Abstract
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness.
Highlights
Ovarian differentiation and female internal and external genitalia are the expected pathway in the mammalian XX foetus (Figure 1)
The ground-breaking observations made by Jost almost seventy years ago [56] taught us that the differentiation of the gonadal ridges into testes is determinant for the virilisation of the foetus. This is due to the fact that the testes have two endocrine cell populations: Leydig cells produce androgens, which induce the differentiation of the Wolffian duct into the epididymis, vas deferens and seminal vesicles and the virilisation of the primordia of the external genitalia [57], and Sertoli cells secrete anti-Müllerian hormone (AMH), responsible for the regression of the Müllerian ducts, which otherwise form the Fallopian tubes, the uterus and the upper vagina [58,59] (Figure 1)
Deletions of chromosome 9p that include the DMRT cluster have been described in 46,XY disorder of sex development (DSD) patients with dysgenetic testes [124] and overexpression of DMRT1 in the gonadal ridges has been shown to induce testicular differentiation and male sex development in transgenic XX mice [123,125], but SRY-negative 46,XX DSD attributable to DMRT1 upregulation has not been described in humans
Summary
Ovarian differentiation and female internal and external genitalia are the expected pathway in the mammalian XX foetus (Figure 1). May XX gonads follow the testicular differentiation pathway, and internal and external genitalia are virilised by testicular hormones. This “sex-reversal” condition was initially characterised in humans and named “XX male” [1], since no hint of a disorder of sex development was present until adulthood, when these males sought medical attention for infertility (see below). WT1, named after Wilms’ tumour (nephroblastoma), is a transcriptional and post-transcriptional regulator [10] that is expressed early in the urogenital ridge and plays an essential role in the development of the kidneys and gonads. SF1 is essential for the development of the gonadal primordium [12]
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