WikiJournal Preprints/Alternative androgen pathways

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



Abstract

The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description 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 of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients.


Introduction[edit | edit source]

The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.[1]

In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.[2] Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway and the potential clinical relevance in conditions involving androgen biosynthesis was proposed.[3] Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.[4] The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases.

Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,[5] understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension.

History[edit | edit source]

Backdoor Pathways to 5α-Dihydrotestosterone[edit | edit source]

In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.[6] While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT.

Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.[7] While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.[8] Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.[7]

In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:[2]

  • 17α-hydroxyprogesterone (17OHP) → 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 (AST) → 5α-androstane-3α,17β-diol (3α-diol)

The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C19 steroids to be 5α-reduced to become ready DHT precursors.

In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:[9]

  • progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)

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

  • 17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)

The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.[10]

5α-Dione Pathway[edit | edit source]

In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:[11]

  • androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)

While this pathway was described as the "5α-dione pathway" in a 2012 review,[12] the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.[13]

A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2.

11-Oxygenated Androgen Pathways[edit | edit source]

11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. While the 11-oxygenated C19 steroids 11OHA4 and 11KA4 were known since the 1950s to be products of the human adrenal, with negligible androgenic activity, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.[4]

Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.[14]

In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.[15] The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.[15] To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.[16] These findings were later confirmed in 2021[17] and 2022.[18]

Bloem et al. in 2015[19] demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,[19] which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.[20][21][22]

A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4.

Definition[edit | edit source]

We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical[23][24] androgen pathway must be considered.

Nomenclature and Background[edit | edit source]

Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches[25][26], we have added this expository section on steroid nomenclature to facilitate the use of correct names.

Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.[27] The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β[28] denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention[29] of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as solid wedges.

The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).[30] The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids[31] that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1).

Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids

Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.[32] This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ4-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ4-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ4-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,[33] i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ5-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ4 steroids (with a double bond between carbons 4 and 5), respectively.[34][32] Canonical androgen synthesis is generally described as having a Δ5 pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ4 pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ4-steroids, while "P5" and "A5" - as Δ5-steroids, respectively.

The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"[25] [sic] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione".

According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).[27] This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.[26]

In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids[35] since as early as 1950s.[36][14] Some studies use the term "11-oxyandrogens"[37][38][39] potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.[40] However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading.

The oxo group (=O) bound to a carbon atom forms a larger, ketone group (R2C=O), hence the prefix "11-keto" used in the medical literature to denote an oxo group bound to carbon at position 11. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the prefix "keto" for steroid names, and favor the prefix "oxo" (e.g., 11-oxo steroids rather than 11-keto steroids), because keto denotes "R2C=O", while only "=O" is attached in steroids to the carbon at a particular position. Therefore, the same carbon atom should not be specified twice.[41]

Biochemistry[edit | edit source]

A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). Full enzyme names can be found in the Abbreviations section.

Backdoor Pathways to 5α-Dihydrotestosterone[edit | edit source]

While 5α-reduction is the last transformation in canonical androgen steroidogenesis, 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.

The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b5, Cytochrome P450 reductase (POR)) are not shown for clarity.

17α-Hydroxyprogesterone Pathway[edit | edit source]

The steroids involved in the metabolic pathway 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 step of this pathway is the 5α-reduction of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1,[42][43] though some authors[Be more specific] suggest SRD5A2 may also catalyze this reaction in some contexts.

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 and AKR1C4)[23][44] or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.[45][46] 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone.

5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C21 steroid (a pregnane) to C19 steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).[24] 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,[47] HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9.[43] This oxidation is not required in the canonical pathway.

The pathway can be summarized as:

  • 17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT

Progesterone Pathway[edit | edit source]

The pathway from 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. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.[23]

The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway.

The pathway can be summarized as:

  • P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT

5α-Dione Pathway[edit | edit source]

5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.[11]

The 5α-dione can also transformed into AST, which can then either converted back to 5α-dione or be transformed into DHT along the common part of the backdoor pathways to DHT (i.e., via 3α-diol).[48][49][8]

This pathway can be summarized as:

  • A4 → 5α-dione → DHT[11]

11-Oxygenated Androgen Pathways[edit | edit source]

Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain 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.

Routes to 11-oxygenated androgens[16][40][50][19] (Figure 4) also fall under our definition of alternative androgen pathways. These routes begin with four Δ4 steroid entry points (P4, 17OHP, A4 and T) and can then enter a lattice-like organization of possible transformations between 19-carbon steroid products. Wether or not a steroid is subject to a given transformation path depends on health status and the expression of a given enzyme in the tissue where that steroid is synthesized or transported to. All the steroid products in this lattice have a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). Only four 11-oxygenated steroids are known to be androgenic: 11OHT, 11OHDHT, 11KT and 11KDHT with activities that are correspondingly comparable to T and DHT. The relative importance of the androgens depends on activity, circulating levels and stability. It may be that 11KT is the main androgen in women since it circulates at similar level to T but 11KT levels may not decline with age as T does (though some evidence suggests that they do[51]). While KDHT is equipotent to DHT, circulating levels of KDHT are lower than DHT and SRD5A1 mediated transformation of KT to KDHT does not seem be significant.

The other steroid products 11OHA4 and 11KA4 have been established as not having any androgen activity, but remain important molecules in this context since they act as androgen precursors.

The complex lattice structure see in Figure 4 can be understood broadly as the four Δ4 steroid entry points that can undergo a common sequence of three transformations:

1. 11β-hydroxylation by CYP11B1/2.[52][53][54]

2. 5α-reduction by SRD5A1/2

3. Reversible 3α-reduction/oxidation of the ketone/alcohol

These steroids correspond to the "11OH" column in Figure 4. This sequence is replicated in the parallel column of "11K" steroids, in which are a result of 11β-reduction/oxidation of the ketone/alcohol (HSD11B1 catalyzes both oxidation and reduction while HSD11B2 only catalyzes the oxidation).[15]

There are additional transformations in the lattice that cross the derivatives of the entry points. AKR1C3 catalyzes (reversibly in some cases) 17β-reduction of the ketone/alcohol to transform between steroids that can be derived from T and A4. Steroids that can be derived from P4 can also be transformed to those that can be derived from 17OHP via CYP17A1 17α-hydroxylase activity. Some members of the 17OHP derived steroids can be transformed to A4 derived members via CYP17A1 17,20 lyase activity.

The next sections describe what are understood to be the primary routes to androgens amongst the many possible routes visible in Figure 4.

C19 Steroid Entry Points[edit | edit source]

A4 that is synthesized in the adrenal where it can undergo 11β-hydroxylation to yield 11OHA4, an important circulating androgen precursor, which is further transformed to 11KA4 and then KT (primarily outside the adrenal in peripheral tissue):

  • A4 → 11OHA4 → 11KA4 → 11KT

This route is regarded as the primary 11-oxygenated androgen pathway in healthy humans. It is thought that the T entry point also operates in normal human physiology, but much less that A4:

  • T → 11OHT → 11OHA4 → 11KA4 → 11KT
  • T → 11OHT → 11KT

The diminished role of these pathways is supported by that fact that the adrenal significantly more produces 11OHA4 than OHT[14][55] .

C21 Steroid Entry Points[edit | edit source]

Currently there is no good evidence for 11-oxygenated androgens from the C21 steroid entry points (P4, 17OHP) operating in healthy humans. These entry points are relevant in the clinical context as discussed in the next section.

Clinical Significance[edit | edit source]

11-Oxygenated Androgens[edit | edit source]

Measurements of the levels of circulating 11KT, in a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.[56]

Unlike T and A4, 11-oxygenated androgens are not known to be aromatized to estrogens in the human body.[57][58] [10] The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women, except perhaps DHEA.[59][60] In a 2021 study, However, it is possible that 11-oxygenated estrogens may be produced in some conditions such as feminizing adrenal carcinoma.[61] DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.[62][63]

Most conditions highlighted in the following sections have had demonstrations of potential roles for 11-oxygenated androgens.

Hyperandrogenism[edit | edit source]

Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.[64] Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.[65][66] Not considering alternative androgen pathways in clinical hyperandrogenism investigations may obfuscate the condition.[64]

Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.[67] Although T has been traditionally used as a biomarker of androgen excess,[68] it correlates poorly with clinical findings of androgen excess.[67] If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.[69][38]

It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterized, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.[70][71][58][72] These ratios have still not been established as a standard clinical as a diagnostic tool.

Congenital adrenal hyperplasia (CAH) is a well known disease of hyperandrogenism, but the contributions of the backdoor pathway to DHT remain under appreciated. CAH refers to a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis[73] caused by a deficiency in any of the enzymes required to produce cortisol in the adrenal.[74][75] This deficiency leads to an excessive accumulation of steroid precursors that are converted to androgens.

In a 2016 study, Turcu et al.[76] showed that in classic CAH due to CYP21A2 deficiency both conventional and 11-oxygenated androgens were elevated 3-4 fold in CAH patients receiving glucocorticoid therapy compared to healthy controls. The levels of 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.[76]

In CAH due to 21-hydroxylase[10] (CYP17A1) or cytochrome P450 oxidoreductase (POR) deficiency,[43][77] the associated elevated 17-OHP levels result in flux through the backdoor pathway to DHT that begins with 5α-reduction. This pathway may be activated regardless of age and sex.[78] Fetal excess of 17-OHP in CAH may contribute to DHT synthesis and lead to external genital virilization in newborn girls with CAH.[43] P4 levels may also be elevated in CAH,[79][80] leading to androgen excess via the backdoor pathway from P4 to DHT.[81] 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.[82][76][83][84] In males with CAH, 11-oxygenated androgens may lead to development of testicular adrenal rest tumors.[79][82][85]

Disorders of Sex Development[edit | edit source]

Both canonical and the backdoor androgen pathway to DHT are required for normal human male genital development.[86][77] Deficiencies in the backdoor pathway to DHT from 17-OHP or from P4[44][42] lead to underverilization of the male fetus,[87][88] as placental P4 is a precursor to DHT in the backdoor pathway.[23]

In 2011 Flück et al. described a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. 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 (Figure 2), the study found that mutations in AKR1C2 only were sufficient for disruption.[44] However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.[89]

Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b5, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). This rare deficiency can lead to DSD in both sexes with affected girls are asymptomatic until puberty, when they show amenorrhea.[89]

11-oxygenated androgens may play important roles in DSDs.[90][91][43] 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 precursors that serve as substrates for CYP11B1 in pathways to 11-oxygenated androgens, which cause abnormal female fetal development.[90]

Polycystic Ovary Syndrome[edit | edit source]

In PCOS, DHT may be produced in the backdoor androgen pathway from upregulation of SRD5A1 activity.[92][93][94][95]

11-oxygenated androgens may also play an important role in PCOS.[39][96][97] In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. Serum 11OHT and 11KT levels have been show to be elevated in PCOS and correlate with body mass index.[98] Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.[99] 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.[100] Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.[39]

Prostate Cancer[edit | edit source]

High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant.[101] There is some preliminary evidence that 11-oxygenated androgen pathway may play an important role at the stage of prostatic carcinogenesis.[102]

Androgen deprivation is a therapeutic approach to prostrate cancer that can be implemented by castration to eliminate gonadal T, but metastatic tumors may then develop into castration-resistant prostate cancer (CRPC). Although castration results in 90-95% reduction of serum T, DHT in the prostate is only decreased by 50%, supporting the notion that the prostrate expresses necessary enzymes to produce DHT without testicular T.[citation needed] The 5α-dione pathway was discovered in the context of CPRC (see History), and is known to mitigate the effects of androgen depravation therapy.

11-Oxygenated androgens contribute significantly to the androgen pool[15][24] and play a previously overlooked role in the reactivation of androgen signaling in the CRPC patient.[102][101][50][15][24][52] Serum 11KT levels are higher than any other androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool, and are not affected by castration.[103]

Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome[edit | edit source]

Androgens play a vital role in the development, growth and maintenance of the prostate.[13] Therefore, the role of androgens should be seriously considered not only in CRPC, but other prostate-related conditions such as BPH[13] and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).[104]

11-oxygenated androgen pathways have been observed in BPH cell models (11OHP4 and 11KP4, a C21 steroid, to 11KDHT), BPH patient tissue biopsy and in their serum.[105]

Future Directions[edit | edit source]

Relative steroid serum levels in CP/CPPS have suggested that CYP21A2 deficiency may play a role in the disease[104] and that non-classic CAH due to 21-hydroxylase deficiency may be a comorbidity. Given the potential roles that alternative androgen pathways play in the previously described disease areas, it seems that CP/CPPS would seem to be a good candidate to investigate the same way. We are not aware of any work looking at the roles of alternative androgen pathways in CP/CPPS.

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 are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways.

11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013.

Abbreviations[edit | edit source]

Steroids[edit | edit source]

  • 11dF 11-deoxycortisol (also known as Reichstein's substance S)
  • 11K-3αdiol 5α-androstane-3α,17β-diol-11-one
  • 11K-5αdione 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione)
  • 11KA4 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G)
  • 11KAST 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone)
  • 11KDHP4 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione)
  • 11KDHT 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone)
  • 11KP4 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone)
  • 11KPdiol 5α-pregnane-3α,17α-diol-11,20-dione
  • 11KPdione 5α-pregnan-17α-ol-3,11,20-trione
  • 11KT 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione)
  • 11OH-3αdiol 5α-androstane-3α,11β,17β-triol
  • 11OH-5αdione 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione)
  • 11OHA4 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione)
  • 11OHAST 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone)
  • 11OHDHP4 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone)
  • 11OHDHT 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one)
  • 11OHEt 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one)
  • 11OHP4 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone)
  • 11OHPdiol 5α-pregnane-3α,11β,17α-triol-20-one
  • 11OHPdione 5α-pregnane-11β,17α-diol-3,20-dione
  • 11OHT 11β-hydroxytestosterone
  • 17OHP5 17α-hydroxypregnenolone
  • 17-OH-DHP 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone)
  • 17-OHP 17α-hydroxyprogesterone
  • 21dE 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone)
  • 21dF 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone)
  • 3,11diOH-DHP4 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one)
  • 3α-diol 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol
  • 3β-diol 5α-androstane-3β,17β-diol (also known as 3β-androstanediol)
  • 5α-DHP 5α-dihydroprogesterone
  • 5α-dione androstanedione (also known as 5α-androstane-3,17-dione)
  • 5α-Pdiol 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone)
  • A4 androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione)
  • A5 androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol)
  • A5-S androstenediol sulfate
  • ALF 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone)
  • AlloP5 5α-pregnan-3α-ol-20-one (also known as allopregnanolone)
  • AST 5α-androstan-3α-ol-17-one (also known androsterone)
  • DHEA dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one)
  • DHEA-S dehydroepiandrosterone sulfate
  • DHT 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one)
  • DOC 11-deoxycorticosterone (also known as Reichstein's substance Q)
  • P4 progesterone
  • P5 pregnenolone
  • T testosterone

Enzymes (Abbreviated by their Gene Names)[edit | edit source]

  • AKR1C2 aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3)
  • AKR1C3 aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5))
  • AKR1C4 aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1)
  • CYP11A1 cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc")
  • CYP11B1 steroid 11β-hydroxylase
  • CYP11B2 aldosterone synthase
  • CYP17A1 steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17)
  • CYP21A2 steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21)
  • DHRS9 dehydrogenase/reductase SDR family member 9
  • HSD11B1 11β-hydroxysteroid dehydrogenase type 1
  • HSD11B2 11β-hydroxysteroid dehydrogenase type 2
  • HSD17B3 17β-hydroxysteroid dehydrogenase type 3
  • HSD17B6 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD)
  • HSD17B10 17β-hydroxysteroid dehydrogenase type 10
  • POR cytochrome P450 oxidoreductase
  • RDH16 retinol dehydrogenase 16 (also known as RODH4)
  • RDH5 retinol dehydrogenase 5
  • SRD5A1 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1
  • SRD5A2 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2
  • SRD5A3 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3

Conditions[edit | edit source]

  • BPH benign prostatic hyperplasia
  • CAH congenital adrenal hyperplasia
  • CP/CPPS chronic prostatitis/chronic pelvic pain syndrome
  • CRPC castration-resistant prostate cancer
  • DSD disorder of sex development
  • PCOS polycystic ovary syndrome

Other[edit | edit source]

  • ACTH adrenocorticotropic hormone
  • STAR steroidogenic acute regulatory protein

Additional Information[edit | edit source]

Competing Interests[edit | edit source]

The authors have no competing interest.

Funding[edit | edit source]

The authors received no financial support for the research, authorship and publication of this article.

Notes on The Use of Abbreviations[edit | edit source]

The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following.

Referencing Convention[edit | edit source]

  1. When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name.
  2. To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text.
  3. When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.

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  28. 3S-1.4. "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur J Biochem 186 (3): 431. 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. "3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper." 
  29. Favre, Henri; Powell, Warren (2014). "P-91". Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. pp. 868. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4. "P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;" 
  30. Favre, Henri; Powell, Warren (2014). "P-13.8.1.1". Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. pp. 66. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4. "P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3)." 
  31. "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur J Biochem 186 (3): 430. 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. "3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1" 
  32. 32.0 32.1 "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur J Biochem 186 (3): 436–437. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. "3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ5-steroids’" 
  33. Favre, Henri; Powell, Warren (2014). "P-3". Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4. "P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them." 
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