Ann Pediatr Endocrinol Metab.  2022 Jun;27(2):83-89. 10.6065/apem.2244124.062.

Classic and backdoor pathways of androgen biosynthesis in human sexual development

• Lee HG
• Kim CJ

• KMID: 2531271
• DOI: http://doi.org/10.6065/apem.2244124.062

Abstract

Both genes and hormones regulate human sexual development. Although ovarian hormones are not essential for female external genitalia development, male sexual development requires the action of testicular testosterone and dihydrotestosterone (DHT). DHT is the most active endogenous androgen formed by the conversion of testosterone in genital skin. This synthesis route from cholesterol to DHT is called the conventional classic pathway. Recent investigations have reported an alternative ("backdoor") route for DHT formation that bypasses fetal testicular testosterone. This alternative route plays a crucial role in human hyperandrogenic disorders like congenital adrenal hyperplasia caused by P450c21 deficiency, polycystic ovary syndrome, and P450 oxidoreductase deficiency. In addition, mutations in AKR1C2 and AKR1C4, genes encoding 3α-reductases, have been implicated in disorders of sexual development, indicating that both the classic and backdoor routes are required for normal human male sexual development. More recently, androsterone was found to be the primary androgen of the human backdoor route. Androsterone and steroidal substrates specific to the backdoor route are predominantly found in the placenta, liver, and adrenal glands rather than in the testes. These findings are essential to understanding human sexual development.

Keyword

Androgen; Testosterone; Sex development; Backdoor pathway

Figure

• 

  Fig. 1. Classic pathway of steroidogenesis. P450scc cleaves the cholesterol side-chain to produce pregnenolone. 3βHSD2 mediates the conversion of Δ5 steroids present in the left-hand column to Δ4 steroids. The 17, 20 lyase activity of P450c17 transforms 17OH-pregnenolone into DHEA in the zona reticularis and testicular Leydig cells; only tiny amounts of 17OH-progesterone are transformed to androstenedione in humans, but this reaction occurs more commonly in other mammals. Testicular 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) transforms DHEA to androstenediol and androstenedione to testosterone; low concentrations of adrenal 17βHSD5 (AKR1C3) in the zona reticularis yield small amounts of testosterone. In ovarian granulosa cells, P450aro (aromatase) transforms androstenedione to estrone and testosterone to estradiol; in estrogenic tissues (breast, ovary, and fat), 17βHSD1 transforms estrone into estradiol. In genital skin, 5α-reductase type 2 further activates testosterone to dihydrotestosterone (DHT). StAR, steroidogenic acute regulatory protein; DOC, deoxycorticosterone; 17OH-Preg, 17OH-pregnenolone; DHEA, dehydroepiandrosterone.

• 

  Fig. 2. Backdoor pathway of androgen biosynthesis. The backdoor route is similar to the classic route presented in Fig. 1, except for the sequential 5α- and 3α-reduction of 17OH-progesterone, first by 5αRed1 to 17OH-dihydroprogesterone, and then 3α-reduction by AKR1C2 or AKR1C4 to produce 17OH-allopregnanolone. P450c17 can catalyze 17, 20 lyase activity using 17OH-allopregnanolone as the substrate; this reaction produces androsterone, which can be catalyzed by testicular 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) or adrenal 17βHSD5 (AKR1C3) to produce androstanediol. Androstanediol may then undergo 3α-oxidization, probably mediated by 17βHSD6 (also called retinol dehydrogenase, RoDH), to produce the most active androgen, DHT. StAR, steroidogenic acute regulatory protein; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; AKR, aldo-ketoreductase.

Reference

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