Androgen receptors in development: biochemical and clinical correlates
I A Hughes
The androgen receptor (AR) is the conduit for androgen-induced fetal male sex differentiation, the acquisition of secondary sexual characteristics at male puberty and subsequently, the onset of spermatogenesis. The AR is expressed ubiquitously in early fetal development to permit male sex differentiation to occur: stabilisation of the Wolffian ducts to form the vas deferens, epididymis and seminal vesicles and morphogenesis of the genital tubercle and folds to form the penis, male urethra and scrotum. The importance of the AR to these processes is vividly illustrated by the clinical syndromes of androgen insensitivity where resistance to androgen action results from a mutant AR. Complete androgen insensitivity syndrome (CAIS) is the hallmark of a hormone resistance syndrome, characterised by complete XY sex reversal despite normal/increased age-appropriate androgen levels. A partial response to androgens (PAIS) manifests as a spectrum of genital anomalies and poses a challenge for the investigation of ambiguous genitalia of the newborn. A mild form of androgen resistance (MAIS) is associated with normal genital development but later onset of gynaecomastia and oligospermia. The AR gene is well characterised with respect to mutations causing AIS sub-types. Functional analysis of mutant ARs has provided novel insights into the mode of AR action in androgen signalling. In turn, this provides an element of certainty in predicting how subjects with PAIS assigned male at birth will virilise at puberty, either spontaneously or with the aid of androgen supplements.