Male sex steroids (androgens) sculpture the human embryo resulting in development of the male internal and external genitalia. At puberty, a surge of androgens leads to the in- itiation of spermatogenesis and growth of accessory sex organs,

Male sex steroids (androgens) sculpture the human embryo resulting in development of the male internal and external genitalia. At puberty, a surge of androgens leads to the initiation of spermatogenesis and growth of accessory sex organs, including the prostate gland. Sperm production is highly dependent on androgens (Zirkin et al., 1989) and it has long been suspected that suboptimal androgen action is one of the aetiological factors in idiopathic male infertility (Aiman and Griffin, 1982). Since most infertile males have normal amounts of serum androgen (Niechlag et al., 1979), it is possible that defective spermatogenesis could be the result of impaired androgen responsiveness. The cloning of the androgen receptor gene (Lubahn et al., 1988) and elucidation of its signal transduction pathway (Jenster et al., 1991) have provided new methods for investigating the role of androgen receptor mutations in male infertility. All androgens transmit their multifaceted effects through a single receptor: the androgen receptor (AR). The AR, a member of the steroid receptor superfamily, is a nuclear transcription factor that, when activated by androgens, switches on androgen-regulated genes that lead to spermatogenesis and prostate gland development (for review see Quigley et al., 1995). Mutations of the androgen receptor are tolerated because the receptor is not essential for life and, in males, mutations of the X-linked receptor are expressed, providing a natural ‘knockout system’ for studying the phenotypic effects of the gene. The AR gene encodes a receptor protein of apparent molecular mass 110–114 kDa including 910–919 amino acids. The fulllength AR, like other steroid receptors, is a single polypeptide composed of three main functional domains: the transactivation domain, the DNA-binding domain and the ligandbinding domain (Fig. 1). Since the definition of the exon–intron boundaries of the androgen receptor gene, over 300 androgen receptor mutations (Gottlieb et al., 1998) have been reported in the ligand-binding and DNA-binding domains, making it the most naturally mutated transcription factor known. Most mutations are identified because they disrupt receptor function totally, causing complete androgen insensitivity syndrome, wherein a healthy 46XY individual is born with female external genitalia (Lim et al., 1997). Mutations that do not completely disrupt androgen receptor function cause the partial syndrome, in which various degrees of ambiguous genitalia, including partial labioscrotal fusion, hypospadias, bifid scrotum and gynaecomastia, occur (Yong et al., 1998a). Mutations of the ligand-binding and DNAbinding domains that cause complete and partial androgen insensitivity syndromes have been reviewed comprehensively by Quigley et al. (1995) and will not be discussed here. Relatively few mutations have been reported in the transactivation domain because its large size (it comprises half of the receptor) and high GC content make genetic screening difficult. The transactivation domain is essential for receptor function and its deletion leads to a non-functional protein in vitro (Jenster et al., 1991). This domain is of particular interest because of its causative relationship to a fatal neuromuscular disease, spinal bulbar muscular atrophy (Kennedy’s syndrome). This review will focus on the novel hypothesis that Androgen receptor transactivation domain and control of spermatogenesis