Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (Sb-75)

Lazaro Bokser, Gordon Srkalovic, Karoly Szepeshazi, Andrew V. Schally

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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 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 cassation 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.

Original languageEnglish (US)
Pages (from-to)136-145
Number of pages10
JournalNeuroendocrinology
Volume54
Issue number2
DOIs
StatePublished - Jan 1 1991
Externally publishedYes

Keywords

  • LH-RH antagonist
  • pituitary gonadal function
  • reversible suppression

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (Sb-75)'. Together they form a unique fingerprint.

  • Cite this