indicate that T inhibits the ability of spermatogonia to differentiate in jsd mice through an androgen receptor-mediated process.
Shetty
G
G
Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. gshetty@audumla.mdacc.tmc.edu
Wilson
G
G
Huhtaniemi
I
I
Boettger-Tong
H
H
Meistrich
M L
ML
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004338:Drug Combinations; D005485:Flutamide / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology*; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology
D000726:Androgen Antagonists; D004338:Drug Combinations; D006727:Hormone Antagonists; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D005485:Flutamide; C062876:cetrorelix