MALE REPRODUCTIVE PHYSIOLOGY IN THE HUMAN

描述（由申请人提供）：使用患有特发性低促性腺激素性性腺功能减退症（IHH）的男性的人类疾病模型，有可能：a）通过施用外源性促性腺激素或脉冲式GnRH来控制其睾丸成熟的时间和速度; B）通过施用类固醇激素抑制剂来操纵其性腺性类固醇激素环境;和c）改变GnRH的下丘脑输入的剂量和频率。这种通过GnRH阻断下丘脑输入垂体的能力，以及IHH男性与正常和去势男性（其下丘脑-垂体轴不受约束）的反应的对比，使我们能够从垂体作用部位解剖下丘脑，并解决人类无法解决的几个生理问题。因此，在具体目标#1中，我们将探索性腺性类固醇和抑制素B（IB）在抑制FSH分泌方面的相对作用，这些作用贯穿性腺发育的全过程，血清IB水平从青春期前水平变化到正常成年男性的水平。我们的初步结果表明，它们的相对作用似乎在性腺成熟过程中发生变化。它也使我们能够了解促性腺激素释放激素的频率在FSH反馈中的作用，从而将其与性类固醇和lB联系起来。在特定目标#2和3中，该模型允许我们测试FSH对性腺不成熟的IHH男性给药时增加支持细胞和生殖细胞数量、睾丸大小和精子计数的能力，并将这些结果与FSH刺激伴随LH通过脉冲式GnRH治疗获得的结果进行比较。在这些研究中，我们还将获得这些男性的睾丸组织，因此可以以定量和统计学有效的方式验证MIS和IB作为支持细胞数量，增殖和成熟的标志物，这在以前是不可能的。与Martin Dym博士合作，我们将通过治疗前后4个月的连续睾丸活检对这些成熟的性腺进行定量组织形态学测量，并将这些组织学结果与IB和MIS的连续测量以及性腺成熟的其他临床和生化方面相关联。最后，在具体目标#4中，这些男性在Sertoli和早期生殖细胞发育过程中连续睾丸组织的可用性将使我们能够深入了解人类在早期睾丸发育过程中激活的特定基因。因此，这些研究提供了一种独特的方法，以获得新的见解，男性生殖轴的生理和发育活检。它们还奠定了基础，为探索新的工具提供了背景，以进一步了解男性生殖功能障碍的复杂性。

DESCRIPTION (provided by applicant): Using the human disease model of men with idiopathic hypogonadotropic hypogonadism (IHH), it is possible to: a) control the timing and pace of their testicular maturation via administration of either exogenous gonadotropins or pulsatile GnRH; b) manipulate their gonadal sex steroid hormonal milieu by administration of steroid hormone inhibitors; and c) vary the dose and frequency of their hypothalamic input of GnRH. This ability to clamp the hypothalamic input to their pituitary via GnRH and contrast the responses of IHH men with those of normal and castrate men (whose hypothalamic-pituitary-axis is unconstrained) allows us to dissect the hypothalamic from pituitary sites of action and address several physiologic issues that are not otherwise approachable in the human. Thus, In Specific Aim #1, we will thus explore the relative roles of gonadal sex steroids and Inhibin B (IB) in restraining FSH secretion across the full spectrum of gonadal development were serum IB levels vary from prepubertal levels to those of normal adult men. Our preliminary results suggest that their relative roles appear to change during gonadal maturation. It also permits us to understand the role of the frequency of GnRH in FSH feedback and thus place it in context with both sex steroids and lB. In Specific Aims # 2 & 3, this model allows us to test the ability of FSH to increase Sertoli and germ cell number, testicular size, and sperm counts when administered to IHH men with immature gonads and compare these results with those obtained when FSH stimulation is accompanied by that of LH via pulsatile GnRH therapy. During such studies we will also have access to testicular tissue in these men and thus can validate both MIS and IB as markers of Sertoli cell numbers, proliferation, and maturation in a quantitative and statistically valid fashion that has not been previously possible. In collaboration with Dr. Martin Dym, we will perform quantitative histomorphometry on these maturing gonads via serial testicular biopsies prior to and following 4 months of therapy and correlate these histological findings with serial measurements of IB and MIS as well as other clinical and biochemical aspects of gonadal maturation. Finally, in Specific Aim #4, the availability of serial testicular tissue in these men during Sertoli and early germ cell development will allow us to gain insight into the specific genes activated in the human during early testicular development. Thus, these studies offer a unique approach to gain new insights into the physiology and developmental biopsy of the male reproductive axis. They also lay the groundwork that provides a context for the exploration of new tools to gain further insights into the complexities of reproductive dysfunction in the male.