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Testosterone Prevents Complete Suppression of Spermatogenesis in the Gonadotropin-Releasing Hormone Antagonist-Treated Nonhuman Primate (Macaco, fascicularis)^*

Max Planck Clinical Research Unit for Reproductive Medicine and Institute of Reproductive Medicine, University of Münster D-4400 Munster, West Germany

Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, Max Planck Clinical Research Unit for Reproductive Medicine, University of Munster, Steinfurter Str. 107, D-4400 Münster, West Germany.

We studied the effects of administration of a GnRH antagonist combined with testosterone (T) as an approach to male contraception as well as the role of intratesticular androgens in spermatogenesis using a nonhuman primate model. Three groups of five adult cynomolgus monkeys (Macaca fascicularis) received daily sc injections of 420–460 µg/kg GnRH antagonist ([Ac-D2Nal¹,D4ClPhe²,DPal³,Arg⁵,DGlu⁶(AA), DALa¹⁰]GnRH) for a period of 15 weeks. T supplementation, commencing on the first day of GnRH antagonist administration, was provided by single im injection of 40 mg (group 2) or 200 mg (group 3) of the long-acting testosterone ester testosterone- trans-4-n-butylcyclohexancarboxylate (20-Aet-l). Serum LH bioactivity was undetectable within 1 week of GnRH antagonist administration in all monkeys. GnRH antagonist administration alone (group 1) reduced serum T levels into the castrate range. Forty milligrams of 20-Aet-l maintained serum T levels in the upper range of normal monkeys, while 200 mg 20-Aet-l maintained serum T levels about 1.5-fold above normal. The response to electroejaculation was fully maintained in all Ttreated monkeys. Sperm counts in the ejaculates dropped to zero among group 1 animals within 7–10 weeks of GnRH antagonist administration. In groups 2 and 3 consistent azoospermia could not be induced, and the sperm counts were significantly (P < 0.05) higher in group 3 than in group 2. Histologically, spermatogenesis in group 1 was arrested at the spermatogonial level in 75% of seminiferous tubules. In group 2, spermatogenesis proceeded to spermatocytes in 50% of tubules and to elongated spermatids in 10% of tubules, while in group 3 elongation of spermatids occurred in 75% of tubules. The mean T and dihydrotestosterone concentrations in baseline testicular biopsies (n = 15) were 43.8 ± 6.8 (±SE) and 5.7 ± 1.5 ng/g, respectively. After GnRH antagonist with or without T administration, the mean (n = 15) intratesticular T and dihydrotestosterone levels were reduced to 20.3 ± 4.9 and 3.2 ± 0.5 ng/g, respectively, and differed little among the three groups. No correlation, however, could be established between testicular androgen levels and spermatogenic status (P > 0.30) or sperm counts (P > 0.60). These results demonstrate that administration of a GnRH antagonist in the presence of constant serum T levels does not induce consistent azoospermia, and that the supporting effects of T on spermatogenesis cannot be explained exclusively on the basis of the testicular androgen concentrations

^* The Nal-Glu GnRH antagonist was synthesized by Drs. Jean Rivier and Carl Hoeger under NIH Contract l-HD-22824 with the Salk Institute.

Received December 28, 1987.

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