WikiJournal Preprints/Alternative androgen pathways
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.
In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby. 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. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant. 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, 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. 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. 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. 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.
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:
- 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:
- 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 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.
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:
- androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)
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.
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.
In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture. 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. 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. These findings were later confirmed in 2021 and 2022.
Bloem et al. in 2015 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, which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.
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 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, 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. 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 denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention 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). The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids 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).
Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene. 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, 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. 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" [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). 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.
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 since as early as 1950s. Some studies use the term "11-oxyandrogens" potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11. 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.
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.
17α-Hydroxyprogesterone Pathway[edit | edit source]
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, though some authors 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) or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity. 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). 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, HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9. 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.
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.
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).
This pathway can be summarized as:
- A4 → 5α-dione → DHT
11-Oxygenated Androgen Pathways[edit | edit source]
Routes to 11-oxygenated androgens (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). 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:
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).
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
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.
Unlike T and A4, 11-oxygenated androgens are not known to be aromatized to estrogens in the human body.  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. In a 2021 study, However, it is possible that 11-oxygenated estrogens may be produced in some conditions such as feminizing adrenal carcinoma. DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.
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. Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility. Not considering alternative androgen pathways in clinical hyperandrogenism investigations may obfuscate the condition.
Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men. Although T has been traditionally used as a biomarker of androgen excess, it correlates poorly with clinical findings of androgen excess. 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.
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. 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 caused by a deficiency in any of the enzymes required to produce cortisol in the adrenal. This deficiency leads to an excessive accumulation of steroid precursors that are converted to androgens.
In a 2016 study, Turcu et al. 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.
In CAH due to 21-hydroxylase (CYP17A1) or cytochrome P450 oxidoreductase (POR) deficiency, 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. Fetal excess of 17-OHP in CAH may contribute to DHT synthesis and lead to external genital virilization in newborn girls with CAH. P4 levels may also be elevated in CAH, leading to androgen excess via the backdoor pathway from P4 to DHT. 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH. In males with CAH, 11-oxygenated androgens may lead to development of testicular adrenal rest tumors.
Disorders of Sex Development[edit | edit source]
Both canonical and the backdoor androgen pathway to DHT are required for normal human male genital development. Deficiencies in the backdoor pathway to DHT from 17-OHP or from P4 lead to underverilization of the male fetus, as placental P4 is a precursor to DHT in the backdoor pathway.
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. However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.
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.
11-oxygenated androgens may play important roles in DSDs. 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.
Polycystic Ovary Syndrome[edit | edit source]
11-oxygenated androgens may also play an important role in PCOS. 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. 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. 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. Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.
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. There is some preliminary evidence that 11-oxygenated androgen pathway may play an important role at the stage of prostatic carcinogenesis.
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.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 and play a previously overlooked role in the reactivation of androgen signaling in the CRPC patient. 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.
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. Therefore, the role of androgens should be seriously considered not only in CRPC, but other prostate-related conditions such as BPH and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
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.
Future Directions[edit | edit source]
Relative steroid serum levels in CP/CPPS have suggested that CYP21A2 deficiency may play a role in the disease 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]
- 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.
- 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.
- 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.
References[edit | edit source]
- Gelmann, Edward P. (2022). "Molecular Biology of the Androgen Receptor". Journal of Clinical Oncology 20 (13): 3001–3015. doi:10.1200/JCO.2002.10.018. ISSN 0732-183X. PMID 12089231. https://ascopubs.org/doi/10.1200/JCO.2002.10.018.
- Wilson, Jean D.; Auchus, Richard J.; Leihy, Michael W.; Guryev, Oleg L.; Estabrook, Ronald W.; Osborn, Susan M.; Shaw, Geoffrey; Renfree, Marilyn B. (2003). "5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate". Endocrinology 144 (2): 575–80. doi:10.1210/en.2002-220721. PMID 12538619.
- Auchus, Richard J. (2004). "The backdoor pathway to dihydrotestosterone". Trends in Endocrinology and Metabolism: TEM 15 (9): 432–8. doi:10.1016/j.tem.2004.09.004. PMID 15519890.
- Pretorius, Elzette; Arlt, Wiebke; Storbeck, Karl-Heinz (2017). "A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids". Mol Cell Endocrinol 441: 76–85. doi:10.1016/j.mce.2016.08.014. PMID 27519632. http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf.
- Pham, Nhung; van Heck, Ruben G. A.; van Dam, Jesse C. J.; Schaap, Peter J.; Saccenti, Edoardo; Suarez-Diez, Maria (2019). "Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling". Metabolites 9 (2): 28. doi:10.3390/metabo9020028. ISSN 2218-1989. PMID 30736318. PMC 6409771. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6409771/.
- Eckstein, B.; Borut, A.; Cohen, S. (1987). "Metabolic pathways for androstanediol formation in immature rat testis microsomes". Biochimica et Biophysica Acta (BBA) - General Subjects 924 (1): 1–6. doi:10.1016/0304-4165(87)90063-8. ISSN 0006-3002. PMID 3828389. https://pubmed.ncbi.nlm.nih.gov/3828389.
- Shaw, G.; Renfree, M. B.; Leihy, M. W.; Shackleton, C. H.; Roitman, E.; Wilson, J. D. (2000). "Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol". Proceedings of the National Academy of Sciences of the United States of America 97 (22): 12256–12259. doi:10.1073/pnas.220412297. ISSN 0027-8424. PMID 11035809. PMC 17328. //www.ncbi.nlm.nih.gov/pmc/articles/PMC17328/.
- Penning, Trevor M. (1997). "Molecular Endocrinology of Hydroxysteroid Dehydrogenases". Endocrine Reviews 18 (3): 281–305. doi:10.1210/edrv.18.3.0302. ISSN 0163-769X. PMID 9183566. https://academic.oup.com/edrv/article/18/3/281/2530742.
- Mahendroo, Mala; Wilson, Jean D.; Richardson, James A.; Auchus, Richard J. (2004). "Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways". Molecular and Cellular Endocrinology 222 (1–2): 113–120. doi:10.1016/j.mce.2004.04.009. ISSN 0303-7207. PMID 15249131. https://pubmed.ncbi.nlm.nih.gov/15249131.
- Kamrath, Clemens; Hochberg, Ze'ev; Hartmann, Michaela F.; Remer, Thomas; Wudy, Stefan A. (2012). "Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis". The Journal of Clinical Endocrinology and Metabolism 97 (3): E367–375. doi:10.1210/jc.2011-1997. ISSN 1945-7197. PMID 22170725. https://pubmed.ncbi.nlm.nih.gov/22170725.
- Chang, K.-H.; Li, R.; Papari-Zareei, M.; Watumull, L.; Zhao, Y. D.; Auchus, R. J.; Sharifi, N. (2011). "Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer". Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences) 108 (33): 13728–13733. doi:10.1073/pnas.1107898108. ISSN 0027-8424. PMID 21795608. PMC 3158152. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3158152/.
- Sharifi, Nima (2012). "The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer". J Investig Med 60 (2): 504–7. doi:10.2310/JIM.0b013e31823874a4. PMID 22064602. PMC 3262939. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3262939/.
- Luu-The, Van; Bélanger, Alain; Labrie, Fernand (2008). "Androgen biosynthetic pathways in the human prostate". Best Practice & Research. Clinical Endocrinology & Metabolism (Elsevier BV) 22 (2): 207–221. doi:10.1016/j.beem.2008.01.008. ISSN 1521-690X. PMID 18471780.
- Rege, Juilee; Nakamura, Yasuhiro; Satoh, Fumitoshi; Morimoto, Ryo; Kennedy, Michael R.; Layman, Lawrence C.; Honma, Seijiro; Sasano, Hironobu et al. (2013). "Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation". J Clin Endocrinol Metab 98 (3): 1182–8. doi:10.1210/jc.2012-2912. PMID 23386646. PMC 3590473. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3590473/.
- Storbeck, Karl-Heinz; Bloem, Liezl M.; Africander, Donita; Schloms, Lindie; Swart, Pieter; Swart, Amanda C. (2013). "11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer?". Mol Cell Endocrinol 377 (1–2): 135–46. doi:10.1016/j.mce.2013.07.006. PMID 23856005.
- Pretorius, Elzette; Africander, Donita J.; Vlok, Maré; Perkins, Meghan S.; Quanson, Jonathan; Storbeck, Karl-Heinz (2016). "11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored". PLOS ONE 11 (7): e0159867. doi:10.1371/journal.pone.0159867. PMID 27442248. PMC 4956299. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4956299/.
- Handelsman, David J.; Cooper, Elliot R.; Heather, Alison K. (2022). "Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells". J Steroid Biochem Mol Biol 218: 106049. doi:10.1016/j.jsbmb.2021.106049. PMID 34990809.
- Snaterse, Gido; Mies, Rosinda; Van Weerden, Wytske M.; French, Pim J.; Jonker, Johan W.; Houtsmuller, Adriaan B.; Van Royen, Martin E.; Visser, Jenny A. et al. (2022). "Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids". Prostate Cancer Prostatic Dis. doi:10.1038/s41391-022-00491-z. PMID 35046557. https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf.
- Bloem, Liezl M.; Storbeck, Karl-Heinz; Swart, Pieter; du Toit, Therina; Schloms, Lindie; Swart, Amanda C. (2015). "Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas". The Journal of Steroid Biochemistry and Molecular Biology 153: 80–92. doi:10.1016/j.jsbmb.2015.04.009. ISSN 1879-1220. PMID 25869556. https://pubmed.ncbi.nlm.nih.gov/25869556.
- Barnard, Lise; Gent, Rachelle; Van Rooyen, Desmaré; Swart, Amanda C. (2017). "Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone". The Journal of Steroid Biochemistry and Molecular Biology 174: 86–95. doi:10.1016/j.jsbmb.2017.07.034. PMID 28774496. https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091.
- van Rooyen, Desmaré; Gent, Rachelle; Barnard, Lise; Swart, Amanda C. (2018). "The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway". The Journal of Steroid Biochemistry and Molecular Biology 178: 203–212. doi:10.1016/j.jsbmb.2017.12.014. PMID 29277707.
- Van Rooyen, Desmaré; Yadav, Rahul; Scott, Emily E.; Swart, Amanda C. (2020). "CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway". The Journal of Steroid Biochemistry and Molecular Biology 199: 105614. doi:10.1016/j.jsbmb.2020.105614. PMID 32007561.
- O'Shaughnessy, Peter J.; Antignac, Jean Philippe; Le Bizec, Bruno; Morvan, Marie-Line; Svechnikov, Konstantin; Söder, Olle; Savchuk, Iuliia; Monteiro, Ana et al. (2019). "Alternative (backdoor) androgen production and masculinization in the human fetus". PLOS Biology 17 (2): e3000002. doi:10.1371/journal.pbio.3000002. PMID 30763313. PMC 6375548. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6375548/.
- Storbeck, Karl-Heinz; Mostaghel, Elahe A. (2019). "Canonical and Noncanonical Androgen Metabolism and Activity". Advances in Experimental Medicine and Biology 1210: 239–277. doi:10.1007/978-3-030-32656-2_11. ISBN 978-3-030-32655-5. PMID 31900912.
- "Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name". 2022.
- "Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name". 2022.
- "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur J Biochem 186 (3): 441. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. "3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions)."
- 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."
- 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-184.108.40.206 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;"
- Favre, Henri; Powell, Warren (2014). "P-220.127.116.11". 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-18.104.22.168 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)."
- "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"
- "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’"
- 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."
- Miller, Walter L.; Auchus, Richard J. (2011). "The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders". Endocr Rev 32 (1): 81–151. doi:10.1210/er.2010-0013. PMID 21051590. PMC 3365799. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3365799/.
- Makin, H.L.J.; Trafford, D.J.H. (1972). "The chemistry of the steroids". Clinics in Endocrinology and Metabolism 1 (2): 333–360. doi:10.1016/S0300-595X(72)80024-0.
- Bongiovanni, A. M.; Clayton, G. W. (1954). "Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia". Proc Soc Exp Biol Med 85 (3): 428–9. doi:10.3181/00379727-85-20905. PMID 13167092.
- Slaunwhite, W.Roy; Neely, Lavalle; Sandberg, Avery A. (1964). "The metabolism of 11-Oxyandrogens in human subjects". Steroids 3 (4): 391–416. doi:10.1016/0039-128X(64)90003-0.
- Kamrath, Clemens; Wettstaedt, Lisa; Boettcher, Claudia; Hartmann, Michaela F.; Wudy, Stefan A. (2018). "Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia". The Journal of Steroid Biochemistry and Molecular Biology (Elsevier BV) 178: 221–228. doi:10.1016/j.jsbmb.2017.12.016. ISSN 0960-0760. PMID 29277706.
- Taylor, Anya E.; Ware, Meredith A.; Breslow, Emily; Pyle, Laura; Severn, Cameron; Nadeau, Kristen J.; Chan, Christine L.; Kelsey, Megan M. et al. (2022). "11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome". J Endocr Soc 6 (7): bvac037. doi:10.1210/jendso/bvac037. PMID 35611324. PMC 9123281. //www.ncbi.nlm.nih.gov/pmc/articles/PMC9123281/.
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- "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur J Biochem 186 (3): 429–58. 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099. "The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O"
- Fukami, Maki; Homma, Keiko; Hasegawa, Tomonobu; Ogata, Tsutomu (2013). "Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development". Developmental Dynamics 242 (4): 320–9. doi:10.1002/dvdy.23892. PMID 23073980.
- Reisch, Nicole; Taylor, Angela E.; Nogueira, Edson F.; Asby, Daniel J.; Dhir, Vivek; Berry, Andrew; Krone, Nils; Auchus, Richard J. et al. (2019). "Alternative pathway androgen biosynthesis and human fetal female virilization". Proceedings of the National Academy of Sciences of the United States of America 116 (44): 22294–22299. doi:10.1073/pnas.1906623116. ISSN 1091-6490. PMID 31611378. PMC 6825302. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6825302/.
- Flück, Christa E.; Meyer-Böni, Monika; Pandey, Amit V.; Kempná, Petra; Miller, Walter L.; Schoenle, Eugen J.; Biason-Lauber, Anna (2011). "Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation". American Journal of Human Genetics 89 (2): 201–218. doi:10.1016/j.ajhg.2011.06.009. ISSN 1537-6605. PMID 21802064. PMC 3155178. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3155178/.
- Biswas, Michael G.; Russell, David W. (1997). "Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate". J Biol Chem 272 (25): 15959–66. doi:10.1074/jbc.272.25.15959. PMID 9188497.
- Muthusamy, Selvaraj; Andersson, Stefan; Kim, Hyun-Jin; Butler, Ryan; Waage, Linda; Bergerheim, Ulf; Gustafsson, Jan-Åke (2011). "Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer". Proc Natl Acad Sci U S A 108 (50): 20090–4. doi:10.1073/pnas.1117772108. PMID 22114194. PMC 3250130. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3250130/.
- "Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells". Chem Biol Interact 143-144: 401–9. February 2003. doi:10.1016/s0009-2797(02)00179-5. PMID 12604227.
- Cite error: Invalid
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- Cite error: Invalid
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- Gent, R.; Du Toit, T.; Bloem, L. M.; Swart, A. C. (2019). "The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis". J Steroid Biochem Mol Biol 189: 116–126. doi:10.1016/j.jsbmb.2019.02.013. PMID 30825506.
- Skiba, Marina A.; Bell, Robin J.; Islam, Rakibul M.; Handelsman, David J.; Desai, Reena; Davis, Susan R. (2019). "Androgens During the Reproductive Years: What Is Normal for Women?". J Clin Endocrinol Metab 104 (11): 5382–5392. doi:10.1210/jc.2019-01357. PMID 31390028.
- Swart, Amanda C.; Schloms, Lindie; Storbeck, Karl-Heinz; Bloem, Liezl M.; Toit, Therina du; Quanson, Jonathan L.; Rainey, William E.; Swart, Pieter (2013). "11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione". J Steroid Biochem Mol Biol 138: 132–42. doi:10.1016/j.jsbmb.2013.04.010. PMID 23685396.
- Haru, Shibusawa; Yumiko, Sano; Shoichi, Okinaga; Kiyoshi, Arai (1980). "Studies on 11β-hydroxylase of the human fetal adrenal gland". Journal of Steroid Biochemistry (Elsevier BV) 13 (8): 881–887. doi:10.1016/0022-4731(80)90161-2. ISSN 0022-4731. PMID 6970302.
- Schloms, Lindie; Storbeck, Karl-Heinz; Swart, Pieter; Gelderblom, Wentzel C.A.; Swart, Amanda C. (2012). "The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells". J Steroid Biochem Mol Biol 128 (3–5): 128–38. doi:10.1016/j.jsbmb.2011.11.003. PMID 22101210.
- Barnard, Monique; Quanson, Jonathan L.; Mostaghel, Elahe; Pretorius, Elzette; Snoep, Jacky L.; Storbeck, Karl-Heinz (2018). "11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer". J Steroid Biochem Mol Biol 183: 192–201. doi:10.1016/j.jsbmb.2018.06.013. PMID 29936123. PMC 6283102. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6283102/.
- Schiffer, Lina; Bossey, Alicia; Kempegowda, Punith; Taylor, Angela E.; Akerman, Ildem; Scheel-Toellner, Dagmar; Storbeck, Karl-Heinz; Arlt, Wiebke (2021). "Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens". Eur J Endocrinol 184 (3): 353–363. doi:10.1530/EJE-20-1077. ISSN 1479-683X. PMID 33444228. PMC 7923147. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7923147/.
- Nagasaki, Keisuke; Takase, Kaoru; Numakura, Chikahiko; Homma, Keiko; Hasegawa, Tomonobu; Fukami, Maki (2020). "Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour". Human Reproduction 35 (11): 2609–2612. doi:10.1093/humrep/deaa221. PMID 32862221.
- Barnard, Lise; Schiffer, Lina; Louw Du-Toit, Renate; Tamblyn, Jennifer A.; Chen, Shiuan; Africander, Donita; Arlt, Wiebke; Foster, Paul A. et al. (2021). "11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool". Endocrinology 162 (3). doi:10.1210/endocr/bqaa231. PMID 33340399. PMC 7814299. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7814299/.
- Chen, Fang; Knecht, Kristin; Birzin, Elizabeth; Fisher, John; Wilkinson, Hilary; Mojena, Marina; Moreno, Consuelo Tudela; Schmidt, Azriel et al. (2005). "Direct agonist/antagonist functions of dehydroepiandrosterone". Endocrinology 146 (11): 4568–76. doi:10.1210/en.2005-0368. PMID 15994348.
- Gao, Wenqing; Bohl, Casey E.; Dalton, James T. (2005). "Chemistry and structural biology of androgen receptor". Chemical Reviews 105 (9): 3352–70. doi:10.1021/cr020456u. PMID 16159155. PMC 2096617. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2096617/.
- Mahesh, Virendra; Herrmann, Walter (1963). "Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma". Steroids 1 (1): 51–61. doi:10.1016/S0039-128X(63)80157-9. ISSN 0039-128X. https://www.sciencedirect.com/science/article/pii/S0039128X63801579.
- Chabab, Aziz; Sultan, Charles; Fenart, Odile; Descomps, Bernard (1986). "Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts". J Steroid Biochem 25 (1): 165–9. doi:10.1016/0022-4731(86)90296-7. PMID 2943941.
- Swerdloff, Ronald S.; Wang, Christina (1998). "Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent". Baillieres Clin Endocrinol Metab 12 (3): 501–6. doi:10.1016/s0950-351x(98)80267-x. PMID 10332569.
- Sumińska, Marta; Bogusz-Górna, Klaudia; Wegner, Dominika; Fichna, Marta (2020). "Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report". Int J Mol Sci 21 (13): 4622. doi:10.3390/ijms21134622. PMID 32610579. PMC 7369945. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7369945/.
- Yildiz, Bulent O. (2006). "Diagnosis of hyperandrogenism: clinical criteria". Best Practice & Research. Clinical Endocrinology & Metabolism (Elsevier BV) 20 (2): 167–176. doi:10.1016/j.beem.2006.02.004. ISSN 1521-690X. PMID 16772149.
- Peigné, Maëliss; Villers-Capelle, Anne; Robin, Geoffroy; Dewailly, Didier (2013). "Hyperandrogénie féminine". Presse Medicale (Paris, France) (Elsevier BV) 42 (11): 1487–1499. doi:10.1016/j.lpm.2013.07.016. ISSN 0755-4982. PMID 24184282.
- Turcu, Adina F.; Auchus, Richard J. (2017). "Clinical significance of 11-oxygenated androgens". Curr Opin Endocrinol Diabetes Obes 24 (3): 252–259. doi:10.1097/MED.0000000000000334. PMID 28234803. PMC 5819755. //www.ncbi.nlm.nih.gov/pmc/articles/PMC5819755/.
- Yang, Yabo; Ouyang, Nengyong; Ye, Yang; Hu, Qin; Du, Tao; Di, Na; Xu, Wenming; Azziz, Ricardo et al. (2020). "The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome". Reprod Biomed Online 41 (4): 734–742. doi:10.1016/j.rbmo.2020.07.013. PMID 32912651.
- Balsamo, Antonio; Baronio, Federico; Ortolano, Rita; Menabo, Soara; Baldazzi, Lilia; Di Natale, Valeria; Vissani, Sofia; Cassio, Alessandra (2020). "Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant". Frontiers in Pediatrics (Frontiers Media SA) 8: 593315. doi:10.3389/fped.2020.593315. ISSN 2296-2360. PMID 33415088. PMC 7783414. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7783414/.
- Carmina, E.; Stanczyk, F. Z.; Chang, L.; Miles, R. A.; Lobo, R. A. (1992). "The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women". Fertil Steril 58 (1): 148–52. doi:10.1016/s0015-0282(16)55152-8. PMID 1623996.
- Lipsett, Mortimer B.; Riter, Barbara (1960). "Urinary ketosteroids and pregnanetriol in hirsutism". J Clin Endocrinol Metab 20 (2): 180–6. doi:10.1210/jcem-20-2-180. PMID 14417423.
- Polson, D. W.; Reed, M. J.; Franks, S.; Scanlon, M. J.; James, V. H. T. (1988). "Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries". J Clin Endocrinol Metab 66 (5): 946–50. doi:10.1210/jcem-66-5-946. PMID 3129451.
- "Congenital adrenal hyperplasia". Lancet 390 (10108): 2194–2210. November 2017. doi:10.1016/S0140-6736(17)31431-9. PMID 28576284.
- "Congenital adrenal hyperplasia". N Engl J Med 349 (8): 776–88. August 2003. doi:10.1056/NEJMra021561. PMID 12930931.
- "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism 103 (11): 4043–4088. 2018. doi:10.1210/jc.2018-01865. PMID 30272171. PMC 6456929. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6456929/.
- Turcu, Adina F.; Nanba, Aya T.; Chomic, Robert; Upadhyay, Sunil K.; Giordano, Thomas J.; Shields, James J.; Merke, Deborah P.; Rainey, William E. et al. (2016). "Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency". Eur J Endocrinol 174 (5): 601–9. doi:10.1530/EJE-15-1181. PMID 26865584. PMC 4874183. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4874183/.
- Lee, Hyun Gyung; Kim, Chan Jong (2022). "Classic and backdoor pathways of androgen biosynthesis in human sexual development". Ann Pediatr Endocrinol Metab 27 (2): 83–89. doi:10.6065/apem.2244124.062. PMID 35793998.
- Turcu, Adina F.; Auchus, Richard J. (2015). "Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia". Endocrinology and Metabolism Clinics of North America (Elsevier BV) 44 (2): 275–296. doi:10.1016/j.ecl.2015.02.002. ISSN 0889-8529. PMID 26038201. PMC 4506691703046. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4506691703046/.
- Turcu, A. F.; Rege, J.; Chomic, R.; Liu, J.; Nishimoto, H. K.; Else, T.; Moraitis, A. G.; Palapattu, G. S. et al. (2015). "Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency". The Journal of Clinical Endocrinology and Metabolism 100 (6): 2283–2290. doi:10.1210/jc.2015-1023. PMID 25850025. PMC 4454804. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4454804/.
- "Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia". Eur J Endocrinol 181 (5): 481–488. November 2019. doi:10.1530/EJE-19-0379. PMID 31505456.
- "High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia". J Obstet Gynaecol Res 43 (5): 946–950. May 2017. doi:10.1111/jog.13288. PMID 28188961.
- Turcu, Adina F; Mallappa, Ashwini; Elman, Meredith S; Avila, Nilo A; Marko, Jamie; Rao, Hamsini; Tsodikov, Alexander; Auchus, Richard J et al. (2017). "11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency". The Journal of Clinical Endocrinology and Metabolism 102 (8): 2701–2710. doi:10.1210/jc.2016-3989. PMID 28472487. PMC 5546849. //www.ncbi.nlm.nih.gov/pmc/articles/PMC5546849/.
- White, Perrin C. (2018). "Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Current Opinion in Endocrinology, Diabetes, and Obesity 25 (3): 178–184. doi:10.1097/MED.0000000000000402. PMID 29718004.
- Turcu, Adina F.; Mallappa, Ashwini; Nella, Aikaterini A.; Chen, Xuan; Zhao, Lili; Nanba, Aya T.; Byrd, James Brian; Auchus, Richard J. et al. (2021). "24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency". Front Endocrinol (Lausanne) 12: 751191. doi:10.3389/fendo.2021.751191. PMID 34867794. PMC 8636728. //www.ncbi.nlm.nih.gov/pmc/articles/PMC8636728/.
- Schröder, Mariska A M.; Turcu, Adina F.; o'Day, Patrick; Van Herwaarden, Antonius E.; Span, Paul N.; Auchus, Richard J.; Sweep, Fred C G J.; Claahsen-Van Der Grinten, Hedi L. (2022). "Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors". J Clin Endocrinol Metab 107 (1): e272–e280. doi:10.1210/clinem/dgab598. PMID 34390337. PMC 8684463. //www.ncbi.nlm.nih.gov/pmc/articles/PMC8684463/.
- Miller, Walter L.; Auchus, Richard J. (2019). "The "backdoor pathway" of androgen synthesis in human male sexual development". PLOS Biology 17 (4): e3000198. doi:10.1371/journal.pbio.3000198. PMID 30943210. PMC 6464227. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6464227/.
- Flück, Christa E.; Pandey, Amit V. (2014). "Steroidogenesis of the testis -- new genes and pathways". Ann Endocrinol (Paris) 75 (2): 40–7. doi:10.1016/j.ando.2014.03.002. PMID 24793988.
- Zachmann, M. (1996). "Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency". J Clin Endocrinol Metab 81 (2): 457–9. doi:10.1210/jcem.81.2.8636249. PMID 8636249.
- "Rare forms of genetic steroidogenic defects affecting the gonads and adrenals". Best Pract Res Clin Endocrinol Metab 36 (1): 101593. 2022. doi:10.1016/j.beem.2021.101593. PMID 34711511.
- Du Toit, Therina; Swart, Amanda C. (2021). "Turning the spotlight on the C11-oxy androgens in human fetal development". J Steroid Biochem Mol Biol 212: 105946. doi:10.1016/j.jsbmb.2021.105946. PMID 34171490.
- Finkielstain, Gabriela P.; Vieites, Ana; Bergadá, Ignacio; Rey, Rodolfo A. (2021). "Disorders of Sex Development of Adrenal Origin". Front Endocrinol (Lausanne) 12: 770782. doi:10.3389/fendo.2021.770782. PMID 34987475. PMC 8720965. //www.ncbi.nlm.nih.gov/pmc/articles/PMC8720965/.
- Marti, Nesa; Galván, José A.; Pandey, Amit V.; Trippel, Mafalda; Tapia, Coya; Müller, Michel; Perren, Aurel; Flück, Christa E. (2017). "Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome". Mol Cell Endocrinol 441: 116–123. doi:10.1016/j.mce.2016.07.029. PMID 27471004.
- Stewart, P. M.; Shackleton, C. H.; Beastall, G. H.; Edwards, C. R. (1990). "5 alpha-reductase activity in polycystic ovary syndrome". Lancet (London, England) 335 (8687): 431–433. doi:10.1016/0140-6736(90)90664-q. ISSN 0140-6736. PMID 1968168. https://pubmed.ncbi.nlm.nih.gov/1968168.
- Vassiliadi, Dimitra A.; Barber, Thomas M.; Hughes, Beverly A.; McCarthy, Mark I.; Wass, John A. H.; Franks, Stephen; Nightingale, Peter; Tomlinson, Jeremy W. et al. (2009). "Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome". J Clin Endocrinol Metab 94 (9): 3558–66. doi:10.1210/jc.2009-0837. PMID 19567518.
- Swart, Amanda C.; du Toit, Therina; Gourgari, Evgenia; Kidd, Martin; Keil, Meg; Faucz, Fabio R.; Stratakis, Constantine A. (2021). "Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS". Pediatric Research (Springer Science and Business Media LLC) 89 (1): 118–126. doi:10.1038/s41390-020-0870-1. ISSN 0031-3998. PMID 32247282. PMC 7541460. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7541460/.
- Kempegowda, Punith; Melson, Eka; Manolopoulos, Konstantinos N.; Arlt, Wiebke; o'Reilly, Michael W. (2020). "Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome". Ther Adv Endocrinol Metab 11: 2042018820934319. doi:10.1177/2042018820934319. PMID 32637065. PMC 7315669. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7315669/.
- o'Reilly, Michael W.; Kempegowda, Punith; Jenkinson, Carl; Taylor, Angela E.; Quanson, Jonathan L.; Storbeck, Karl-Heinz; Arlt, Wiebke (2017). "11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome". J Clin Endocrinol Metab 102 (3): 840–848. doi:10.1210/jc.2016-3285. PMID 27901631. PMC 5460696. //www.ncbi.nlm.nih.gov/pmc/articles/PMC5460696/.
- Yoshida, Tomoko; Matsuzaki, Toshiya; Miyado, Mami; Saito, Kazuki; Iwasa, Takeshi; Matsubara, Yoichi; Ogata, Tsutomu; Irahara, Minoru et al. (2018). "11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome". Endocr J 65 (10): 979–990. doi:10.1507/endocrj.EJ18-0212. PMID 30012903.
- Torchen, Laura C.; Sisk, Ryan; Legro, Richard S.; Turcu, Adina F.; Auchus, Richard J.; Dunaif, Andrea (2020). "11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity". J Clin Endocrinol Metab 105 (11): e3903–e3909. doi:10.1210/clinem/dgaa532. PMID 32797203. PMC 7500474. //www.ncbi.nlm.nih.gov/pmc/articles/PMC7500474/.
- Miller, Walter L. (2019). "Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol". Hormone Research in Paediatrics 91 (6): 416–420. doi:10.1159/000501396. ISSN 1663-2826. PMID 31450227. https://pubmed.ncbi.nlm.nih.gov/31450227.
- Du Toit, Therina; Swart, Amanda C. (2018). "Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer". Mol Cell Endocrinol 461: 265–276. doi:10.1016/j.mce.2017.09.026. PMID 28939401.
- "Urinary androgens excretion patterns and prostate cancer in Mexican men". Endocr Relat Cancer 28 (12): 745–756. October 2021. doi:10.1530/ERC-21-0160. PMID 34520388.
- Snaterse, G.; Van Dessel, L. F.; Van Riet, J.; Taylor, A. E.; Van Der Vlugt-Daane, M.; Hamberg, P.; De Wit, R.; Visser, J. A. et al. (2021). "11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration". JCI Insight 6 (11). doi:10.1172/jci.insight.148507. PMID 33974560. PMC 8262344. //www.ncbi.nlm.nih.gov/pmc/articles/PMC8262344/.
- Dimitrakov, Jordan; Joffe, Hylton V.; Soldin, Steven J.; Bolus, Roger; Buffington, C.A. Tony; Nickel, J. Curtis (2008). "Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome". Urology 71 (2): 261–6. doi:10.1016/j.urology.2007.09.025. PMID 18308097. PMC 2390769. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2390769/.
- Du Toit, Therina; Swart, Amanda C. (2020). "The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone". The Journal of Steroid Biochemistry and Molecular Biology 196: 105497. doi:10.1016/j.jsbmb.2019.105497. PMID 31626910.