Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (SB-75).
Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (SB-75).
复制标题
长期服用黄体生成素释放激素（SB-75）的强效拮抗剂后，雄性和雌性大鼠的垂体-性腺功能恢复。
DOI：
10.1159/000125862
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发表时间：
1991
影响因子：
4.1
通讯作者：
Schally,AV
中科院分区：
文献类型：
--
作者：
Bokser,L;Srkalovic,G;Szepeshazi,K;Schally,AV
在雄性和雌性大鼠中研究了长期给药LH-RH拮抗类似物[Ac-D-Nal(2) ', D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH （SB-75）诱导的抗生育作用的可逆性。雄性大鼠植入微型渗透泵，每天释放50µg SB-75，持续60天。对照大鼠植入只含载药的微型泵。拮抗剂显著降低了睾丸、精囊和前列腺腹侧重量（p < 0.01），降低了血清LH和睾酮水平（p < 0.01）。治疗后大鼠睾丸组织学显示精子发生完全被抑制。在精管中没有发现成熟的细长或圆形精细胞，精母细胞是100%睾丸小管中最先进的生殖细胞形式。这些变化表明，在接受治疗的动物中发生了完全的精子发生停止。停用rh - rh拮抗剂90天后，睾丸、精囊和腹侧前列腺重量完全恢复，LH和睾酮恢复到控制水平。组织学研究显示精子发生完全恢复，99.2%的精管含有成熟的细长精子。在停止使用SB-75治疗后，立即发现垂体rh - rh受体显著下调，但90天后，这种现象完全逆转。雌性大鼠每3周注射一次SB-75微胶囊，连续注射6周，剂量计算为释放27µg/天的拮抗剂。SB-75治疗打乱了正常的发情周期。拮抗剂对体重无影响，但显著降低了卵巢和子宫重量（p < 0.01和p < 0.05）。治疗组大鼠LH （p < 0.05）和雌二醇（p < 0.01）水平显著低于对照组。sb -75处理组卵巢组织学显示成熟小卵泡与成熟大卵泡之比显著增加（p < 0.01），黄体缺失。停止治疗两个月后，观察到器官重量和激素水平完全恢复，治疗组和未治疗组的卵巢没有组织学差异。这些综合结果表明，rh - rh拮抗剂SB-75对雄性和雌性动物性腺功能的抑制是完全可逆的。这些发现将有助于使用无副作用的现代rh - rh拮抗剂，用于治疗激素敏感型癌症、妇科疾病和其他需要抑制垂体-性腺轴的疾病。
The reversibility of the antifertility effects induced by long-term administration of the LH-RH antagonistic analog [Ac-D-Nal(2)’, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH (SB-75) was investigated in male and female rats. Male rats were implanted with osmotic minipumps releasing 50 µg of SB-75/day for 60 days. The control rats were implanted with minipumps containing only vehicle. The treatment with the antagonist caused a significant decrease in the weights of the testes, seminal vesicles and ventral prostates (p < 0.01) and reduced serum LH and testosterone levels (p < 0.01). The histology of the testes from the treated rats showed that spermatogenesis was totally depressed. No mature elongated or round spermatids were found in the seminiferous tubules, spermatocytes being the most advanced germ cell form in 100% of the testicular tubules. These changes indicate that a total spermatogenetic arrest occurred in the treated animals. Ninety days after cessation of treatment with the LH-RH antagonist, there was a complete recovery of the weights of the testes, seminal vesicles and ventral prostates and LH and testosterone returned to control levels. Histological studies revealed a complete recovery of spermatogenesis, with 99.2% of seminiferous tubules containing mature elongated spermatids. Immediately after the discontinuation of treatment with SB-75, a significant down-regulation of the pituitary LH-RH receptors was found, but 90 days later, this phenomenon was completely reversed. Female rats were injected every 3 weeks for 6 weeks with SB-75 microcapsules, at a dose calculated to release 27 µg/day of the antagonist. The treatment with SB-75 disrupted the normal estrous cycle. Body weights were not affected, but ovarian and uterine weights were significantly decreased (p < 0.01 and p < 0.05, respectively) in the animals treated with the antagonist. Treated rats had significantly lower LH (p < 0.05) and estradiol (p < 0.01) levels than controls. The histology of the ovaries from the SB-75-treated group showed that the ratio of small to large maturing follicles increased significantly (p < 0.01) and corpora lutea were absent. Two months after the cessation of treatment, a complete recovery in the organ weights and in hormonal levels was observed and no histological differences were found between the ovaries in treated and untreated rats. These collective results indicate that the suppression of gonadal function induced by the treatment with LH-RH antagonist SB-75 is completely reversible both in male and female animals. These findings should facilitate the use of modern LH-RH antagonists, free of side effects, for the treatment of hormone-sensitive cancers, gynecologic conditions and other disorders where inhibition of the pituitary-gonadal axis is desirable.