Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine and the Program for Disorders of Sexual Development, University of Michigan, Ann Arbor, MI 48109, USA.
Semin Reprod Med. 2012 Oct;30(5):417-26. doi: 10.1055/s-0032-1324726. Epub 2012 Oct 8.
At least one genetic defect in each reaction of the classical androgen biosynthesis pathway has been described. For some steps, such as the conversion of cholesterol to pregnenolone and the 17,20-lyase reaction, two or three genetic defects cause similar disorders with overlapping phenotypes and biochemical profiles. The elucidation of the molecular basis for these diseases has helped to define the pathways, essential genes, and enzymatic steps required to make androgens, and this knowledge is being exploited to develop better treatments of androgen-dependent diseases. Furthermore the description of nonclassical lipoid CAH and the protean manifestations of P450 oxidoreductase (POR) deficiencies has expanded the spectrum of human disease caused by disordered steroidogenesis. Finally, the recognition of the backdoor pathway to DHT has added a new dimension to our understanding of how steroid flux is maintained in normal and pathologic states. The traditional view of male external genital development has been that fetal testicular testosterone is converted to DHT by 5α-reductase Type 2 in genital skin, which then acts in a paracrine fashion to stimulate fusion of the labio-scrotal folds and phallic growth. This view is consistent with the incomplete external genital development in persons with severe deficiencies of 5α-reductase type 2. The new observations concerning AKR1C2/4 and the backdoor pathway indicate that DHT produced in the testis via the backdoor pathway also acts as a hormone to induce labio-scrotal fusion. Thus, both the classic and backdoor pathways are needed, and DHT acts in male genital development as both a paracrine factor and as a hormone. These surprising findings are revising our understanding of the mechanisms by which male sexual differentiation occurs, and illustrate the importance of detailed studies of rare patients with 46,XY DSD.
至少有一个遗传缺陷在经典雄激素生物合成途径的每个反应中都有描述。对于某些步骤，如胆固醇转化为孕烯醇酮和 17,20-裂解酶反应，两个或三个遗传缺陷导致具有重叠表型和生化特征的相似疾病。这些疾病的分子基础的阐明有助于定义途径、必需基因和酶步骤，以制造雄激素，并且这些知识正在被利用来开发更好的治疗雄激素依赖性疾病的方法。此外，非经典脂质性 CAH 的描述和 P450 氧化还原酶 (POR) 缺乏的多种表现形式扩大了由类固醇生物合成障碍引起的人类疾病谱。最后，认识到 DHT 的后门途径增加了我们对正常和病理状态下类固醇通量如何维持的理解的新维度。男性外生殖器发育的传统观点是，胎儿睾丸中的睾酮在生殖器皮肤中被 5α-还原酶 2 转化为 DHT，然后以旁分泌的方式作用于刺激阴唇阴囊褶的融合和阴茎的生长。这一观点与严重缺乏 5α-还原酶 2 的个体的外生殖器发育不完全一致。关于 AKR1C2/4 和后门途径的新观察结果表明，通过后门途径在睾丸中产生的 DHT 也作为一种激素起作用，诱导阴唇阴囊融合。因此，经典和后门途径都是必需的，DHT 在男性生殖器发育中既作为旁分泌因子，也作为激素起作用。这些令人惊讶的发现正在修正我们对男性性分化发生机制的理解，并说明了对 46,XY DSD 罕见患者进行详细研究的重要性。
