Protection of spermatogenesis in rats from the cytotoxic procarbazine by the depot formulation of Zoladex, a gonadotropin-releasing hormone agonist.
The hypothesis that adjuvant treatment designed to produce testicular atrophy would preserve fertility in males receiving cancer chemotherapy was examined in the rat. Testicular atrophy was induced by a depot formulation of Zoladex [D-Ser(Bu(t))6-Aza-Gly10-GnRH], a gonadotropin-releasing hormone (GnRH) analogue. The experiments were conducted in albino Wistar as well as in the piebald variegated rat. Rats received the depot Zoladex formulation 2 weeks before and immediately prior to being treated with four weekly doses of procarbazine (200 mg/kg). Testicular function was evaluated 50 and 90 days after the last procarbazine dose. Procarbazine induced testicular atrophy concomitant with marked germinal cell aplasia in both strains of rat. In the Wistar rat adjuvant treatment with Zoladex caused slight but not significant alleviation of the testicular toxicity of procarbazine. The testicular toxicity of procarbazine was more extensive in the piebald variegated rat, and 50 days after the last procarbazine treatment the testes were small, sperm were absent, and the stem cell index was close to zero. Serum luteinizing hormone (LH) concentrations were raised and testicular LH receptor binding was low in the presence of normal serum and testicular testosterone concentrations, indicating compensated Leydig cell failure. Testicular weight and sperm content, as well as LH receptor binding, were still decreased in rats which received both Zoladex and procarbazine, suggesting that the analogue offered no protection. However, the stem cell index of the seminiferous tubules in the procarbazine-Zoladex-treated rats was not significantly different from vehicle-treated rats, which suggested that recovery from the effects of procarbazine was in progress. Ninety days after the end of procarbazine treatment alone the testes of rats were still atrophied and there was little evidence of active spermatogenesis. Leydig cell failure appeared to have progressed as, in addition to the low testicular LH receptor content and raised serum LH concentration, the prostate and seminal vehicle weights were decreased. The combination of Zoladex treatment with procarbazine was successful in preserving testicular function in the piebald variegated rats as virtually all the functional and morphological parameters of both the seminiferous tubule and the Leydig cell were not significantly different from those of vehicle-treated rats. This study demonstrates for the first time that effective gonadal protection from the toxic effects of procarbazine chemotherapy can be achieved by administration of the depot formulation of the gonadotropin-releasing hormone analogue Zoladex. The results show clearly that complete suppression of spermatogenesis is not a prerequisite for the successful outcome of treatments designed to protect the gonad from cytotoxic chemotherapy.
Ward
J A
JA
Department of Physiological Sciences, University of Manchester Medical School, United Kingdom.
Robinson
J
J
Furr
B J
BJ
Shalet
S M
SM
Morris
I D
ID
D000818:Animals; D002064:Buserelin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003692:Delayed-Action Preparations; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D017273:Goserelin; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011344:Procarbazine / Q000009:adverse effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011974:Receptors, LH / Q000378:metabolism; D012671:Seminiferous Tubules / Q000166:cytology / Q000187:drug effects; D013076:Sperm Count / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013093:Spermatogonia / Q000187:drug effects; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects*
D003692:Delayed-Action Preparations; D011974:Receptors, LH; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone; D011344:Procarbazine; D002064:Buserelin