title: Gonadotropin-releasing hormone analogs stimulate and testosterone inhibits the recovery of spermatogenesis in irradiated rats.
abstract: We investigated the effects of GnRH analogs, different doses of testosterone (T), an androgen receptor antagonist (flutamide), and combinations of these on the recovery of spermatogenesis after irradiation. Treatment with a GnRH agonist (Lupron) for 10 weeks after irradiation reduced the intratesticular T concentration (ITT) to 4% of that in irradiated rats and serum FSH to undetectable levels without altering serum LH levels. Injection of a GnRH antagonist (Cetrorelix) at 3 weeks after irradiation suppressed LH, FSH, and ITT to <7%, 32%, and 10%, respectively, of levels in irradiated-only rats within 2 weeks; suppression was maintained for approximately 3 to 4 weeks. The percentage of tubules with differentiated germ cells (repopulation index, RI) was <0.6% at weeks 10 to 20 after irradiation. Spermatogenic recovery was induced by both the GnRH agonist (RI = 58% at week 10; 91% at week 20) and antagonist (RI = 70% at week 13). There was a dose-dependent suppression of testicular germ cell repopulation when T was combined with GnRH analogs. The ability of T to abolish the spermatogenic stimulatory effect of the GnRH antagonist was evident by the similar RI obtained for irradiated rats given antagonist + T or T alone. This suppression of GnRH-induced recovery of spermatogenesis by T could be reversed by flutamide. The RI best correlated with the degree of ITT suppression. In ITT-suppressed rats, the RI also showed an inverse correlation with serum T levels. Thus, T and/or its androgenic metabolites either directly or indirectly inhibit spermatogenic recovery after irradiation through an androgen receptor-mediated process. In addition, there was a close negative correlation between RI and FSH levels, and hence, a spermatogenic inhibitory role for FSH in the irradiated rats cannot be ruled out.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. gshetty@audumla.mdacc.tmc.edu
authors.forename: G
authors.initials: G
authors.lastname: Shetty
authors.forename: G
authors.initials: G
authors.lastname: Wilson
authors.forename: I
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: G A
authors.initials: GA
authors.lastname: Shuttlesworth
authors.forename: T
authors.initials: T
authors.lastname: Reissmann
authors.forename: M L
authors.initials: ML
authors.lastname: Meistrich
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D005485:Flutamide / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051381:Rats; D013091:Spermatogenesis / Q000187:drug effects*; D013093:Spermatogonia / Q000166:cytology; D013737:Testis / Q000528:radiation effects*; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D000726:Androgen Antagonists; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D005485:Flutamide; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone