EXTRAPITUITARY ACTIONS OF LHRH AGONISTS

本课题的主要目的是分离、表征和合成A

A major aim of this proposal is to isolate, characterize and synthesize a testicular and ovarian LHRH-like substance(s) which probably plays a role in the intracellular regulation of gonadal functions. Isolation of quantities sufficient for amino acid sequencing will be conducted on material obtained from rat, bull and human testes. When the amino acid sequence of the pure material is known, it will be synthesized and the synthetic peptide and its analogs will be examined for in vivo and in vitro bioactivity in various species. It will also be determined if these substances are species specific. A LHRH-like substance in bovine semial plasma and follicular fluid will also be studied. This will be accomplished using various extraction methods, disaggregation and reduction of the LHRH-like substance, desalting, afficity chromatography, and reverse phase and/or ion exchange HPLC. We propose that a gonadal LHRH-like substance is the endogenous ligand for gonadal LHRH receptors. Such receptors have been found in the testes of rats, but not in those of mice and humans. Failures to demonstrate the presence of LHRH receptors in mouse and human gonads and the apparent failure of LHRH agonists to have antireproductive actions in mice might be related. We suggest that interactions between LHRH agonists, gonadotropins and sex steroids necessitate further investigation of these findings. Occupation of testicular LHRH receptors by endogenous ligand could account for the apparent lack of these receptors in mice and humans. It is also possible that the testes of these non-rat species contain LHRH-like material. We will first examine mice to determine if LHRH agonists directly suppress their gonadal function. These experiments will be designed to minimize possible interactions between LHRH agonists, gonadotropins and/or sex steroids. The weights of the testes, ventral prostate and seminal vesicles, testicular morphology, testicular LHRH receptor content, and in vivo and in vitro testosterone production with be examined during and after LHRH agonist treatment. In vitro experiments using cultured testicular or ovarian tissue from different species will also be conducted.