In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development
In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development
复制标题
DOI：
10.1172/jci25091
复制
发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Hanley, NA
中科院分区：
文献类型：
--
作者：
Goto, M;Hanley, KP;Hanley, NA
在人类中，外生殖器的性别分化是在受孕后7-12周（wpc）建立的。在此期间，维持适当的宫内激素环境至关重要。与其他物种相比，这种调节延伸到人类胎儿肾上腺皮质，如与各种形式的先天性肾上腺增生相关的男性化所证明的。这些临床发现背后的机制仍然难以捉摸。在这里，我们表明，人胎儿肾上腺皮质合成皮质醇比以前记录的要早得多，与孤儿核受体神经生长因子IB样（NGFI-B）及其调控靶点，类固醇生成酶2型3 β-羟基类固醇脱氢酶（HSD 3B 2）的瞬时表达相关的效果。在ACTH的调节下，这种皮质醇的生物合成在8-9 wpc时达到最大。负反馈在垂体前叶促肾上腺皮质激素细胞明显。ACTH还刺激肾上腺分泌雄烯二酮和睾酮。一致地，这些数据促进了正常人类发育的独特机制，其中皮质醇的产生由瞬时NGFI-B和HSD 3B 2表达决定，在垂体前叶提供反馈以调节雄激素生物合成并保护正常的女性性分化。
In humans, sexual differentiation of the external genitalia is established at 7-12 weeks post conception (wpc). During this period, maintaining the appropriate intrauterine hormone environment is critical. In contrast to other species, this regulation extends to the human fetal adrenal cortex, as evidenced by the virilization that is associated with various forms of congenital adrenal hyperplasia. The mechanism underlying these clinical findings has remained elusive. Here we show that the human fetal adrenal cortex synthesized cortisol much earlier than previously documented, an effect associated with transient expression of the orphan nuclear receptor nerve growth factor IB-like (NGFI-B) and its regulatory target, the steroidogenic enzyme type 2 3 beta-hydroxysteroid dehydrogenase (HSD3B2). This cortisol biosynthesis was maximal at 8-9 wpc under the regulation of ACTH. Negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. In concert, these data promote a distinctive mechanism for normal human development whereby cortisol production, determined by transient NGFI-B and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.