Aromatase Inhibitor in Males with Adrenal Hyperplasia

描述(申请人提供)：我们的目标是用芳香酶抑制剂治疗先天性肾上腺增生症(CAH)和精子生成减少的男性，以研究其对激素参数和精子发生的影响。CAH是一种遗传性疾病，由皮质醇合成所需的酶活性降低引起。皮质醇产生减少会增加脑下垂体分泌ACTH，并通过负反馈增加肾上腺雄激素的产生。反过来，肾上腺雄激素水平的增加在腺体(即睾丸)和腺外组织中被芳香化/转化为芳香酶，导致雌激素水平升高。理想情况下，CAH患者肾上腺雄激素的产生可以通过糖皮质激素替代疗法恢复正常。然而，即使控制良好的CAH患者仍表现出不良反应(最终身高受损、多囊卵巢疾病、男性不育等)。雄激素/雌激素升高。糖皮质激素治疗不能持续使ACTH水平正常化，因为它缺乏与ACTH脉冲的密切时间关系，任何肾上腺活动都会导致比正常雄激素(从而雌激素)产生更多的激素。我们推测这些升高的雌激素水平通过以下机制影响男性CAH患者的精子发生：(1)雌激素升高通过负反馈抑制下丘脑-垂体-性腺轴。正常的促黄体生成素/促性腺激素分泌对睾丸功能的启动和维持以及正常的精子发生是必不可少的。长期升高的雌激素水平(雌二醇)影响睾丸形态和睾丸类固醇生成(A)通过抑制垂体性腺的分泌，以及(B)雌二醇对睾丸组织的直接毒性作用，导致睾丸睾酮生成减少，雄激素受体数量减少，并在性腺水平造成睾酮与雌二醇比率的进一步负失衡；(2)如对暴露于过量雌激素的啮齿动物的实验所示，雌激素升高会对睾丸功能产生不利影响，包括睾丸间质细胞、支持细胞和生殖细胞发育；(3)雌激素水平升高会导致传出小管和附睾管功能障碍。因此，我们研究的首要问题是：控制性腺组织将升高的肾上腺雄激素转化/芳构化为雌激素对CAH男性精子发生有多大程度的积极影响？我们认为，用芳香酶抑制剂抑制雄激素芳构化为雌激素，将通过在性腺水平上使雌二醇/睾酮比值正常化，并逆转雌激素升高对雄激素受体、睾丸类固醇激素生成和垂体促性腺激素的负面影响，从而改善睾丸功能和精子生成。芳香酶抑制剂具有选择性作用，患者耐受性良好，不会干扰其他相关细胞色素P450依赖酶产生类固醇激素，使其成为CAH患者的理想选择。

DESCRIPTION (provided by applicant): Our objective is to treat males who have congenital adrenal hyperplasia (CAH) and decreased spermatogenesis with an aromatase inhibitor in order to investigate its effects on hormonal parameters and spermatogenesis. CAH is a family of inherited disorders caused by reduced activity of the enzyme required for cortisol synthesis. Decreased cortisol production increases the secretion of ACTH from the pituitary and increases the production of adrenal androgens through negative feedback. In turn, the increased levels of adrenal androgens are aromatized/converted in glandular (i.e., testes) and extraglandular tissues by the aromatase enzyme and result in elevated estrogen levels. Ideally, the production of adrenal androgens is normalized in CAH patients by glucocorticoid replacement therapy. However, even well controlled CAH patients still manifest the adverse effects (compromised final height, polycystic ovarian disease, male infertility, etc.) of elevated androgens/estrogens. Glucocorticoid therapy does not continually normalize ACTH levels because it lacks the close temporal relationship to ACTH pulses and any adrenal activity will result in greater than normal androgen (and thus estrogen) production. We hypothesize that these elevated estrogen levels affect spermatogenesis in males with CAH through the following mechanisms: (1) Elevated estrogens suppress the hypothalamic-pituitary-gonadal axis through negative feedback. Normal LH/FSH gonadotropin secretion is essential for the initiation and maintenance of testicular function and normal spermatogenesis. Chronically elevated estrogen levels (estradiol) affect testicular morphology and testicular steroidogenesis (a) by suppressing pituitary-gonadal secretion, and (b) by a direct toxic effect of estradiol on testicular tissue resulting in a decrease in testicular testosterone production, decrease number of androgen receptors, and create a further negative imbalance in the testosterone-to-estradiol ratio at the gonadal level; (2) Elevated estrogens adversely affect testicular function including Leydig cell, Sertoli cell and germ cell development as shown in experiments with rodents that have been exposed to excess estrogens; (3) Elevated estrogens cause dysfunction of the efferent ductules and epididymis. Therefore, the overarching question of our study is the following: What degree of positive effect will controlling the conversion/aromatization of elevated adrenal androgens into estrogens by gonadal tissue have on spermatogenesis in CAH males? We propose that inhibiting aromatization of androgens to estrogens with an aromatase inhibitor, will improve testicular function and spermatogenesis by normalizing the estradiol to testosterone ratio at the gonadal level and reversing the negative effects of elevated estrogen on androgen receptors, testicular steroidogenesis and pituitary gonadotropins. Aromatase inhibitors have selective action, are well tolerated by patients, and do not interfere with the production of steroid hormones by other related cytochrome P450-dependent enzymes making it ideal for use in CAH patients.