A CLINICIAN LOOKS AT ANDROGEN RESISTANCE

Androgen resistance in genetic males occurs when gonadotropins and tes tosterone are normal, but the physiological androgen response in andro gen target organs is absent or decreased. In androgen-dependent target tissues two main defects may be found: 1) defective testosterone meta bolism (5 alpha-reductase type 2 deficiency) and 2) anomalies in andro gen receptors (androgen insensitivity syndrome (AIS)). The clinical ma nifestations of these defects vary from subjects with female external genitalia to subjects with mild forms of impaired masculinization. In particular, in the complete form of AIS (CAIS) the phenotype is femini ne, and in the partial form (PAIS) the external genitalia are ambiguou s with an extremely variable phenotype. The diagnosis requires clinica l, hormonal, genetic, and molecular investigation for appropriate gend er assignation and treatment. In AIS, cloning of androgen receptor cDN A using the polymerase chain reaction, denaturing gradient gel electro phoresis, and nucleotide sequencing have enabled a variety of molecula r defects in the androgen receptor to be identified. The complexity of phenotypic presentation of AIS probably reflects the heterogeneity of androgen receptor gene mutations, but to date a relationship between genotype/phenotype has been difficult to establish, with the same poin t mutation reported to be associated with different phenotypic express ions. Other factors must therefore also contribute to the clinical pre sentation of AIS, although none have yet been identified Establishing the functional consequences of androgen receptor mutations in in vitro systems and correlating them with clinical presentation may ultimatel y provide an explanation for the variable clinical presentation of AIS and perhaps enable prediction of the response to androgen therapy in infants with PAIS.