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Meiosis constitutes a crucial phase of spermatogenesis since the recombination of genetic information and production of haploid round spermatids need to be achieved. Although it is well established that gonadotrophic hormones are required for completion of the spermatogenic process, little is known about the dynamic and kinetic aspects of development of spermatocytes into spermatids and its endocrine control in the primate. In this study, S-phase germ cells were labelled using 5-bromodeoxyuridine (BrdU) incorporation and were then followed throughout meiosis under normal conditions and following GnRH antagonist (ANT)-induced gonadotrophin withdrawal in a nonhuman primate model, the cynomolgus monkey (Macaca fascicularis). Adult animals received either vehicle (VEH, n = 4) or the ANT cetrorelix (n = 5) throughout 25 days. On day 7 all animals received a bolus injection of BrdU. A biopsy was performed after 3 h, one testis was removed 9 days later (day 16 of treatment) and the other testis after 18 days (day 25 of treatment). Serum testosterone and inhibin levels, and testis weight were reduced (P < 0.05) by ANT treatment. BrdU localized to pachytene spermatocytes 9 days after BrdU and to round spermatids 18 days after BrdU in both groups, demonstrating that BrdU-labelled pachytene spermatocytes had undergone meiosis. Flow cytometric analysis revealed that the relative number and number per testis of BrdU-tagged 2C and 4C cells were reduced significantly (P < 0.05) within 16 days of ANT treatment. Numbers of 1C cells were lowered by day 25. The cell ratio for 1C:4C was similar with VEH and ANT (P > 0.05). These findings indicate that ANT reduced the number of cells available for meiosis but did not alter the rate of transition into round spermatids. Unexpectedly, however, the stage-dependent progression of BrdU-tagged round spermatids was significantly (P < 0.05) retarded under ANT as seen from the frequency of tubules containing BrdU-labelled round spermatids. The average duration of spermatogenic cycle was slightly prolonged (9.8 days in the VEH group and 10.8 days in the ANT group (P = 0.09)). Since no atypical germ cell associations could be found, it remains unclear whether this slight prolongation is entirely due to altered spermatid progression or whether earlier phases are affected. We conclude for the nonhuman primate that (1) BrdU-labelling of premeiotic germ cells is suitable for tracing their meiotic transition into postmeiotic cells, (2) unlike in the rat, gonadotrophin suppression initially affects premeiotic cell proliferation and thus the number of cells available for meiosis, (3) the meiotic process continues quantitatively despite gonadotrophin deficiency and (4) prolonged gonadotrophin deficiency might alter the timing of germ cell development.
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Chemotherapy and radiation often damage spermatogenesis irreversibly in oncological patients and various approaches to gonadal protection have been tested with equivocal results. In rats, hormonal protection of spermatogenesis can be achieved by blocking gonadotropin secretion. However, whether the same mechanisms can effect gonadal protection in primates remains questionable. To clarify this Issue we conducted a placebo-controlled trial in a preclinical animal model using macaques (Macaca fascicularis). Twenty adult male monkeys (five in each group) were randomized to receive either recombinant human FSH, GnRH antagonist or saline injections (two groups) for 36 days. On day 29 all groups except one saline-treated control group were exposed to a single testicular irradiation of 4 Gy. Every 2 weeks before, during and after the treatment, ejaculates, body weight, testicular Volume and hormones were analyzed until day 539. In addition, repeated testicular biopsies were performed. Testicular Volume and inhibin B decreased significantly in all irradiated groups compared with baseline and with the non-irradiated control group, followed by a gradual recovery of these parameters, which was, especially at the earlier time points, significantly better in the FSH-treated group compared with both other irradiated groups. Irradiation caused a drastic decrease of sperm parameters in all groups, followed by a partial recovery of sperm parameters, which was significantly slower in the early phases of recovery in the GnRH antagonist group compared with the vehicle group. Testicular histology showed a significant depletion on study day 261 in all irradiated animals. In conclusion, in clear contrast to rodent studies, GnRH antagonist treatment did not provide gonadal protection in this primate model. FSH treatment resulted in slightly better recovery of spermatogenesis, which appears to be of no or only little clinical relevance.