The Jost hypothesis states that androgens are necessary for normal development of the male external genitalia. In this review, we explore the complementary hypothesis that estrogens can elicit abnormal development of male external genitalia. Herein, we review available data in both humans and mice on the deleterious effects of estrogen on external genitalia development, especially during the “window of susceptibility” to exogenous estrogens.

The male and female developing external genitalia in both the human and mouse express ESR1 and ESR2, along with the androgen receptor (AR). Human clinical data suggests that exogenous estrogens can adversely affect normal penile and urethral development, resulting in hypospadias. Experimental mouse data also strongly supports the idea that exogenous estrogens cause penile and urethral defects. Despite key differences, estrogen-induced hypospadias in the mouse displays certain morphogenetic homologies to human hypospadias, including disruption of urethral fusion and preputial abnormalities. Timing of estrogenic exposure, or the “window of susceptibility,” is an important consideration when examining malformations of the external genitalia in both humans and mice. In addition to a review of normal human and mouse external genital development, this article aims to review the present data on the role of estrogens in normal and abnormal development of the mouse and human internal and external genitalia. Based on the current literature for both species, we conclude that estrogen-dependent processes may play a role in abnormal genital development.

约斯特假说指出，雄激素是男性外生殖器正常发育所必需的。在这篇综述中，我们探讨了雌激素可以引起男性外生殖器异常发育的互补假设。在这里，我们回顾了人类和小鼠关于雌激素对外生殖器发育的有害影响的现有数据，特别是在外源性雌激素的“易感性窗口”期间。

人类和小鼠的外生殖器发育的雄性和雌性表达 ESR1 和 ESR2，以及雄激素受体 (AR)。人体临床数据表明，外源性雌激素会对正常的阴茎和尿道发育产生不利影响，导致尿道下裂。实验小鼠数据也强烈支持外源性雌激素导致阴茎和尿道缺陷的观点。尽管存在关键差异，但雌激素诱导的小鼠尿道下裂与人类尿道下裂显示出某些形态遗传学同源性，包括尿道融合中断和包皮异常。在检查人类和小鼠外生殖器畸形时，雌激素暴露的时间或“易感性窗口”是一个重要的考虑因素。除了回顾正常人和小鼠外生殖器的发育，本文旨在回顾有关雌激素在小鼠和人类内外生殖器正常和异常发育中的作用的现有数据。基于这两个物种的当前文献，我们得出结论，雌激素依赖性过程可能在异常生殖器发育中起作用。