Hypothalamic-pituitary-testicular function in rats after supraphysiological doses of a highly active LRH analogue (buserelin)

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Abstract
Male prepubertal rats (60g) were treated with LRH [luteinizing hormone-releasing hormone, luliberin] analog, [D-Ser(But)6]LRH(1-9)-nonapeptide-ethylamide (buserelin, Hoe 766), during 4 wk by daily s.c. injections of 5, 50 or 500 ng peptide (group I, II and III). At the end of treatment, hypothalamic LRH content and arylamidase activity (LRH degrading enzyme) were not changed. Pituitary arylamidase activity was reduced, but the pituitary LRH receptors (tested by analog binding in vitro) were diminished. Pituitary accumulation of [125I]buserelin 60 min after i.v. injection was not modified and organ distribution in liver and kidney was unchanged. Pituitary responsiveness to the analog was reduced at the highest dose, but there was significant LH[lutropin]-release at all 3 dose levels. Testosterone production in vitro (stimulated by hCG [human chorionic gonadotropin]) was unaltered in group I and dramatically reduced in group II and III. Testicular testosterone content and hCG binding by testes homogenates were dose-dependently reduced. Histology of the testes after 4 wk treatment showed minimal impairment of spermatogenesis at the highest dose; the epididymis was almost devoid of sperm. Low dose treatment with a highly active LRH analog, buserelin, does not interfere with pituitary responsiveness (LRH receptors and LH-release) and testicular function (testosterone production, testosterone content, LH-receptor level). At higher doses, pituitary and testicular responsiveness are dose-dependently inhibited. At the pituitary level, LRH receptors were not reduced. The antifertility effect of supraphysiological doses at the testicular level is explained by an LH-dependent loss of LH-receptors.