The differential role of androgens in early human sex development

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.

Figure 1

The prenatal development of the external genitalia. From an initially undifferentiated appearance and after an initial primarily genetically driven process, androgenization leads to formation of the phallus and scrotum, and to elongation of the urethra. This requires a differentiated, time-controlled and dose-dependent androgen action as depicted by the different arrows.

Figure 2

The androgen specific cell differentiation is dependent on testosterone uptake, its intracellular metabolism and the specificity of the androgen-androgen receptor (AR) complex in concert with coregulators in transcriptional control. CoR, coregulators; GTF, general transcription factors; HRE, hormone response elements; HSP, heat shock proteins; P, phosphorylation sites.

Figure 3

A highly specific and time-dependent androgen response index for each cell must be proposed. This is an overall time-related effect (T), which is seen in a specific time period (Tp) on n cells, where each cell responds according to specific androgens (androgen × androgenization factor) in relation to the androgen sensitivity as a ratio of the AR to its modulators evidenced by activation versus repression.