MALE REPRODUCTIVE PHYSIOLOGY IN THE HUMAN

描述(申请人提供)：使用特发性低促性腺激素减退症(IHH)男性的人类疾病模型，有可能：a)通过注射外源性促性腺激素或搏动性GnRH来控制他们睾丸成熟的时间和速度；b)通过给予类固醇激素抑制剂来控制他们的性腺类固醇激素环境；以及c)改变他们下丘脑输入GnRH的剂量和频率。这种通过促性腺激素释放激素夹住下丘脑输入到垂体的能力，并将IHH患者的反应与正常和去势男性(其下丘脑-垂体轴不受限制)的反应进行对比，使我们能够从垂体活动部位解剖下丘脑，并解决人类无法处理的几个生理问题。因此，在特定的目标#1中，我们将探索性腺类固醇和抑制素B(IB)在整个性腺发育过程中抑制FSH分泌的相对作用，因为血清IB水平从青春期前水平到正常成年男性不同。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。它还允许我们理解GnRH在FSH反馈中的作用，从而将其与性类固醇和Lb放在一起。在特定的目标2和3中，这个模型允许我们测试FSH在给有未成熟性腺的IHH男性使用时增加支持细胞和生殖细胞数量、睾丸大小和精子数量的能力，并将这些结果与通过脉冲式GnRH治疗结合FSH刺激和促黄体生成素时获得的结果进行比较。在这样的研究中，我们还将获得这些男性的睾丸组织，从而可以验证MIS和IB作为支持细胞数量、增殖和成熟的标记，以一种以前不可能的定量和统计有效的方式。与Martin Dym博士合作，我们将在治疗前和治疗4个月后通过连续睾丸活检对这些成熟的性腺进行定量组织形态测量，并将这些组织学结果与IB和MIS以及性腺成熟的其他临床和生化方面的系列测量相关联。最后，在特定的目标#4中，这些男性在Sertoli和早期生殖细胞发育期间获得连续的睾丸组织将使我们能够深入了解人类在睾丸发育早期激活的特定基因。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学和发育活检的新见解。它们还奠定了基础，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.