ANDROGEN INSENSITIVITY IN HUMAN MALE INFERTILITY

不孕症影响美国15%的已婚夫妇，男性因素 造成了多达50%的不孕问题。 由于正常 精子发生需要促性腺激素和雄激素， 下丘脑-垂体-睾丸轴预计是主要的 少精症或无精症的原因。 然而，内分泌异常是 相对罕见的“特发性”不孕症占25%或更多 的案件。 此外，隐睾症是一种常见的疾病， 常与不孕症有关。 睾丸的正常下降也 需要促性腺激素和雄激素的作用。 我们的假设是 终末器官对雄激素作用的不敏感性可能是 某些受试者的精子发生不足， 不孕症和在少数患者的异质性组内， 睾丸发育不良 将对患有“特发性”不育症的男性进行评估，以确定 雄激素不敏感的频率。 患者将 根据病史、体格检查、血激素 水平和精液分析（包括无透明带仓鼠卵 适当时进行渗透试验）。 阴囊皮肤活检将 将测定获得和培养的皮肤成纤维细胞的定量和 与受体数量相关的雄激素受体质量缺陷 （Bmax）、结合亲和力（Kd）、核摄取、温度不稳定性， 对蔗糖密度梯度的稳定性，上调，解离速率， 以及其中指示DNA-纤维素、凝胶过滤和离子交换 层析和等电聚焦。 旨在降低的治疗试验方案的有效性 雌激素水平，从而改变有效的雄激素/雌激素比例 将在具有以下可识别异常的不育男性中进行评价： 雄激素受体功能 我们对雄激素受体功能和不孕症的研究将扩展到 双侧隐睾的孩子。 达到正常水平的患者 6周hCG刺激后血浆雄激素水平，但没有 睾丸下降将评估雄激素受体异常 使用生殖器皮肤成纤维细胞。 长期目标是：1）将可能的光谱 雄激素作用的分子水平异常， 男性不育症的病理生理学，2）进一步确定的作用， 雄激素在睾丸下降和3）测试某些治疗 可能改善敏感性降低的男性生育能力的方式 雄激素。

Infertility affects 15% of married couples in the U.S. and a male factor(s) contributes to as many as 50% of the infertility problems. Since normal spermatogenesis requires gonadotropins and androgens, abnormalities in the hypothalamic-pituitary-testicular axis would be expected to be the major cause of oligo- or azoospermia. However, endocrine abnormalities are relatively rare and "idiopathic" forms of infertility comprise 25% or more of the cases. In addition, cryptorchidism is a common disorder which is frequently associated with infertility. Normal descent of the testes also requires gonadotropin and androgen action. Our working hypothesis is that end-organ insensitivity to androgen action may be the molecular basis for inadequate spermatogenesis in certain subjects with otherwise unexplained infertility and in a few patients within the heterogenous group with testicular maldescent. Males with "idiopathic" infertility will be evaluated to determine the frequency of androgen insensitivity among them. Patients will be ascertained on the basis of history, physical examination, blood hormone levels, and semen analysis (including the zonapellucida free hamster egg penetration test where appropriate). Scrotal skin biopsies will be obtained and cultured skin fibroblasts will be assayed for quantitative and qualitative defects in androgen receptors related to receptor number (Bmax), binding affinity (Kd), nuclear uptake, temperature lability, stability on sucrose density gradients, up-regulation, dissociation rates, and where indicated DNA-cellulose, gel filtration and ion-exchange chromatography and isoelectric focusing. The effectiveness of a therapeutic trial regimen intended to decrease estrogen levels and thereby alter the effective androgen/estrogen ratio will be evaluated in infertile males with an identifiable abnormality of androgen receptor function. Our study of androgen receptor function and infertility will be extended to children with bilateral cryptorchidism. Patients who achieve normal levels of plasma androgens following 6-weeks hCG stimulation but who do not have testicular descent will be evaluated for androgen receptor abnormalities using genital skin fibroblasts. The long term objectives are 1) to relate the possible spectrum of abnormalities at the molecular level of androgen action to the pathophysiology of male infertility, 2) to further define the role of androgens in testicular descent and 3) to test certain therapeutic modalities which may improve fertility in men with diminished sensitivity to androgens.