Molecular basis of androgen insensitivity

Androgens are important steroid hormones fur expression of the male phenoty pe. They have characteristic roles during male sexual differentiation, duri ng development and maintenance of secondary male characteristics, and durin g the initiation and maintenance of spermatogenesis. The two most important androgens in this respect are testosterone and 5 alpha -dihydrotestosteron e. Each androgen has its own specific role during male sexual differentiati on. testosterone is involved in the: development and differentiation of Wol ffian duct derived structures, whereas 5 alpha -dihydrotestosterone, a meta bolite of testosterone, is the active ligand in the urogenital sinus and tu bercle and their derived structures. The actions of androgens are mediated by the androgen receptor. This ligand dependent transcription factor belong s to the superfamily of nuclear receptors, including those for the other st eroid hormones. The androgen receptor gene is located on the X-chromosome a t Xq11-12 and codes for a protein with a molecular mass of approximately 11 0 kDa. Only one androgen receptor cDNA has been identified sofar, despite t wo different ligands. It is generally accepted that defects in the androgen receptor gene prevent the normal development of both internal and external male structures in 46, XY individuals. The end-organ resistance to androge ns has been designated as androgen insensitivity syndrome (AIS) and is dist inct from other forms of male pseudohermaphroditism like 17 beta -hydroxy-s teroid dehydrogenase type 3 deficiency, leydig cell hypoplasia due to inact ivating LH receptor mutations or Sx-reductase type 2 deficiency. Furthermor e. two additional pathological situations are associated with abnormal andr ogen receptor structure and Function - spinal and bulbar muscular atrophy ( SBMA, or Kennedy's disease) and prostate cancer. In the AR gene. four diffe rent types of mutations have been detected in DNA from individuals with AIS - (i) single point mutations resulting in amino acid substitutions or prem ature stopcodons; (ii) nucleotide insertions or deletions most often leadin g to a frame shift and premature termination: (iii) complete or partial gen e deletions, and (iv) intronic mutations in either splice donor or acceptor sites, which affect the splicing of AR RNA. The main phenotypic characteri stics of individuals with the complete androgen insensitivity syndrome (CAI S) are, Female external genitalia. a short. blind ending vagina, the absenc e of Wolffian duct derived structures, the absence of a prostate, developme nt of gynecomastia and the absence of pubic and axillary hair. Usually test osterone levels are elevated at the time of puberty, while also elevated LH levels are found. In the partial androgen insensitivity syndrome (PAIS) se veral different phenotypes are evident, ranging from individuals with predo minantly a Female appearance to persons with ambiguous genitalia, or indivi duals with a predominantly male phenotype. At puberty. elevated LH, testost erone: and estradiol levels are observed. individuals with mild symptoms of undervirilization (mild androgen insensitivity syndrome (MAIS)) and infert ility have been described as well. Phenotypic variation between individuals in different families has been described for several mutations. However, i n eases of CAIS no phenotypic variation has been described within one singl e family, in contrast to families with individuals with PAIS. In general AI S, can be routinely analyzed and more than 150 different mutations have bee n reported now. Differential diagnosis of AIS is possible with syndromes pr esenting with almost similar phenotypes but with a completely different mol ecular cause. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.