Defects of
androgen biosynthesis cause 46,XY disorder of sexual development (DSD). All
steroids are produced from
cholesterol and the early steps of steroidogenesis are common to
mineralocorticoid,
glucocorticoid and sex
steroid production. Genetic mutations in
enzymes and
proteins supporting the early biosynthesis pathways cause
adrenal insufficiency (AI), DSD and gonadal insufficiency. The classic
androgen biosynthesis defects with AI are lipoid CAH,
CYP11A1 and
HSD3B2 deficiencies. Deficiency of CYP17A1 rarely causes AI, and HSD17B3 or SRD5A2 deficiencies only cause
46,XY DSD and gonadal insufficiency. All
androgen biosynthesis depends on
17,20 lyase activity of CYP17A1 which is supported by P450
oxidoreductase (POR) and
cytochrome b5 (CYB5). Therefore
46,XY DSD with apparent
17,20 lyase deficiency may be due to mutations in CYP17A1, POR or CYB5. Illustrated by patients harboring mutations in SRD5A2, normal development of the male external genitalia depends largely on
dihydrotestosterone (DHT) which is converted from circulating testicular
testosterone (T) through SRD5A2 in the genital skin. In the classic
androgen biosynthetic pathway, T is produced from
DHEA and
androstenedione/-diol in the testis. However, recently found mutations in AKR1C2/4 genes in undervirilized 46,XY individuals have established a role for a novel, alternative, backdoor pathway for fetal testicular DHT synthesis. In this pathway, which has been first elucidated for the tammar wallaby pouch young,
17-hydroxyprogesterone is converted directly to DHT by 5α-3α reductive steps without going through the
androgens of the classic pathway.
Enzymes AKR1C2/4 catalyse the critical 3αHSD reductive reaction which feeds 17OH-DHP into the backdoor pathway. In conclusion,
androgen production in the fetal testis seems to utilize two pathways but their exact interplay remains to be elucidated.