The backdoor pathway to dihydrotestosterone

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Dihydrotestosterone (DHT) is the androgen responsible for formation of the male external genitalia during embryogenesis and for most androgen-mediated events at male puberty. In most circumstances, testosterone (T) derived from the testis is converted to DHT by 5α-reductase type 2 in genital skin and prostate. By contrast, the testes of pouch young of the tammar wallaby and immature postnatal testes of several species synthesize 5α-androstane-3α,17β-diol, which is the proximal precursor of DHT in androgen-target tissues. Human steroidogenic enzymes efficiently catalyze all the required steps in a route to DHT that does not involve the T intermediate, called the ‘backdoor pathway’. This alternative pathway of DHT production appears to explain how potent androgens are produced in some normal and pathological conditions when the conventional androgen-biosynthetic pathways fail to account completely for the of patterns androgen synthesis that are observed.

Section snippets

The pathway to androstanediol in testes of tammar wallaby pouch young

Androstanediol can be synthesized in testis from T [2], but experiments with immature rat testis indicated another pathway for androstanediol synthesis that did not involve the conventional intermediates AD and T [6]. To characterize this pathway, pouch young testes have been incubated with [3H]progesterone and the metabolites identified by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) (Figure 1, Box 1). Progesterone is metabolized rapidly to

Androstanediol synthesis in immature mouse testis

Although T is the principal 19-carbon product of adult mouse and rat testes, androstanediol is the principal 19-carbon product of immature mouse testes [4] and adult rodent testes under gonadotropin suppression. However, it was not known whether androstanediol derives from the 3α-reduction of DHT in the testis or by an alternate pathway; neither was it known whether androstanediol is synthesized in the fetal mouse testes. Although Pdiol had been identified as a progesterone metabolite in

In vitro studies of human enzymes with 5α-reduced substrates

Using human recombinant CYP17 expressed in yeast microsomes [8], the 5α-reduced 21-carbon steroids 5α-pregnan-3,20-dione and 5α-prenan-3α-ol-20-one have been shown to be excellent substrates for the 17α-hydroxylase activity of human CYP17 [13]. Furthermore, Pdiol is an better substrate for the 17,20-lyase activity of human CYP17 than 17α-hydroxypregnenolone, with a comparable Km and 10-fold higher Vmax. In addition, the conversion of Pdiol to androsterone is stimulated only three-fold by

Factors that govern relative flux through the conventional and backdoor pathways

By comparing the results of studies using mouse and tammar wallaby testes, some general principles emerge that explain the variations in flux through the various pathways to androstanediol and DHT. The relative abundance of CYP17 compared with 5α-reductase (presumably always type 1) and the efficiency with which CYP17 from different species catalyzes the 17,20-lyase reaction with Δ4 steroids appear to be the two key factors that regulate the partitioning of steroid flux to 19-carbon steroids

Conclusions

The 5α-reduction of T is not the only biosynthetic pathway to DHT. DHT can be formed efficiently from the 5α-reduced 21-carbon precursor Pdiol via the pathway(s) progesterone→→→Pdiol→androsterone→androstanediol→DHT, which is the principal route to DHT in the testis of the tammar wallaby pouch young during sexual differentiation. The relevant human steroidogenic enzymes perform all the chemical transformations contained in this route to DHT.

The backdoor pathway might provide the basis for some

Acknowledgements

I am indebted to my colleagues in Dallas and Australia, particularly Jean Wilson, who participated in the studies referenced in this review that led to the elucidation of this pathway. Their helpful discussions and insightful comments have been essential in developing our thoughts about this topic. This work was supported by NIH grant R21DK56642 and grant I-1493 from the Robert A. Welch Foundation.

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