Aromatase Inhibitor in Males with Adrenal Hyperplasia

描述（由申请人提供）：我们的目的是用芳香化酶抑制剂治疗患有先天性肾上腺皮质增生（CAH）和精子发生减少的男性，以研究其对激素参数和精子发生的影响。CAH是一个家族的遗传性疾病所造成的减少活性的酶所需的皮质醇合成。皮质醇的减少会增加垂体ACTH的分泌，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中被芳香化/转化（即，睾丸）和腺外组织中的芳香化酶，并导致雌激素水平升高。理想情况下，CAH患者通过糖皮质激素替代治疗使肾上腺雄激素的产生正常化。然而，即使是控制良好的CAH患者仍然表现出不良反应（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，因为它与ACTH脉冲缺乏密切的时间关系，并且任何肾上腺活动都会导致雄激素（因此雌激素）产生高于正常水平。我们推测这些升高的雌激素水平通过以下机制影响CAH男性的精子发生：（1）升高的雌激素通过负反馈抑制下丘脑-垂体-性腺轴。正常的LH/FSH促性腺激素分泌对于启动和维持睾丸功能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（a）通过抑制垂体-性腺分泌，和（B）通过雌二醇对睾丸组织的直接毒性作用影响睾丸形态和睾丸类固醇生成，导致睾丸睾酮产生减少，雄激素受体数量减少，并在性腺水平上造成睾酮-雌二醇比率的进一步负失衡;（2）雌激素水平升高会对睾丸功能产生不利影响，包括Leydig细胞、Sertoli细胞和生殖细胞的发育，如暴露于过量雌激素的啮齿动物实验所示;（3）雌激素水平升高会导致传出小管和附睾功能障碍。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？我们建议，抑制芳香化酶抑制剂的雄激素的雌激素的芳香化，将改善睾丸功能和精子发生正常化的雌二醇与睾酮的比例在性腺水平和逆转的负面影响升高的雌激素对雄激素受体，睾丸类固醇和垂体促性腺激素。芳香化酶抑制剂具有选择性作用，患者耐受性良好，并且不干扰其他相关细胞色素P450依赖性酶产生类固醇激素，因此非常适合用于CAH患者。

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.