Bokser L, Srkalovic G, Szepeshazi K, Schally A V
Endocrine, Polypeptide and Cancer Institute, VA Medical Center, New Orleans, La.
Neuroendocrinology. 1991 Aug;54(2):136-45. doi: 10.1159/000125862.
The reversibility of the antifertility effects induced by long-term administration of the LH-RH antagonistic analog [Ac-D-Nal(2)1, 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 micrograms 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 less than 0.01) and reduced serum LH and testosterone levels (p less than 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 micrograms/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 less than 0.01 and p less than 0.05, respectively) in the animals treated with the antagonist. Treated rats had significantly lower LH (p less than 0.05) and estradiol (p less than 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 less than 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.(ABSTRACT TRUNCATED AT 400 WORDS)
研究了长期给予促黄体生成素释放激素（LH-RH）拮抗类似物[Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH（SB-75）所诱导的抗生育作用在雄性和雌性大鼠中的可逆性。雄性大鼠植入能每天释放50微克SB-75的渗透微型泵，持续60天。对照大鼠植入仅含赋形剂的微型泵。用拮抗剂治疗导致睾丸、精囊和前列腺重量显著减轻（p<0.01），血清促黄体生成素（LH）和睾酮水平降低（p<0.01）。治疗大鼠的睾丸组织学显示精子发生完全受抑制。在生精小管中未发现成熟的长形或圆形精子细胞，在100%的睾丸小管中，精母细胞是最成熟的生殖细胞形式。这些变化表明在治疗动物中发生了完全的精子发生停滞。停用LH-RH拮抗剂治疗90天后，睾丸、精囊和前列腺重量完全恢复，LH和睾酮恢复到对照水平。组织学研究显示精子发生完全恢复，99.2%的生精小管含有成熟长形精子细胞。停用SB-75治疗后立即发现垂体LH-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，共注射6周，剂量经计算可每天释放27微克拮抗剂。用SB-75治疗扰乱了正常的发情周期。体重未受影响，但拮抗剂治疗的动物卵巢和子宫重量显著减轻（分别为p<0.01和p<0.05）。治疗大鼠的LH（p<0.05）和雌二醇（p<0.01）水平显著低于对照组。SB-75治疗组卵巢的组织学显示，小成熟卵泡与大成熟卵泡的比例显著增加（p<0.01），且无黄体。停药两个月后，观察到器官重量和激素水平完全恢复，治疗组和未治疗组大鼠的卵巢在组织学上无差异。这些总体结果表明，用LH-RH拮抗剂SB-75治疗所诱导的性腺功能抑制在雄性和雌性动物中都是完全可逆的。（摘要截短至400字）
