The "backdoor pathway" of androgen synthesis in human male sexual development

Abstract

Mammalian sex determination (male versus female) is largely controlled by genes, whereas sex differentiation (development of reproductive structures) is largely controlled by hormones. Work in the 20th century indicated that female external anatomy was a "default" pathway of development not requiring steroids, whereas male genital development required testicular testosterone plus dihydrotestosterone (DHT) made in genital skin according to a "classic" pathway. Recent work added the description of an alternative "backdoor" pathway of androgen synthesis discovered in marsupials. Unique "backdoor steroids" are found in human hyperandrogenic disorders, and genetic disruption of the pathway causes disordered male sexual development, suggesting it plays an essential role. O'Shaughnessy and colleagues now show that the principal human backdoor androgen is androsterone and provide strong evidence that it derives from placental progesterone that is metabolized to androsterone in nontesticular tissues. These studies are essential to understanding human sexual development and its disorders.

Fig 1. The “conventional” pathway of steroidogenesis.

The figure combines adrenal and gonadal pathways. The left-hand column shows the ∆5 pathway, in which steroids retain the double bond between carbons 5 and 6 in cholesterol’s B-ring. The StAR protein facilitates import of cholesterol into mitochondrial, in which P450scc (CYP11A1) cleaves off the side-chain to yield Preg, the first C21 steroid. ∆5 steroids are converted to corresponding ∆4 steroids by 3βHSD2 (HSD3B2) in the adrenal and gonad or by 3βHSD1 in placenta and peripheral tissues. In the absence of P450c17 (in the adrenal zona glomerulosa), progesterone is 21-hydroxylated by P450c21 (CYP21A2). P450c11AS (Aldo synthase, CYP11B2) then catalyzes 11-hydroxylase, 18-hydroxylase, and 18-methyl oxidase activities to yield Aldo. In the gonads and adrenal zona fasciculata, the 17α-hydroxylase activity of P450c17 (CYP17A1) permits synthesis of 17OHP, which is 11-hydroxylated to cortisol by P450c11β (CYP11B1). The 17,20 lyase activity of P450c17 requires allosteric action of cytochrome b5 (b5) in the adrenal zona reticularis and testicular Leydig cells, permitting conversion of C21 to C19 steroids. Human P450c17 converts 17OHP to androstenedione with only approximately 2–3% of its activity to convert 17OH-Preg to DHEA so that testosterone synthesis proceeds via DHEA and not via 17OHP; by contrast, rodent and ungulate P450c17 catalyzes this reaction efficiently. Testicular 17βHSD3 converts DHEA to androstenediol and androstenedione to testosterone; low levels of adrenal 17βHSD5 (AKR1C3) permit synthesis of small amounts of testosterone. In the ovary and elsewhere, P450aro (aromatase, CYP19A1) converts C19 androgens to C18 estrogens. In genital skin, 5α-reductase type 2 (5αRed2, SRD5A2) further activates testosterone to DHT. 17OHP, 17OH-progesterone; Aldo, aldosterone; C21, 21-carbon; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; Preg, pregnenolone; StAR, steroidogenic acute regulatory protein.

Fig 2. The “backdoor” pathway of androgen synthesis.

Steroids in the left-hand column (the Δ5 pathway) may be acted on by either 3βHSD1 or 3βHSD2 to yield the corresponding Δ4 steroids. Following the production of Preg, the backdoor pathway typically features its conversion to 17OH-Preg, which is then converted to the key intermediary, 17OHP. In the brain (and elsewhere), progesterone may be converted to the neuroactive steroid, allopregnanolone. 17OHP is 5α-reduced by 5αRed1 (SRD5A1) to 5α-pregnan-17α-ol-3,20-dione, which is then 3α-reduced by AKR1C2 or AKR1C4 to yield 17OH-allopregnanolone. P450c17 catalyzes its 17,20 lyase activity very efficiently when 17OH-allopregnanolone is the substrate, yielding androsterone, which O’Shaughnessy and colleageus show is the principal androgen in human male fetal circulation. Androsterone may then acted on by testicular 17βHSD3 (or, to a minor degree, by adrenal 17βHSD5 [AKR1C3]) to yield androstanediol, which may be 3α-oxidized, probably by 17βHSD6 (HSD17B6; also known as RoDH, to yield the most potent androgen, DHT. The work of O’Shaughnessy and colleagues shows that the human fetal testis instead uses progesterone produced by the placenta to generate the 17OHP that initiates the backdoor pathway. The identities of all of the enzymes catalyzing the reductive and oxidative 3αHSD reactions have not been determined unambiguously. 17OHP, 17OH-progesterone; DHT, dihydrotestosterone; Preg, pregnenolone; RoDH, retinol dehydrogenase.