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Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center (G.S., G.W., M.L.M.), Houston, Texas 77030; Department of Physiology, University of Turku (I.H.), 20520 Turku, Finland; and Department of Obstetrics and Gynecology, Baylor College of Medicine (H.B.-T.), Houston, Texas 77030.
Address all correspondence and requests for reprints to: Dr. Gunapala Shetty, Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030. E-mail: gshetty{at}audumla.mdacc.tmc.edu
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.
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  G. Shetty, S. H. Shao, and C. C. Y. Weng p53-Dependent Apoptosis in the Inhibition of Spermatogonial Differentiation in Juvenile Spermatogonial Depletion (Utp14bjsd) Mice Endocrinology, June 1, 2008; 149(6): 2773 - 2781. [Abstract] [Full Text] [PDF]
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G. Shetty, C. C. Y. Weng, K. L. Porter, Z. Zhang, P. Pakarinen, T. R. Kumar, and M. L. Meistrich Spermatogonial Differentiation in Juvenile Spermatogonial Depletion (jsd) Mice with Androgen Receptor or Follicle-Stimulating Hormone Mutations Endocrinology, July 1, 2006; 147(7): 3563 - 3570. [Abstract] [Full Text] [PDF]
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G. Shetty, C. C. Y. Weng, S. J. Meachem, O. U. Bolden-Tiller, Z. Zhang, P. Pakarinen, I. Huhtaniemi, and M. L. Meistrich Both Testosterone and Follicle-Stimulating Hormone Independently Inhibit Spermatogonial Differentiation in Irradiated Rats Endocrinology, January 1, 2006; 147(1): 472 - 482. [Abstract] [Full Text] [PDF]
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 G. Shetty and M. L. Meistrich Hormonal Approaches to Preservation and Restoration of Male Fertility After Cancer Treatment J Natl Cancer Inst Monographs, March 1, 2005; 2005(34): 36 - 39. [Abstract] [Full Text] [PDF]
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 J. Rohozinski and C. E. Bishop The mouse juvenile spermatogonial depletion (jsd) phenotype is due to a mutation in the X-derived retrogene, mUtp14b PNAS, August 10, 2004; 101(32): 11695 - 11700. [Abstract] [Full Text] [PDF]
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 S. E. Malstrom, O. Tornavaca, A. Meseguer, A. F. Purchio, and D. B. West The Characterization and Hormonal Regulation of Kidney Androgen-Regulated Protein (Kap)-Luciferase Transgenic Mice Toxicol. Sci., June 1, 2004; 79(2): 266 - 277. [Abstract] [Full Text] [PDF]
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 J. Eberhard, O. Stahl, Y. Giwercman, M. Cwikiel, E. Cavallin-Stahl, K.B. Lundin, P. Flodgren, and A. Giwercman Impact of therapy and androgen receptor polymorphism on sperm concentration in men treated for testicular germ cell cancer: a longitudinal study Hum. Reprod., June 1, 2004; 19(6): 1418 - 1425. [Abstract] [Full Text] [PDF]
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G. Shetty and C. C. Y. Weng Cryptorchidism Rescues Spermatogonial Differentiation in Juvenile Spermatogonial Depletion (Jsd) Mice Endocrinology, January 1, 2004; 145(1): 126 - 133. [Abstract] [Full Text] [PDF]
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G. Rothschild, C. M. Sottas, H. Kissel, V. Agosti, K. Manova, M. P. Hardy, and P. Besmer A Role for Kit Receptor Signaling in Leydig Cell Steroidogenesis Biol Reprod, September 1, 2003; 69(3): 925 - 932. [Abstract] [Full Text] [PDF]
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M. Ohmura, T. Ogawa, M. Ono, M. Dezawa, M. Hosaka, Y. Kubota, and H. Sawada Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal Biol Reprod, June 1, 2003; 68(6): 2304 - 2313. [Abstract] [Full Text] [PDF]
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 M. L. Meistrich and G. Shetty Inhibition of Spermatogonial Differentiation by Testosterone J Androl, March 1, 2003; 24(2): 135 - 148. [Full Text] [PDF]
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 T. R. Pak, G. R. Lynch, D. M. Ziegler, J. B. Lunden, and P.-S. Tsai Disruption of pubertal onset by exogenous testosterone and estrogen in two species of rodents Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E206 - E212. [Abstract] [Full Text] [PDF]
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G. Shetty, G. Wilson, M. P. Hardy, E. Niu, I. Huhtaniemi, and M. L. Meistrich Inhibition of Recovery of Spermatogenesis in Irradiated Rats by Different Androgens Endocrinology, September 1, 2002; 143(9): 3385 - 3396. [Abstract] [Full Text] [PDF]
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