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Authors: Maxim G Masiutin[i]ORCID iD.svg , Maneesh K Yadav ORCID iD.svg 

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Abstract

The term "backdoor pathway" has been used to describe different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially used to describe the metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes to 11-oxygenated androgens have been discovered, which are also described as backdoor pathways. This review aims to highlight ambiguities and inconsistencies in the literature on androgen steroidogenic pathways towards resolving a clear, comprehensive definition that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge on androgen backdoor pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients.


Introduction[edit | edit source]

The canonical view of androgen steroidogenesis consists of the union of adrenal and gonadal pathways that ultimately transform cholesterol to testosterone to the potent androgen 5α-dihydrotestosterone. In 2003, a metabolic route from an intermediate in the canonical pathway, 17α-hydroxyprogesterone, to 5α-dihydrotestosterone that did not proceed through testosterone was discovered in the tammar wallaby.[1] Shortly after this study, it was recognized that human enzymes are capable of catalyzing this backdoor pathway[2] and the potential clinical relevance in conditions involving androgen synthesis was proposed. Since then, androgen steroidogenic backdoor pathway[3] pathways to potent 11-oxygenated androgens[4] have been discovered and proposed as clinically relevant. Thus there are at least two distinct androgen steroidogenic backdoor pathways which can confuse the search for clinical information. In addition to multiple pathways, various authors used different names for the same metabolic intermediates, further confusing matters. While naming inconsistencies are notoriously common when it comes to biomolecules,[5] establishing consensus names would facilitate accessibility to information. At the time of writing, the authors of the present review have submitted[6] these pathways to MetaCyc, a public database of metabolic pathways.[7]

This review intends to provides a unifying definition of "androgen backdoor pathway" that encompasses recently discovered androgen steroidogenesis pathways and jointly describes their relevance in the clinical context.

Androgen backdoor pathways are now known to be responsible for the generation of bioactive androgens in humans and evidence is accumulating that they play roles in conditions such as hyperandrogenism. Understanding androgen steroidogenesis from the a comprehensive understanding of backdoor pathways can be crucial to the diagnosis of the patient.

Definition[edit | edit source]

The central feature that distinguishes the canonical[8][9][10] androgen steroidogenesis pathway from backdoor pathways is the involvement of testosterone (Figure 1). In the canonical pathway, 5α-dihydrotestosterone (DHT) is synthesized directly from testosterone by 5α-reduction. Therefore, this review proposes that any androgen steroidogenesis pathway that does not proceed through testosterone, but produces potent androgens, is an androgen backdoor pathway. This definition subsumes both the generation of DHT from 17α-hydroxyprogesterone (17-OHP) with roundabout of testosterone, and the generation of 11-oxygenated androgen products from the C11-oxy C21 pathway that are not derived from testosterone and have potency comparable to that of DHT.

Although some metabolic intermediates can be technically considered as androgens, not all androgens are necessarily potent or clinically relevant agonists of the androgen receptors.

The routes to 5α-dihydrotestosterone[edit | edit source]

The androgen backdoor pathway from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone (red arrows) roundabout testosterone embedded within conventional androgen synthesis (black arrows) leading to 5α-dihydrotestosterone through testosterone.[9][11]

In canonical androgen steroidogenesis, a 5α-reductase enzyme catalyzes the direct chemical reaction from testosterone to 5α-dihydrotestosterone (DHT). However, in a backdoor pathway, this enzyme first 5α-reduces the steroids e 17α-hydroxyprogesterone, progesterone or androstenedione (A4), that are ultimately converted to DHT. Some enzymes take part are common across reactions but in all backdoor pathways to DHT, the 5α-reduction of a steroid is a first step rather than the last as in the canonical androgen steroidogenesis.

5α-reduction of 17α-hydroxyprogesterone[edit | edit source]

The steroids involved in the metabolic route from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.

The first metabolic route that falls under the definition of an androgen backdoor pathway can be described as 5α-reduction of 17α-hydroxyprogesterone (17-OHP) that is finally converted to 5α-dihydrotestosterone (DHT) within a set of enzymatic transformations that bypass the conventional[8] intermediates A4 and testosterone.[2][12]

In mammals, this route is activated during normal prenatal development and leads to early male sexual differentiation.[9][13][14][15] It was first described in the marsupials and later confirmed in humans.[16] This route is essential for the the development of the penis.[9]

In congenital adrenal hyperplasia due to cytochrome P450c21 (21-hydroxylase) deficiency including late-onset non-classical forms,[17] or cytochrome P450 oxidoreductase deficiency,[18] this route may be activated regardless of age and sex by even a mild increase in circulating 17-OHP levels.[19][17] Cytochrome P450c21 is encoded by CYP21A2 gene in humans.

Compared with the Δ5 reaction (from 17α-hydroxypregnenolone to dehydroepiandrosterone (DHEA)), the catalytic efficiency of human cytochrome P450c17 (17,20-lyase, CYP17A1) for the Δ4 reaction (from 17-OHP to A4) is about 100 times lower. 17-OHP is a primary substrate for P450c21, not for P450c17, which explains the accumulation of 17-OHP in 21-hydroxylase deficiency.[19]

The first step of this route is conversion of 17-OHP by 5α-reductase isozymes, the 3-oxo-5α-steroid 4-dehydrogenase type 1 (5αRed1) and type 2 (5αRed2), encoded in humans by SRD5A1 and SRD5A2 genes, respectively. The conversion is done by 5α-reduction of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (Figure 2), also known as 17α-hydroxy-dihydroprogesterone (17-OH-DHP).[20][18][12][13] 17-OHP is a better substrate for 5α-reductase than for 17,20-lyase,[21] which explains that elevated 17-OHP is converted in higher quantities to to 17-OH-DHP via the backdoor pathway than to A4 via the conventional Δ4 pathway.

17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)[20][9][13][16] or 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6), encoded by the HSD17B6 gene in humans, that also has the 3α-reduction activity.[22] 5α-pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone.

5α-pdiol is then converted to 5α-androstan-3α-ol-17-one (androsterone) by 17,20-lyase activity of cytochrome P450c17 (CYP17A1) which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C21 steroid (a pregnane) to C19 steroid (androgen).[12][9][23][20]

Androsterone, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. The type 3 (17βHSD3) is encoded by the HSD17B3 gene in humans. The type 5 (17βHSD5), sometimes also abbreviated as HSD17B5, is actually a aldo-keto reductase family 1 member C3, encoded by the AKR1C3 gene in humans.[10]

The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (RL-HSD (HSD17B6), HSD17B10, RODH4, RDH5, and DHRS9).[2][10][18][23] It is a reverse oxidative step not required in the canonical pathway.

Therefore, the pathway can be outlined as 17α-hydroxyprogesterone (17-OHP) → 5α-pregnan-17α-ol-3,20-dione (17‐OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) → 5α-androstan-3α-ol-17-one (androsterone) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT).[24]

5α-reduction of progesterone[edit | edit source]

This pathway is similar to one above, but the initial substrate for 5α-reductase is progesterone rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and have been confirmed first in mice[15] and later in humans[9], as well as in abnormally upregulated 5αRed1, such as in polycystic ovarian syndrome[25] or in prostate cancer[10].

In male fetuses, placental progesterone acts as a substrate to synthesize backdoor androgens, which occur in multiple tissues. Enzymes related to the backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the backdoor steroids are also primarily present in non-gonadal tissues.[9] If this pathway is disrupted, it will lead to disordered sex development, i.e., the failure of normal masculinization.[16]

The first step in this pathway is 5α-reduction of progesterone towards 5α-dihydroprogesterone (5α-DHP) by 5αRed1. 5α-DHP is then converted to 5α-pregnane-3α-ol-20-one (allopregnanolone) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). Allopregnanolone is then converted to 5α-pdiol by the 17α-hydroxylase activity of cytochrome P450c17. Then this metabolic route proceeds to DHT the same way as the pathway that started with 17-OHP.[9]

Therefore, the pathway can be outlined as: progesterone → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnane-3α-ol-20-one (allopregnanolone) → 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) → 5α-androstan-3α-ol-17-one (androsterone) → 5α-androstane-3α,17β-diol (3α-diol).

5α-reduction of androstenedione[edit | edit source]

In prostate cancer, 5αRed1 reduces androstenedione (A4) to 5α-androstane-3,17-dione (5α-dione), which can be converted directly to DHT by 17βHSD3 / 17βHSD5 or in a longer route via androsterone and 3α-diol. In this longer route, AKR1C2 converts 5α-dione to 3α-diol, which is then converted to DHT in a similar way as in the pathway that starts from 17-OHP. So, the backdoor pathways that starts from A4 can be outlined as following:[26][10]

  • androstenedione (A4) → 5α-androstane-3,17-dione (5α-dione) → 5α-dihydrotestosterone (DHT);
  • androstenedione (A4) → 5α-androstane-3,17-dione (5α-dione) → 5α-androstan-3α-ol-17-one (androsterone) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT).

The routes to 11-oxygenated androgens[edit | edit source]

The other routes that fall under the definition of the androgen backdoor pathway lead to production of 11-oxygenated (oxygen atom on C11 position forms a ketone group) 19-carbon steroids, also termed 11-oxyandrogens: 11-ketotestosterone and 11-ketodihydrotestosterone, which are 11-keto forms of testosterone and DHT, respectively. The synthesis of 11-oxyandrogens in this pathway does not require testosterone or DHT as intermediate products. 11-oxyandrogens are potent and clinically relevant agonists of the androgen receptors.[27] Potency of 11-ketotestosterone is similar to that of testosterone.[28] In addition, 11-ketotestosterone can also act at the hypothalamic and pituitary levels, causing feedback inhibition similar to testosterone.[17] 11-ketotestosterone may serve as the main androgen for healthy women.[29]

11-oxygenated androgens may be produced in physiologic quantities in healthy mammalian organisms,[29] and in excessive quantities in the pathological conditions like congenital adrenal hyperplasia due to 21-hydroxylase deficiency[4][30] polycystic ovary syndrome,[3] benign prostatic hyperplasia[31] in prostate cancer[10] and disorders of sex development in neonates and in children.[32]

In congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the steroid 11β-hydroxylase (11βOH) enzyme, encoded by CYP11B1 gene in humans, stays at the initial step of 11-oxyandrogen production.[19][33]

There are several routes that may lead to production of 11-oxyagenated androgens:

  • 17-OHP is converted by 11βOH to 21-deoxycortisol, which is finally converted to 11-ketotestosterone and 11-ketodihydrotestosterone.[34][35]
  • Progesterone is converted by 11βOH to 11β-hydroxyprogesterone.[36] There are multiple studies conducted since 1987 that demonstrate increased levels of 11β-hydroxyprogesterone in congenital adrenal hyperplasia.[37][38][39] In vitro studies predict that excess of 11β-hydroxyprogesterone may ultimately leads to production of 11-ketodihydrotestosterone and 11-ketoandrosterone.[40][36][31] The in vitro catalytic activity (min−1) of 11βOH for progesterone is to 12.3, comparing to 96.8 for 11-deoxycortisol, the main substrate of 11βOH.[41]
  • A4 is converted by 11βOH to 11β-hydroxyandrostenedione and then to 11-ketotestosterone and 11-ketodihydrotestosterone.[42][31][17]

History[edit | edit source]

In April 1987, Benjamin Eckstein and colleagues reported that 3α-diol, a direct precursor to DHT, is synthesized in immature rat testes in a pathway that predominantly involves 17-OHP but not A4 as an intermediate.[43]

In October 2000, Geoffrey Shaw and colleagues demonstrated that prostate formation in a marsupial (tammar wallaby pouch young) was mediated by the testicular androgen 3α-diol, which is higher in male than in female plasma during early sexual differentiation, identifying it as a key hormone in male development. They have shown that 3α-diol acts in target tissues via DHT, i.e. is converted to DHT in target tissues, so that testosterone is not the only source of DHT.[14]

In February 2003, Jean Wilson and colleagues described that DHT, a 5α-reduced androgen, can be synthesized from 17-OHP by two pathways: with and without testosterone as an intermediate. They have demonstrated that 3α-diol, a precursor to DHT, is formed in the testes of tammar wallaby pouch young with 5α-pdiol and androsterone as intermediates.[1]

In July 2004, Mala Mahendroo and colleagues described that 3α-diol is the predominant androgen in immature mouse testes, and that it is formed by two pathways; the main one involves testosterone, and a second utilizes the pathway progesterone → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnane-3α-ol-20-one (allopregnanolone) → 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) → 5α-androstan-3α-ol-17-one (androsterone) → 5α-androstane-3α,17β-diol (3α-diol).[15]

In November 2004, Richard Auchus coined the term "backdoor pathway" in a review called "The backdoor pathway to dihydrotestosterone". He defined the backdoor pathway as a "route to DHT that does not involve the testosterone intermediate". He emphasized that this alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences.[2]

Clinical Significance[edit | edit source]

Androgen backdoor pathway has high clinical significance.

Unlike testosterone and A4, androgens produced by the backdoor pathway, i.e., DHT, 11-ketotestosterone and other 11-oxygenated androgens, are not converted by aromatase into estrogens in vivo.[44][45]

Juilee Rege and colleagues have demonstrated in a 2018 study that levels of 11-ketotestosterone in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of testosterone by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of testosterone in girls with premature adrenarche was higher by just 13% compared to age-matched healthy controls.[46]

The androgen backdoor pathway is not always considered in the clinical evaluation of patients with hyperandrogenism. If testosterone levels are normal, ignoring the backdoor pathway may lead to diagnostic flaws and confusion, since hyperandrogenism may be caused by very potent androgens, like DHT and 11-oxygenated androgens, produced by the backdoor pathway.[47][48] Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.[49][50]

In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal testosterone depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce dihydrotestosterone in the tumor in metabolic pathways in which testosterone is not involved. Instead, 5αRed1, expression of which increases in CRPC, 5α-reduces A4 to 5α-androstane-3,17-dione, which is then converted to DHT.[26][10] Therefore, the DHT produced within a backdoor pathway hampers the androgen deprivation therapy. In men whose testicles have been removed, although the blood testosterone level is reduced by 90-95%, the DHT level in the prostate is only reduced by 50%, thus indicating the presence in the prostate of a metabolic pathway that does not require testicular testosterone to produce DHT.[51]

PubChem CIDs[edit | edit source]

In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below aim to resolve the ambiguity caused by the fact that various authors in describing androgen backdoor pathways used different synonyms for the same metabolic intermediates that do not yet have a commonly agreed conventional names.

3α-diol: 15818; 5α-DHP: 92810; 5α-dione: 222865; 5α-pdiol: 111243; 5α-dihydroprogesterone: 92810; allopregnanolone: 92786; 11-ketotestosterone: 104796; 11-ketoandrosterone: 102029; 11-ketodihydrotestosterone: 11197479; 11-deoxycortisol: 440707; 11β-hydroxyandrostenedione: 94141; 11β-hydroxyprogesterone: 101788; 17‐OH-DHP: 11889565; 17-OHP: 6238; 21-deoxycortisol: 92827; A4: 6128; androsterone: 5879; DHT: 10635.

Abbreviations[edit | edit source]

  • 11βOH 11β-hydroxylase, CYP11B1
  • 17‐OH-DHP 5α-pregnan-17α-ol-3,20-dione
  • 17-OHP 17α-hydroxyprogesterone
  • 3α-diol 5α-androstane-3α,17β-diol
  • 17βHSD3 17β-hydroxysteroid dehydrogenase type 3, HSD17B3
  • 17βHSD5 17β-hydroxysteroid dehydrogenase type 5, HSD17B5, also the aldo-keto reductase family 1 member C3, AKR1C3
  • 17βHSD6 17β-hydroxysteroid dehydrogenase type 6, HSD17B6
  • 5α-DHP 5α-dihydroprogesterone
  • 5α-dione 5α-androstane-3,17-dione
  • 5α-pdiol 5α-pregnane-3α,17α-diol-20-one
  • 5αRed1 3-oxo-5α-steroid 4-dehydrogenase type 1, SRD5A1
  • 5αRed2 3-oxo-5α-steroid 4-dehydrogenase type 2, SRD5A2
  • A4 androstenedione
  • Allopregnanolone 5α-pregnane-3α-ol-20-one
  • Androsterone 5α-androstan-3α-ol-17-one
  • DHT 5α-dihydrotestosterone

Additional information[edit | edit source]

Competing interests[edit | edit source]

The authors have no competing interest.

Acknowledgements[edit | edit source]

Funding[edit | edit source]

Ethics statement[edit | edit source]

References[edit | edit source]

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