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Authors: Maxim G Masiutin[lower-roman 1] 

 , Maneesh K Yadav 
 

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    1. ↑ maxim.masiutin@gmail.com

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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 route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other metabolic routes to 11-oxyandrogens have been discovered which are also described as backdoor pathways. The aim of this review is 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 that this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients.
    Androgen backdoor pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone.
    Maxim Masiutin CC-BY 4.0

    Introduction

    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-oxyandrogens[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 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

    The central feature that distinguishes the canonical[8][9] androgen steroidogenesis pathway from backdoor pathways is the involvement of testosterone. 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 both 5α-dihydrotestosterone (DHT) from 17α-hydroxyprogesterone (17-OHP) with roundabout of testosterone as well as 11-oxyandrogen 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 be technically considered as androgens, not all androgens are necessarily are potent or clinically relevant agonists of the androgen receptors.

    Therefore, the present review defines the term "androgen backdoor pathway" as "a metabolic pathway where potent androgens are synthesized with roundabout of testosterone as an intermediate product".

    Case Studies

    The route to 5α-dihydrotestosterone

    The first metabolic route that fall under the definition of the 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 androstenedione and testosterone.[2][10]

    In mammals, this route is activated during normal prenatal development and leads to early male sexual differentiation.[11][12][13] It was first described in the marsupials and later confirmed in humans.[14]

    In congenital adrenal hyperplasia due to 21-hydroxylase deficiency or cytochrome P450 oxidoreductase deficiency,[15] this route may be activated regardless of age and sex by even a mild increase in circulating 17-OHP levels.[16][17]

    The first step of this route is conversion of 17-OHP by 5α-reductase enzymes, the 3-oxo-5α-steroid 4-dehydrogenase type 1 (SRD5A1) and type 2 (SRD5A2), to 5α-pregnan-17α-ol-3,20-dione, also known as 17α-hydroxy-dihydroprogesterone (17‐OH-DHP).[18][15][10][11] The next two intermediate products are 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) and 5α-androstan-3α-ol-17-one (androsterone).[9][17][19][18] The final step is conversion of 5α-androstane-3α,17β-diol (3α-diol) to DHT by several 3α-oxidoreductases (HSD17B6, RDH16, etc).[15][19] Hence, the 3α-diol has been proposed a marker of the backdoor pathway of DHT synthesis.[20]

    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).[21]

    The routes to 11-oxyandrogens

    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.[22] Potency of 11-ketotestosterone is similar to that of testosterone.[23] 11-ketotestosterone may serve as the main androgen for healthy women.[24]

    11-oxyandrogens may be produced in physiologic quantities in healthy mammalian organisms,[24] and in excessive quantities in the pathological conditions like congenital adrenal hyperplasia due to 21-hydroxylase deficiency,[4][16][25] polycystic ovary syndrome,[3] benign prostatic hyperplasia[26] in prostate cancer[27] and disorders of sex development in neonates and in children.[28]

    In congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the steroid 11β-hydroxylase (11βOH) enzyme, also known is CYP11B1, stays at the initial step of 11-oxyandrogen production.[29]

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

    • 17-OHP is converted by 11βOH to 21-deoxycortisol, which is finally converted to 11-ketotestosterone and 11-ketodihydrotestosterone.[30][31]
    • Progesterone is converted by 11βOH to 11β-hydroxyprogesterone.[32] There are multiple studies conducted since 1987 that demonstrate increased levels of 11β-hydroxyprogesterone in congenital adrenal hyperplasia.[33][34][35] In vitro studies predict that excess of 11β-hydroxyprogesterone may ultimately leads to production of 11-ketodihydrotestosterone and 11-ketoandrosterone.[36][32][26] 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.[37]
    • Androstenedione is converted by 11βOH to 11β-hydroxyandrostenedione and then to 11-ketotestosterone and 11-ketodihydrotestosterone.[38][26][16]

    History

    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 androstenedione as an intermediate.[39]

    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.[12]

    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-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).[13]

    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 conventional androgen biosynthetic pathway cannot fully explain the observed consequences.[2]

    Conclusion

    Androgen backdoor pathway has high clinical significance. Unlike testosterone and androstenedione, androgens produced by the backdoor pathway, i.e. DHT and 11-ketotestosterone, cannot be converted by aromatase into estrogens.[40]

    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, because very potent androgens produced by the backdoor pathway like DHT and 11-ketotestosterone may be the cause of hyperandrogenism.

    PubChem IDs

    In order to unambiguously define all the steroids mentioned in the present review, we give their respective PubChem IDs 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 canonical names. This practice of unambiguously identifying such substances by their PubChem IDs or IDs from other respectful databases is strongly encouraged.

    3α-diol: 15818; 5α-pdiol: 111243; 5α-Dihydroprogesterone: 92810; 5α-Pregnane-3α-ol-20-one: 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; Androsterone: 5879; DHT: 10635.

    Abbreviations

    • 11βOH 11β-hydroxylase
    • 17‐OH-DHP 5α-pregnan-17α-ol-3,20-dione
    • 17-OHP 17α-hydroxyprogesterone
    • 3α-diol 5α-androstane-3α,17β-diol
    • 5α-pdiol 5α-pregnane-3α,17α-diol-20-one
    • Androsterone 5α-androstan-3α-ol-17-one
    • DHT 5α-dihydrotestosterone
    • SRD5A1 3-oxo-5α-steroid 4-dehydrogenase type 1
    • SRD5A2 3-oxo-5α-steroid 4-dehydrogenase type 2

    Additional information

    Competing interests

    The authors have no competing interest.

    Acknowledgements

    Funding

    Ethics statement

    References

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