EXTRAPITUITARY ACTIONS OF LHRH AGONISTS

该提案的一个主要目的是分离、表征和合成 睾丸和卵巢的LHRH样物质，可能起作用 在性腺功能的细胞内调节中的作用。 分离 将进行足以进行氨基酸测序的量， 从大鼠、公牛和人睾丸中获得的材料。 当氨基酸 纯物质的序列是已知的，它将被合成， 将在体内和体外检查合成肽及其类似物 在不同物种中的生物活性。 还将确定这些 物质是物种特异性的。 牛精液中的一种LHRH样物质 还将研究血浆和卵泡液。 这将是 使用各种提取方法、分解和还原 LHRH样物质，反相，亲和层析， 相和/或离子交换HPLC。 我们提出，性腺LHRH样 该物质是性腺LHRH受体的内源性配体。 等 在大鼠的睾丸中发现了受体，但在小鼠的睾丸中没有发现 还有人类 未能证明LHRH受体的存在 小鼠和人类的性腺和LHRH激动剂的明显失败， 小鼠的抗生殖作用可能有关。 我们建议 LHRH激动剂、促性腺激素和性类固醇之间的相互作用 需要进一步调查这些发现。 占领 睾丸LHRH受体的内源性配体可以解释 小鼠和人类明显缺乏这些受体。 也可以 这些非大鼠物种的睾丸含有LHRH样物质。 我们 将首先检查小鼠，以确定LHRH激动剂是否直接抑制 它们的性腺功能 这些实验将被设计成最小化 LHRH激动剂、促性腺激素和/或性别之间可能的相互作用 类固醇. 睾丸、腹侧前列腺和精液的重量 囊泡，睾丸形态，睾丸LHRH受体含量， 体内和体外睾酮的产生， LHRH激动剂治疗。 使用培养的睾丸或 还将对来自不同物种的卵巢组织进行分析。

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.