Classic genetic and hormonal switches during fetal sex development and beyond

Abstract

Critical genetic and hormonal switches characterize fetal sex development in humans. They are decisive for gonadal sex determination and subsequent differentiation of the genital and somatic sex phenotype. Only at the first glace these switches seem to behave like the dual 0 and 1 system in computer sciences and lead invariably to either typically male or female phenotypes. More recent data indicate that this model is insufficient. In addition, in case of distinct mutations, many of these switches may act variably, causing a functional continuum of alterations of gene functions and -dosages, enzymatic activities, sex hormone levels, and sex hormone sensitivity, giving rise to a broad clinical spectrum of biological differences of sex development (DSD) and potentially diversity of genital and somatic sex phenotypes. The gonadal anlage is initially a bipotential organ that can develop either into a testis or an ovary. Sex-determining region Y (SRY) is the most important upstream switch of gonadal sex determination inducing SOX9 further downstream, leading to testicular Sertoli cell differentiation and the repression of ovarian pathways. If SRY is absent (virtually "switched off"), e. g., in 46,XX females, RSPO1, WNT4, FOXL2, and other factors repress the male pathway and promote ovarian development. Testosterone and its more potent derivative, dihydrotestosterone (DHT) as well as AMH, are the most important upstream hormonal switches in phenotypic sex differentiation. Masculinization of the genitalia, i. e., external genital midline fusion forming the scrotum, growth of the genital tubercle, and Wolffian duct development, occurs in response to testosterone synthesized by steroidogenic cells in the testis. Müllerian ducts will not develop into a uterus and fallopian tubes in males due to Anti-Müllerian-Hormone (AMH) produced by the Sertoli cells. The functionality of these two hormone-dependent switches is ensured by their corresponding receptors, the intracellular androgen receptor (AR) and the transmembrane AMH type II receptor. The absence of high testosterone and high AMH is crucial for anatomically female genital development during fetal life. Recent technological advances, including single-cell and spatial transcriptomics, will likely shed more light on the nature of these molecular switches.

Figure 1:

Display of sex determination (gene-controlled development of the gonads) and sex differentiation (hormone-controlled development of the internal and external genitalia) in the form of a simplified “switch-on – switch-off” model of developmental pathways. In case of mutations, many of these “switches” may act variably – virtually more like “sliders” – causing a functional continuum of alterations of gene functions, gene dosages, enzymatic activities, sex hormone levels, and sex hormone sensitivity, giving rise to a broad phenotypical spectrum of biological differences of sex development (DSD) which is a potential model for diversity of genital and somatic sex phenotypes.

Figure 2:

Classification of phenotypes in androgen insensitivity syndrome ranging from minimal androgen insensitivity syndrome (MAIS) with normal external virilization (1) over different types of partial androgen insensitivity syndrome (PAIS) (2–4) to complete androgen insensitivity syndrome (CAIS) (5) with completely female external genitalia [61]. The figure also illustrates the continuum of external virilization in AIS due to a continuum of functional variability at the level of the androgen receptor in addition to a simplified “on-off-model”. Reproduced with permission from Springer Nature.