MALE REPRODUCTIVE PHYSIOLOGY IN THE HUMAN

描述（由申请人提供）：使用特发性促性腺功能减退症（IHH）男性的人类疾病模型，有可能：a)通过外源性促性腺激素或脉动性GnRH的管理来控制睾丸成熟的时间和速度；B)通过使用类固醇激素抑制剂来控制他们的性腺类固醇激素环境；c)改变下丘脑输入GnRH的剂量和频率。这种通过GnRH将下丘脑输入到垂体的能力，并将IHH男性与正常男性和阉割男性（其下丘脑-垂体轴不受约束）的反应进行对比，使我们能够从垂体的作用部位解剖下丘脑，并解决一些在人类中无法接近的生理问题。因此，在Specific Aim #1中，我们将探讨性腺激素和抑制素B （IB）在抑制卵泡刺激素分泌方面的相对作用，在整个性腺发育过程中，从青春期前到正常成年男性的血清IB水平是不同的。我们的初步结果表明，在性腺成熟过程中，它们的相对作用似乎发生了变化。它也允许我们理解的作用促性腺激素FSH反馈的频率,因此将它放在上下文性类固醇和磅。在特定目标# 2 & 3,该模型允许我们测试FSH增加足的能力和生殖细胞数量,睾丸大小,和精子数量当管理本次事件的男人不成熟的生殖腺和比较这些结果时,所得结果与FSH刺激是伴随着的LH通过脉动的促性腺激素疗法。在这些研究中，我们还将接触到这些男性的睾丸组织，从而可以以定量和统计有效的方式验证MIS和IB作为支持细胞数量、增殖和成熟的标记物，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性腺进行定量组织形态学测量，并将这些组织学发现与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Specific Aim #4中，这些男性在支持期和早期生殖细胞发育期间的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期间激活的特定基因。因此，这些研究提供了一种独特的方法来获得对男性生殖轴的生理和发育活检的新见解。他们还奠定了基础，为探索新工具提供了背景，以进一步深入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.