Upon binding, the DHT-AR complex translocates from cytoplasm to the nucleus and activates the androgen receptor-regulated genes involved in processes that include male sexual differentiation.Some mutations in 5αR2 impair the synthesis of DHT resulting in 5αR2D. In the male fetus, T mediates Wolffian ductal differentiation while DHT mediates external genital and prostate differentiation. The fact that women with the same 5αR2 mutations as affected male siblings have normal female phenotypes and normal reproductive function supports the notion that 5αR2 does not play an important role in female biology. Most aspects of virilization in male puberty are driven by testosterone, which is why most affected males undergo virilization at that time.Though 5αR2D only affects a small number of people, study of this disorder revealed fundamental aspects of 5α-reductases (including cloning of the underlying genes), androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior. Genetics
Two of three isozymes of 5αR can catalyze the transformation of T to DHT, but it is only 5αR2D that causes 46XY, DSD. 5αR2 is encoded by the gene SRD5A2 which is located on the short arm of chromosome 2 and contains five exons and four introns. 5αR2 consists of 254 amino acid residues with reported mutations at 67 of them with multiple different mutations at some residues.The first known mutation SRD5A2 was almost a complete deletion which was discovered from analysis of affected males in Papua New Guinean tribe.
With the determination of an XY karyotype and normal SRY, the differential diagnosis of 46,XY DSD is made with endocrinological measurements of T/DHT ratios (which indicate 5αR2 activity) and precise anatomical imaging since 5αR2D can be difficult to distinguish from other causes of 46,XY DSD (e.g., partial androgen insensitivity syndrome and 17β- hydroxysteroid dehydrogenase type 3 enzyme deficiencies).The measurement of the serum DHT concentration is challenging since the concentrations are low and DHT has a high level of cross-reactivity. A high level of assay specificity is required to measure concentrations of DHT since serum T levels are generally 10 fold higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret since the normal ratio level varies according to age and severity of 5αR2 activity impairment. Affected young males of at least pubertal age with normal serum T levels demonstrate elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with human chorionic gonadotropin (hCG) (alternatively, testosterone enanthate) is required in prepubertal children (with stimulation and samples taken over several days) to increase serum testosterone levels for measurement. Interpreting T/DHT ratios in male newborns is especially challenging due to neonatal testosterone surge and higher than normal 5a-reductase type 1 activity. SRD5A2 gene analysis is recommended for diagnosis in newborns. Broadly, 5αR2D is diagnosed with T/DHT ratios greater than 18 while ratios greater than 30 have been observed in severely affected individuals.