Androgen backdoor pathway

The androgen backdoor pathway is a collective name for all metabolic pathways where clinically relevant androgens are synthesized from 21-carbon steroids (pregnanes) by their 5α-reduction with a roundabout of testosterone and/or androstenedione.[1]

A backdoor pathway is an alternative to the conventional,[2] canonical[3] androgenic pathway that involves testosterone and/or androstenedione. In the canonical pathway, 5α-dihydrotestosterone is synthesized directly from testosterone through the action of the enzyme 5α-reductase in tissues where 5α-reductase enzymes are highly expressed, such as the prostate gland, hair follicles, and skin. In both pathways (canonical and backdoor), the enzyme 5α-reductase plays a crucial role. However, in the androgen backdoor pathway, 5α-reductase acts on the 21-carbon steroids (pregnanes), leading to the reduction of the 4,5-double bond in these 21-carbon steroids starting a long chain of transformations to 5α-dihydrotestosterone, whereas in a canonical pathway 5α-reductase acts on the 4,5-double bond in testosterone to produce 5α-dihydrotestosterone directly.

Initially described as pathway where 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone,[4] several other pathways have been since then discovered that lead to 11-oxygenated androgens which are also clinically relevant androgens.[5]

Introduction

The androgen backdoor pathways are critical metabolic processes involved in the synthesis of clinically relevant androgens from 21-carbon steroids (pregnanes) through their 5α-reduction (a 21-carbon steroid is a steroid that has 21 carbon atoms in its molecule). These pathways occur without the involvement of testosterone (T) and/or androstenedione (A4), which are part of the conventional, canonical androgenic pathway.[6][7]

In the early 2000s, the 5α-reduction of 17α-hydroxyprogesterone was described in medical literature as the start of the backdoor pathway. An example of such literature is the article "The backdoor pathway to dihydrotestosterone" by Richard Auchus, published in 2004 in Trends in Endocrinology and Metabolism.[4] In that literature, 5α-reduction of 17α-hydroxyprogesterone was described as a pathway that ultimately leads to the production of 5α-dihydrotestosterone. However, over the following two decades, several other distinct pathways have been discovered that lead to the synthesis of 11-oxygenated androgens, which are potent agonists of the androgen receptors.

The androgen response mechanism involves androgens binding to androgen receptors in the cytoplasm, which then move into the nucleus and control gene transcription by interacting with specific DNA regions called androgen responsive elements.[8] This response mechanism plays a crucial role in male sexual differentiation and puberty, as well as other tissue types and processes, such as the prostate gland (regulate secretory functions), hair follicles (androgens influence hair growth patterns), skin (androgens regulate sebum production and the thickening and maturation of the skin), and muscle (contribute to the development and maintenance of muscle mass and strength).[9][10]

Importance

The discovery of the backdoor pathway to 5α-dihydrotestosterone in the tammar wallaby in the early 2000s[11] opened new avenues for understanding the biosynthesis of androgens in humans, by suggesting the possibility of alternative pathways for androgen synthesis in humans in addition to conventional pathways. This finding observed in tammar wallaby prompted research into identifying and characterizing similar pathways in humans, leading to a better understanding of the regulation, metabolism, and therapeutic targeting of androgen biosynthesis in human health and diseases related to excessive or insufficient androgen biosynthesis when the classical androgen pathway could not fully explain the observed conditions in patients. Subsequently, other backdoor pathways leading to potent 11-oxygenated androgens have also been characterized,[12] providing further insight into the synthesis of androgens in vivo. Understanding these pathways is critical for the development of effective treatments for conditions related to androgen biosynthesis.[1]

Biochemistry

Dihydrotestosterone backdoor biosynthesis
The androgen backdoor pathway (red arrows) roundabout testosterone embedded in within conventional androgen synthesis that lead to 5α-dihydrotestosterone through testosterone.[1][3][12]

The primary feature of the androgen backdoor pathway is that 17α-hydroxyprogesterone (17-OHP) can be 5α-reduced and finally converted to 5α-dihydrotestosterone (DHT) via an alternative route that bypasses the conventional[2] intermediates androstenedione and testosterone.[4][13]

This route is activated during normal prenatal development and leads to early male sexual differentiation.[14][15][16] 5α-dihydrotestosterone synthesized by this route plays a critical role in the development of male sexual characteristics, including the differentiation and maturation of the male external genitalia, the prostate gland, and other male reproductive structures. By bypassing the conventional intermediates (androstenedione and testosterone), this pathway ensures the timely and appropriate development of male sexual traits in early embryonic and fetal stages. Both canonical and backdoor pathways are essential in normal male embryonic development.[17][14][18] A disruption in the backdoor pathway can lead to incomplete or altered male sexual differentiation. This may result in abnormalities or underdevelopment of the male external genitalia, prostate gland, and other male reproductive structures. The specific consequences can vary depending on the nature and extent of the disruption and may lead to conditions such as ambiguous genitalia or disorders of sexual development (DSD), where the individual's physical, sexual characteristics do not align clearly with typical male, i.e., undervirilization of male infants.[17]

This pathway was first described in the marsupials and later confirmed in humans.[19] Both the canonical and backdoor pathways of DHT biosynthesis are required for normal human male genital development, thus defects in the backdoor pathway from 17-OHP or progesterone (P4) to DHT lead to undervirilization in male fetuses because placental P4 is the precursor of DHT via the backdoor pathway.[1]

In 21-hydroxylase deficiency[13] or cytochrome P450 oxidoreductase deficiency,[20] this route may be activated regardless of age and sex by even a mild increase in circulating 17-OHP levels.[21]

While 5α-reduction is the last transformation in the classical androgen pathway, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[1]

17α-Hydroxyprogesterone pathway

The first step of this pathway is the 5α-reduction of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (referred to as 17OHDHP or 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.[22][20] 17OHDHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)[3][19] or HSD17B6, that also has 3α-reduction activity.[23][24] 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one, also known as androsterone (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a 21-C carbon steroid (a pregnane) to C19 steroid (an androstane or androgen). AST is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by HSD17B3 or AKR1C3.[25] The final step is 3α-oxidation of 3α-diol in target tissues to DHT by an enzyme that has 3α-hydroxysteroid oxidase activity, such as AKR1C2,[26] HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9.[20] This oxidation is not required in the classical androgen pathway.[1] The pathway can be summarized as: 17-OHP → 17OHDHP → 5α-Pdiol → AST → 3α-diol → DHT.[1]

Progesterone pathway

The pathway from progesterone (P4) to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. Placental P4 in the male fetus is the feedstock, that is, a starting point, the initial substrate, for the backdoor pathway found operating in multiple non-gonadal tissues.[3] The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to allopregnanolone (AlloP5) via 3α-reduction by AKR1C2 or AKR1C4. AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. The pathway then proceeds the same way as the pathway that starts from 17-OHP, and can be summarized as: P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT.[1]

11-Oxygenated androgen backdoor biosynthesis
Abbreviated routes to 11-oxygenated androgens with transformations (black arrow). The two groups of steroids are distinguished by the C17 substituent configuration associated with four distinct precursors. The first group is the conversion of progesterone. The second group is the conversion of 17-hydroxyprogesterone. CYP17A1 catalyzes the 21-carbon steroids (pregnanes) to 19-carbon steroids (androstanes). Some transformations which are presumed to exist but not yet shown to exist are depicted with dotted arrows. Some CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ5 compounds that are transformed to Δ4 compounds are also omitted for clarity.

There are two known 11-oxygenated androgens, 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT), which both bind and activate the androgen receptor with affinities, potencies, and efficacies that are similar to that of testosterone (T) and DHT, respectively.[1]

As for 11β-hydroxytestosterone (11OHT) and 11β-hydroxydihydrotestosterone (11OHDHT), the androgenicity of these steroids is a point of research. Although some studies[27][28][29] suggest that though 11β-hydroxytestosterone (11OHT) and 11β-hydroxydihydrotestosterone (11OHDHT) may not have significant androgenic activity as they were once thought to possess, they may still be important precursors to androgenic molecules.[1] The relative importance of the androgens depends on their activity, circulating levels and stability. The steroids 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4) have been established as having minimal androgen activity,[30][1][31] but remain important molecules in this context since they act as androgen precursors.

The backdoor pathways to 11-oxygenated androgens can be broadly as two Δ4 steroid entry points (17-OHP and P4) that can undergo a common sequence of three transformations:

  1. 11β-hydroxylation by CYP11B1 in the adrenal cortex,
  2. 5α-reduction by SRD5A1/SRD5A1,
  3. reversible 3α-reduction/oxidation of the ketone/alcohol by AKR1C2 or AKR1C4.

Clinical significance

In congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase[13] or cytochrome P450 oxidoreductase (POR),[20][17] the associated elevated 17-OHP levels result in flux through the backdoor pathway to DHT that begins with 5α-reduction of 17-OHP . This pathway may be activated regardless of age and sex.[32] Fetal excess of 17-OHP in CAH may contribute to DHT synthesis that leads to external genital virilization in newborn girls with CAH.[20] P4 levels may also be elevated in CAH,[33][34] leading to androgen excess via the backdoor pathway from P4 to DHT.[35] 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.[36]

Serum levels of the 21-carbon 11-oxygenated steroids: 21-deoxycorticosterone (11OHP4) and 21-deoxycortisol (21dF), have been known to be elevated in both non-classical and classical forms of CAH since about 1990,[37][38] and liquid chromatography–mass spectrometry profiles that include these steroids have been proposed for clinical applications.[39] Classical CAH patients receiving glucocorticoid therapy had C19 11-oxygenated steroid serum levels that were elevated 3-4 fold compared to healthy controls.[40] In that same study, the levels of C19 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition. In adult women with CAH, the ratio of DHT produced in a backdoor pathway to that produced in a conventional pathway increases as control of androgen excess by glucocorticoid therapy deteriorates.[41] In CAH patients with poor disease control, 11-oxygenated androgens remain elevated for longer than 17-OHP, thus serving as a better biomarker for the effectiveness of the disease control.[42][43] In males with CAH, 11-oxygenated androgen levels may indicate the presence testicular adrenal rest tumors.[43][44]

Both the classical and backdoor androgen pathway to DHT are required for normal human male genital development.[17][14] Deficiencies in the backdoor pathway to DHT from 17-OHP or from P4[19][22] lead to underverilization of the male fetus,[45][46] as placental P4 is a precursor to DHT in the backdoor pathway.[3]

A case study[19] of five 46,XY (male) patients from two families demonstrated that atypical genital appearance were attributed to mutations in AKR1C2 and/or AKR1C4, which operate exclusively in the backdoor pathway to DHT. Mutations in the AKR1C3 and genes involved in the classical androgen pathway were excluded as the causes for the atypical appearance. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway, the study found that mutations in AKR1C2 only were sufficient for disruption.[19] However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.[47] This case study highlights the role of AKR1C2/4 in the alternative androgen pathways.

Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b5, and POR may also disrupt the backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both classical and backdoor androgen pathways.[45] This rare deficiency can lead to DSD in both sexes, with affected girls being asymptomatic until puberty, when they show amenorrhea.[47]

11-oxygenated androgens may play important roles in DSDs.[48][49][20] 11-oxygenated androgen fetal biosynthesis may coincide with the key stages of production of cortisol — at weeks 8–9, 13–24, and from 31 and onwards. In these stages, impaired CYP17A1 and CYP21A2 activity lead to increased ACTH due to cortisol deficiency and the accumulation of substrates for CYP11B1 in pathways to 11-oxygenated androgens and could cause abnormal female fetal development.[48][50]

History

In 1987, Eckstein et al.[51] demonstrated that 5α-androstane-3α,17β-diol (3α-diol) is preferentially produced from 17α-hydroxyprogesterone (17-OHP). The function of 3α-diol was not known at that time.

In 2000, Shaw et al.[15] demonstrated that circulating 3α-diol mediates prostate development in tammar wallaby pouch young via conversion to DHT in target tissues. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development which suggested that another androgenization mechanism was responsible. While 3α-diol's androgen receptor binding affinity is five orders of magnitude lower than DHT (generally described as AR inactive), it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.[52]

In 2003, Wilson et al.[11] demonstrated that 5α-reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate.

In 2004, Mahendroo et al.[16] demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby.

The term "backdoor pathway" was coined by Auchus in 2004[4] and defined as a route to DHT that: (1) bypasses conventional intermediates androstenedione (A4) and T; (2) involves 5α-reduction of 21-carbon pregnanes to 19-carbon androstanes; and (3) involves the 3α-oxidation of 3α-diol to DHT. The backdoor pathway explained how androgens are produced under certain normal and pathological conditions in humans when the classical androgen pathway cannot fully explain the observed consequences.

The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al.[13] attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (encoded by the gene CYP21A2) enzyme deficiency.

Barnard et al.[12] in 2017 demonstrated metabolic pathways from C21 steroids to 11KDHT that bypasses A4 and T, an aspect that is similar to that of the backdoor pathway to DHT. These newly discovered pathways to 11-oxygenated androgens were also described as "backdoor" pathways due to this similarity, and were further characterized in subsequent studies.[53][36]

Note

This article was submitted to WikiJournal of Medicine for external academic peer review in 2022 (reviewer reports). The updated content was reintegrated into the Wikipedia page under a CC-BY-SA-3.0 license (2023). The version of record as reviewed is: Maxim Masiutin; Maneesh Yadav; et al. (3 April 2023). "Alternative androgen pathways" (PDF). WikiJournal of Medicine. 10 (1): 3. doi:10.15347/WJM/2023.003. ISSN 2002-4436. Wikidata Q100737840.

See also

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