Abstract
Sexual development in humans is only partly understood at the molecular level. It is dependent on genetic control primarily induced by the sex chromosomal differences between males and females. This leads to the development of the gonads, whereby afterwards the differentiation of the apparent phenotype is controlled by hormone action. Sex steroids may exert permanent and temporary effects. Their organizational features of inducing permanent changes in phenotype occur through genetic control of downstream genes. In this, androgens are the key elements for the differentiation of male internal and external genitalia as well as other sexual organs and general body composition, acting through a single androgen receptor. The androgen receptor is a nuclear transcription factor modulating DNA transcription of respective target genes and thereby driving development and growth in a stringent manner. The specificity of androgen action seems to be a strictly time-controlled process with the androgen receptor acting in concert with different metabolites and an array of cofactors modulating the cellular response and thereby permanently altering the phenotype of any given individual. For every cell programmed by androgens, a specific ‘androgen response index’ must be proposed.
Highlights
Human sex development can be divided into three major steps
An ‘opposite’ naturally occurring model is seen in individuals with 46,XX karyotype and normally developed ovaries that have high amounts of androgens during embryogenesis, for example, in congenital adrenal hyperplasia (CAH) and adrenal androgen excess where testosterone levels can reach the usual reference intervals observed in males [12,13,14,15]
This proposal has its foundation in the following experiments again in cells derived from 46,XY controls and cells derived from 46,XY females mostly with complete androgen insensitivity syndrome (CAIS): Genital skin fibroblasts, which play a role in the differentiation of the external genitalia and facilitate androgenization, are almost ‘androgen insensitive’ postnatally [37]
Summary
Human sex development can be divided into three major steps. First, the determination of the chromosomal set with the presence or absence of a specific gene on the Y chromosome termed SRY, as well as the sex differences induced from the inequality of the sex chromosomes and their corresponding genes [1,2]. The major hormones for differential male and female sex development are mainly secreted from the testes [3]. Testosterone is metabolized, and the 5α-reduced compound dihydrotestosterone (DHT) is required for androgen-induced differentiation of the external genitalia.
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