Sex, infertility and the molecular biology of the androgen receptor

Mutations that totally disrupt androgen receptor function cause the well kn own testicular feminizing syndrome or complete androgen insensitivity syndr ome, wherein a 46 XY individual is completely feminized at birth. Recently it has been increasingly obvious that androgen receptor mutations not only result in the complete androgen insensitivity syndrome, but can cause a wid e spectrum of milder insensitivity syndromes including ambiguous genitalia in newborn infants, and 'idiopathic' male infertility in otherwise normal m ales. Characterization of the molecular and structural mechanisms of androg en receptor dysfunction in these cases has led to directed hormonal therapy . Thus the differential response of a Met807Thr mutant androgen receptor to dihydrotestosterone but not testosterone, have been used to restore male g enital development in an infant with partial AIS. Of greater significance, because they affect larger numbers of patients, are the mutations and polym orphisms that result in depressed spermatogenesis and male infertility in p henotypic males, Studies involving Singaporean, Australian, North American and Japanese subjects have established that increases in length of a trinuc leotide repeat (CAG) tract, encoding a polyglutamine stretch in the transac tivation domain of the androgen receptor, are associated with increased ris k of defective spermatogenesis and undermasculinization. Independent of the CAG repeats, missense amino-acid substitutions in the ligand-binding domai n, involving residues 727, 798 and 886 cause infertility through a novel me chanism. Pathogenicity is transmitted, not through defective ligand binding , but through defective protein-protein interactions between receptor domai ns and coactivator proteins that are essential for gene transcription. Eluc idation of the molecular and structural basis of androgen receptor dysfunct ion in these cases allows precise genetic counseling and can lead to the de sign of rational hormonal therapy. Curr Opin Obstet Gynecol 13:315-321. (C) 2001 Lippincott Williams & Wilkins.