MECHANISM OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELLS

肽激素在类固醇细胞中的作用机制

• 批准号: 3842248
• 负责人: M L DUFAU
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3842248
• 关键词: Leydig cells; corticotropin releasing factor; cyclic AMP; fertility; growth hormone releasing hormone; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; laboratory rat; luteinizing hormone; peptide hormone; propranolol; radioimmunoassay; receptor sensitivity; serotonin; steroid biosynthesis; steroid hormone biosynthesis; testis; testosterone; tissue /cell culture

Gonadotropins are the primary support for Leydig and Sertoli cell function and the most prominent local regulatory hormone of testicular function is testosterone, which is synthesized by the Leydig cells and acts as the major paracrine stimulator of germ cell development. Many additional local regulatory substances act as autocrine modulators and mediate paracrine interactions between the different intratesticular compartments. These include growth factors, several neuropeptides such as GnRH and most importantly, corticotropin releasing hormone (CRF) and opioids, and amines such as serotonin. Corticotropin-releasing hormone factor, the key neuropeptide in the stress cascade, has major inhibitory actions on testicular function in addition to its known antireproductive effects at the central level (inhibition of sexual behavior and LH secretion). Leydig cells in culture are able to produce hypothalamic releasing hormones such as CRF, which acts through distinct high- affinity receptors as a negative autocrine regulator of Leydig cell function by inhibiting gonadotropin-stimulated cAMP generation and steroidogenesis. The secretion of CRF by the Leydig cell is stimulated by LH, acting via release of serotonin (5HT) and autocrine activation of 5HT2 receptors distinct from brain sites (DOI, an agonist for 5HT2 sites in the brain, acts as an antagonist of the high-affinity sites and an agonist to the low-affinity sit in the Leydig cell). Propranolol, the prototype beta-adrenergic blocker frequently used in the control of blood pressure in patients with hypertension, and often associated with impotence, acts in the Leydig cell via serotonergic mechanism to stimulate CRF secretion and causes marked inhibition of LH-induced cAMP production and steroidogenesis. Propranolol, acting as an antagonist of the Leydig cell low-affinity receptor sites (with properties of autoreceptors), promotes the release of serotonin which in turn acts through high-affinity sites to stimulate CRF release. This serotonergic action of the drug could contribute to the impairment of sexual function reported during propranolol treatment. Other studies revealed that another neuropeptide hormone, growth hormone releasing hormone (GHRH), is present in the Leydig cell. The peptide is actively released from cells in culture, is under gonadotropin control, and acts via a VIP receptor as a direct stimulator of Leydig cell function/or facilitator of LH-induced cAMP production and steroidogenesis. Since GHRH is also a stimulus of basal and FSH-stimulated Sertoli cell function, it is concluded that testicular GHRH is an autocrine/paracrine positive regulator of male gonadal function. Altered secretion and actions of testicular GHRH may be involved in certain disorders of androgen production and some forms of male idiopathic infertility.

促性腺激素是间质和支持细胞的主要支持 睾丸的功能及其最突出的局部调节激素 功能是睾酮，它是由间质细胞和 作为生殖细胞发育的主要旁分泌刺激因子。许多 额外的地方调节物质作为自分泌调节剂和 在不同的睾丸内调节旁分泌相互作用 车厢。这些包括生长因子，几种神经肽，如 作为GnRH，最重要的是促肾上腺皮质激素释放激素(CRF)和 阿片类药物和5-羟色胺等胺类药物。促肾上腺皮质激素释放激素 因子是应激级联反应中的关键神经肽，具有主要的抑制作用。 除已知的抗生殖作用外，对睾丸功能的作用 中央一级的影响(抑制性行为和促黄体生成素 分泌物)。培养的间质细胞能够产生下丘脑 释放激素，如CRF，它通过不同的高水平 亲和力受体作为间质细胞的负性自分泌调节因子 通过抑制促性腺激素刺激的cAMP生成和 类固醇合成。间质细胞分泌CRF受到刺激 通过促黄体生成素，通过释放5-羟色胺和自分泌激活 不同于脑部位的5HT2受体(DOI，一种5HT2部位的激动剂 在大脑中，充当高亲和力部位的拮抗剂 低亲和力的激动剂位于间质细胞中)。普萘洛尔， β-肾上腺素能阻滞剂的原型常用于控制 高血压患者的血压，并经常与 阳萎通过5-羟色胺能机制作用于间质细胞 刺激CRF分泌并明显抑制促黄体生成素诱导的cAMP 产生和类固醇的生成。心得安，作为阿司匹林的拮抗剂 间质细胞低亲和力受体部位(具有 自身受体)，促进5-羟色胺的释放，而5-羟色胺反过来又起作用 通过高亲和力部位刺激CRF释放。这种5-羟色胺能 这种药物的作用可能导致性功能受损。 在心得安治疗期间报告。其他研究表明， 另一种神经肽激素，生长激素释放激素(GHRH)， 存在于间质细胞中。这种多肽是从 细胞在培养中，受促性腺激素控制，并通过VIP发挥作用 受体作为间质细胞功能的直接刺激因子或促进剂 促黄体生成素诱导的cAMP生成和类固醇合成。因为GHRH也是一个 刺激基础和FSH刺激的Sertoli细胞功能，它是 结论：睾丸GHRH为自分泌/旁分泌阳性 男性性腺功能的调节器。变化的分泌物和作用 睾丸GHRH可能参与某些雄激素紊乱 生产和某些形式的男性特发性不育。