Why Boys Will Be Boys: Two Pathways of Fetal Testicular Androgen Biosynthesis Are Needed for Male Sexual Differentiation

In the citing paper

“These data demonstrate that both the canonical and backdoor pathways are essential for normal fetal masculinization.”

In the citing paper

“studies by Flück and colleagues [15] have shown that disordered sex development (DSD) will arise if the pathway is disrupted. In one individual with mutations in aldo-keto reductase type 1C2 (AKR1C2) and in another family with an added mutation in aldo-keto reductase type 1C4 (AKR1C4), there was failure of normal masculinization.”

In the citing paper

“Currently, the accepted model for masculinization is that circulating DHT, formed via the backdoor pathway in the fetal testis [15,16], is important for virilization alongside circulating testosterone.”

In the citing paper

“More recently, however, it has been reported that an alternative pathway to DHT formation exists that does not require testosterone as an intermediate. This alternative, “backdoor” pathway (Fig 1) was first described in the testes of pouch young marsupials [13], and a similar pathway has since been reported in the prepubertal mouse testis [14] and the fetal human testis [15].”

In the citing paper

“Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway.”

In the citing paper

“However, the recent demonstration that the alternative, backdoor pathway to DHT synthesis is also required for normal human fetal male development [15,16] has shown that the process involves a complex interaction between different steroidogenic pathways.”

In the citing paper

“two 46,XY individuals who are known heterozygotes for a mutation in AKR1C2 show divergent phenotypes, with one showing a normal male phenotype and the other DSD [15]”

In the citing paper

“the normal process of masculinization in the human depends on two separate pathways of androgen synthesis, the canonical and backdoor pathways [15]”

In the citing paper

“Recently several inherited mutations in the AKR1C2 and AKR1C4 genes have been identified in two Swiss families which were associated with disordered sexual dysgenesis (DSD).”

In the citing paper

“The mutants Ile79Val, His90Gln, Asn300Thr and His222Gln have been prepared in recombinant forms or over-expressed in COS-1 cells and showed reduced enzymatic activities [103].”

In the citing paper

“The authors observed AKR1C2 and AKR1C4 expression in fetal testes thus they concluded that these enzymes are needed for fetal 5α-DHT synthesis via the backdoor pathway and normal development of the genitalia [103].”

In the citing paper

“In addition to these AKR1C2 mutations these individuals also carried a mutation causing aberrant splicing of the AKR1C4 gene (Val29_Lys84del).”

In the citing paper

“In the first family identified with DSD, missense AKR1C2 muations: Ile79Val, His906Glu, and Asn300Thr were identified in the affected individuals.”

In the citing paper

“So far SNPs in AKR1C1, AKR1C2 and AKR1C4 have been studied at the protein level and Phe46Tyr has been associated with disease [95–97, 99, 103, 104].”

In the citing paper

“In the second family recombination between AKR1C1 and AKR1C3 was detected and a missense AKR1C2 mutation His222Gln was identified.”