The androgen backdoor pathway is a collective name for all metabolic pathways where physiologically significant androgens are synthesized from 21-carbon (C
21) steroids (pregnanes) by their 5α-reduction, bypassing testosterone and/or androstenedione.

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

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

The role of these backdoor pathways relates to early male sexual differentiation, hair growth patterns, regulation of secretory functions, sebum production by skin cells, and various biological processes where androgens are involved. Understanding these processes is essential for developing effective treatments for conditions associated with hyperandrogenism. In individuals with congenital adrenal hyperplasia (CAH) due to enzyme deficiencies like 21-hydroxylase deficiency or cytochrome P450 oxidoreductase deficiency (POR), activation of these alternate routes can occur at any age when there is an increase in circulating levels of certain precursors such as progesterone or 17α-hydroxyprogesterone, and can lead to symptoms of hyperandrogenism, such as acne, hirsutism (growth of hair where they should not normally grow), polycystic ovary syndrome or prostate gland enlargement.

Function

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[1]

The androgen backdoor pathways occur without the involvement of testosterone (T) and/or androstenedione (A4), which are part of the conventional, canonical androgenic pathway.[2][3]

In the canonical pathways of androgen biosynthesis, DHT is synthesized from T via 5α-reduction, so that 5α-reduction of T, a C
19 steroid, is the last step of the pathway (see Dihydrotestosterone § Biosynthesis). In the backdoor pathways, to the contrary, 5α-reduction of C
21 steroids is the first step. The 5α-reduction is a chemical reaction where a functional group attached to the carbon in position 5α of the steroid nucleus is reduced, and a double bond between carbon atoms numbered 4 and 5 (see § Figure 1) in the steroid molecule is replaced to the single bond in a chemical reaction catalyzed by the SRD5A1 enzyme (see examples on the § Figure 2 denoted by arrows marked by "SRD5A1" in the square box).[1]

The androgen backdoor pathways are vital for creating androgens from 21-carbon (C
21) steroids, known as pregnanes. A 21-carbon steroid is a steroid molecule with 21 carbon atoms,[4] hence, their chemical formula contains C
21. For example, the chemical formula of progesterone is C
21H
30O
2. That's why 21-carbon steroids are denoted as C
21-steroids, 19-carbon steroids are denoted as C
19 steroids, and so on.[5][6]

The androgen response mechanism involves androgens binding to androgen receptors in the cytoplasm, which then move into the nucleus and control gene transcription by interacting with specific DNA regions called androgen responsive elements.[7] This response mechanism plays a crucial role in male sexual differentiation and puberty, as well as other tissue types and processes, such as the prostate gland (regulate secretory functions), hair follicles (androgens influence hair growth patterns), skin (androgens regulate sebum production and the thickening and maturation of the skin), and muscle (contribute to the development and maintenance of muscle mass and strength).[8][9]

Different androgens have different effects on androgen receptors because they have different degrees of binding and activating the receptors. Clinically significant androgens are those androgens that have a strong influence on the development and functioning of male sexual characteristics, unlike clinically insignificant androgens, which have low biological activity or are quickly metabolized into other steroids. Clinically insignificant androgens do not have a notable influence on the development and functioning of male or female sexual characteristics, they can be products of the metabolism of more active androgens, such as testosterone (T), or their precursors.[10]

Sexual differentiation is a process by which hormones determine anatomic phenotype, mainly the development of the reproductive organs.[11]

The function of androgen backdoor pathways is to produce clinically significant androgens in normal conditions where the conventional pathway is insufficient, such as in male early sexual differentiation.[12] Still, androgen backdoor pathways can be activated in pathologic conditions, such as congenital adrenal hyperplasia (CAH), leading to hyperandrogenism.[4][13]

Biochemistry

Dihydrotestosterone backdoor biosynthesis

Figure 2. The canonical pathway of androgen biosynthesis and the backdoor pathways from progesterone (P4) or 17α-hydroxyprogesterone (17OHP) to 5α-dihydrotestosterone (DHT)[11]
Enzymes involved in canonical and backdoor DHT biosynthesis[11]
Gene Enzyme Pathway Directional
preference		 Tissue distribution
AKR1C1 3α-HSD4 Backdoor Reductive Liver, testis, lung, breast, uterus, brain
AKR1C2 3α-HSD3 Backdoor Reductive Liver, prostate, lung, uterus, brain
AKR1C3 3α-HSD2 Backdoor Reductive Prostate, breast, liver, adrenal, testis, lung
AKR1C4 3α-HSD1 Backdoor Reductive Liver >> adrenal/gonad
HSD3B1 3β-HSD1 Backdoor/Canonical Oxidative Testis, adrenal, placenta
HSD3B2 3β-HSD2 Backdoor/Canonical Oxidative Testis, adrenal
HSD17B3 17β-HSD3 Backdoor/Canonical Oxidative Leydig cells (testis)
HSD17B6 17β-HSD6 (RoDH) Backdoor Oxidative Prostate
SRD5A1 5α-reductase, type 1 Backdoor/Canonical Reductive Wide tissue expression
SRD5A2 5α-reductase, type 2 Backdoor/Canonical Reductive Prostate
SRD5A3 5α-reductase, type 3 Backdoor/Canonical Reductive Wide tissue expression
StAR steroidogenic acute regulatory protein Backdoor/Canonical N/A Adrenal gland and Leydig cells
CYP11A1 P450scc Backdoor/Canonical Oxidative Adrenal gland and testis
CYP17A1 Steroid 17-alpha-hydroxylase Backdoor/Canonical Oxidative Adrenal gland and testis
POR cytochrome b5, P450 oxidoreductase Backdoor/Canonical N/A Liver, lower levels in other tissues

The primary feature of the androgen backdoor pathway is that 17α-hydroxyprogesterone (17OHP) can be 5α-reduced and finally converted to 5α-dihydrotestosterone (DHT) via an alternative route that bypasses the conventional[14] intermediates androstenedione (A4) and testosterone (T).[4][15]

This route is activated during normal prenatal development and leads to early male sexual differentiation.[12][16][17] 5α-dihydrotestosterone synthesized by this route plays a critical role in the development of male sexual characteristics, including the differentiation and maturation of the male external genitalia, the prostate gland, and other male reproductive structures. By bypassing the conventional intermediates (A4 and T), this pathway ensures the timely and appropriate development of male sexual traits in early embryonic and fetal stages. Both canonical and backdoor pathways are essential in normal male embryonic development.[18][12][19] A disruption in the backdoor pathway can lead to incomplete or altered male sexual differentiation. This disruption may result in abnormalities or underdevelopment of the male external genitalia, prostate gland, and other male reproductive structures. The specific consequences can vary depending on the nature and extent of the disruption and may lead to conditions such as ambiguous genitalia or other disorders of sexual development (DSD), where the individual's physical and sexual characteristics do not align clearly with typical male, i.e., undervirilization of male infants.[18][20][21][11] Undervirilization refers to insufficient development of male characteristics due to below-normal effects of androgens during prenatal development. After birth, it may manifest as markedly underdeveloped male genitalia.[22]

The backdoor pathway of DHT biosynthesis from 17OHP to DHT was first described in the marsupials and later confirmed in humans.[23][11] Both the canonical and backdoor pathways of DHT biosynthesis are required for normal development of male genitalia in humans. As such, defects in the backdoor pathway from 17OHP or progesterone (P4) to DHT lead to undervirilization in male fetuses because placental P4 is the precursor of DHT via the backdoor pathway.[18]

In 21-hydroxylase deficiency[15] or cytochrome P450 oxidoreductase deficiency,[24] this route may be activated regardless of age and sex by even a mild increase in circulating 17OHP levels.[25]

While 5α-reduction is the last transformation in the classical androgen pathway, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17OHP or P4 which are ultimately converted to DHT.[4]

17α-Hydroxyprogesterone pathway

The first step of this pathway is the 5α-reduction of 17OHP to 5α-pregnan-17α-ol-3,20-dione (referred to as 17OHDHP or 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.[26][24]

17OHDHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)[20][23] or HSD17B6, that also has 3α-reduction activity.[27][28] 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17OH-allopregnanolone.[4]

5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one, also known as androsterone (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a 21-C carbon steroid (a pregnane) to C
19 steroid (an androstane or androgen).[4]

AST is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by HSD17B3 or AKR1C3.[29]

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,[30] HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9.[24] This oxidation is not required in the classical androgen pathway. The pathway can be summarized as: 17OHP → 17OHDHP → 5α-Pdiol → AST → 3α-diol → DHT.[4]

Progesterone pathway

The pathway from progesterone (P4) to DHT is similar to that described above from 17OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17OHP. Placental P4 in the male fetus is the feedstock, that is, a starting point, the initial substrate, for the backdoor pathway found operating in multiple non-gonadal tissues.[20] The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to allopregnanolone (AlloP5) via 3α-reduction by AKR1C2 or AKR1C4. AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. The pathway then proceeds the same way as the pathway that starts from 17OHP, and can be summarized as: P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT.[4]

11-Oxygenated androgen backdoor biosynthesis

Figure 3. The backdoor pathways from progesterone or 17α-hydroxyprogesterone to 11-oxygenated androgens, with transformations (black arrow). The two groups of steroids are distinguished by the C17 substituent configuration associated with four distinct precursors. The first group is the conversion of progesterone. The second group is the conversion of 17-hydroxyprogesterone. CYP17A1 catalyzes the C
21 steroids (pregnanes) to C
19 steroids (androstanes). Some transformations which are presumed to exist but not yet shown to exist are depicted with dotted arrows. Some CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ5 compounds that are transformed to Δ4 compounds are also omitted for clarity.[1]

There are two known clinically significant 11-oxygenated androgens, 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT), which both bind and activate the androgen receptor with affinities, potencies, and efficacies that are similar to that of testosterone (T) and DHT, respectively.[31]

As for 11β-hydroxytestosterone (11OHT) and 11β-hydroxydihydrotestosterone (11OHDHT), the androgenicity of these steroids is a point of research. Although some studies[32][33][1] suggest that though 11β-hydroxytestosterone (11OHT) and 11β-hydroxydihydrotestosterone (11OHDHT) may not have significant androgenic activity as they were once thought to possess, they may still be important precursors to androgenic molecules. The relative importance of the androgens depends on their activity, circulating levels and stability. The steroids 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4) have been established as having minimal androgen activity, but remain important molecules in this context since they act as androgen precursors.[34][35]

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

  1. 11β-hydroxylation by CYP11B1 in the adrenal cortex,
  2. 5α-reduction by SRD5A1/SRD5A2,
  3. reversible 3α-reduction/oxidation of the ketone/alcohol (an oxo (=O) functional group or hydroxyl (−OH) functional group, respectively) by AKR1C2 or AKR1C4.[36]

Clinical significance

Congenital adrenal hyperplasia

In congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase[15] or cytochrome P450 oxidoreductase (POR),[24][18] the associated elevated 17OHP levels result in flux through the backdoor pathway to DHT that begins with 5α-reduction of 17OHP. This pathway may be activated regardless of age and sex and cause symptoms of androgen excess[37] In adult females, excess androgens can cause hirsutism (excessive hair growth), alopecia (hair loss), menstrual irregularities, infertility, and polycystic ovary syndrome (PCOS). In adult males, excess androgens can cause prostate enlargement, prostate cancer, and reduced sperm quality. In adults of both sexes, excess androgens can also cause metabolic disturbances, such as insulin resistance, dyslipidemia, hypertension, and cardiovascular disease.[38] In fetus, excess of androgens due to excess of fetal 17OHP in CAH may contribute to DHT synthesis that leads to external genital virilization in newborn girls with CAH.[24] P4 levels may also be elevated in CAH,[39][40] leading to androgen excess via the backdoor pathway from P4 to DHT.[41] 17OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.[42]

Masculinization of female external genitalia in a fetus due to the mother's intake of certain exogenous hormones—the so-called progestin-induced virilization—is usually less noticeable than in congenital adrenal hyperplasia (CAH), and unlike CAH, it does not cause progressive virilization.[43]

Serum levels of the C
21 11-oxygenated steroids: 21-deoxycorticosterone (11OHP4) and 21-deoxycortisol (21dF), have been known to be elevated in both non-classical and classical forms of CAH since about 1990,[44][45] and liquid chromatography–mass spectrometry profiles that include these steroids have been proposed for clinical applications,[46] including newborn screening.[47] Classical CAH patients receiving glucocorticoid therapy had C
19 11-oxygenated steroid serum levels that were elevated 3-4 fold compared to healthy controls.[48] In that same study, the levels of C
19 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition. In adult women with CAH, the ratio of DHT produced in a backdoor pathway to that produced in a conventional pathway increases as control of androgen excess by glucocorticoid therapy deteriorates.[49] In CAH patients with poor disease control, 11-oxygenated androgens remain elevated for longer than 17OHP, thus serving as a better biomarker for the effectiveness of the disease control.[50][51] In males with CAH, 11-oxygenated androgen levels may indicate the presence of testicular adrenal rest tumors.[51][52]

Fetal development

In order for the male genitalia to develop properly in humans, both the classical and backdoor pathways are essential as means of DHT biosynthesis.[12][18] Deficiencies in the backdoor pathway that converts 17OHP or P4 into DHT can result in undervirilization of the male fetus.[53][54] This underviriliztion may happen because placental P4 acts as an important precursor to fetal DHT specifically within the backdoor pathway that should not be disrupted.[20][23][26]

Undervirilization refers to an incomplete masculinization of the male fetus. It can have consequences such as ambiguous genitalia or underdeveloped reproductive organs including the penis and testes.[55] These conditions may impact fertility, sexual function, and can also affect an individual's overall gender identity later in life.[56]

A case study[23] involving five individuals with a 46,XY (male) chromosomal pattern from two families revealed that their DSD, manifested in unusual genital appearance, was caused by mutations in the AKR1C2 and/or AKR1C4 genes. These genes are exclusively involved in the backdoor pathway of 5α-dihydrotestosterone (DHT) production. Mutations in the AKR1C3 and genes involved in the classical androgen pathway were excluded as the causes for the atypical genital appearance. Interestingly, their female relatives with a 46,XX chromosomal pattern who had the same mutations exhibited normal physical characteristics and fertility. Although both AKR1C2 and AKR1C4 enzymes are needed for DHT synthesis in a backdoor pathway, the study found that mutations in AKR1C2 only were sufficient for disruption.[23] However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.[57] This case study highlights the role of AKR1C2/4 in the alternative androgen pathways.[11]

Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b5, and POR may also disrupt the backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both classical and backdoor androgen pathways.[53] This rare deficiency can lead to DSD in both sexes, with affected girls being asymptomatic until puberty, when they show amenorrhea.[57]

11-oxygenated androgens may play important roles in DSDs.[58][59][24] 11-oxygenated androgen fetal biosynthesis may coincide with the key stages of production of cortisol — at weeks 8–9, 13–24, and from 31 and onwards. In these stages, impaired CYP17A1 and CYP21A2 activity lead to increased ACTH due to cortisol deficiency and the accumulation of substrates for CYP11B1 in pathways to 11-oxygenated androgens and could cause abnormal female fetal development.[58][60]

Benign prostatic hyperplasia, chronic prostatitis/chronic pelvic pain syndrome

Androgens are known to play a crucial role not only in prostate cancer but also in other prostate-related conditions such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).[61] In BPH, C
21 11-oxygenated steroids (pregnanes) have been identified are precursors to androgens in BHP.[62] Specifically, steroids like 11OHP4 and 11KP4 can be converted to 11KDHT, an 11-oxo form of DHT with the same potency. These precursors have also been detected in tissue biopsy samples from patients with BPH, as well as in their serum levels. The relationship between steroid serum levels and CP/CPPS suggests that deficiencies in the enzyme CYP21A2 may contribute to the development of this condition. Non-classical congenital adrenal hyperplasia (CAH) resulting from CYP21A2 deficiency is typically considered asymptomatic in men. However, non-classical CAH could be a comorbidity associated with CP/CPPS.[63][64][65]

Prostate Cancer

The backdoor pathway to DHT plays a role in the development of androgen-sensitive cancers, such as prostate cancer. In some cases, tumor cells have been found to possess higher levels of enzymes involved in this pathway, resulting in increased production of DHT.[66]

Androgen deprivation therapy (ADT) is a common treatment for prostate cancer, which involves reducing the levels of androgens, specifically T and DHT, in the body.[66] This treatment is done through the use of medications that aim to block the production or action of these hormones. While ADT can be effective in slowing the growth of prostate cancer, it also has several drawbacks, one of which is the potential for increased production of P4 and activation of the backdoor pathway of DHT biosynthesis where P4 serves as a substrate. Normally, this pathway is not very active in healthy adult males, as the majority of DHT is produced through the classical pathway, which involves the direct conversion of T into DHT by one of the SRD5A isozymes. However, when T levels are reduced through ADT, the body may compensate by increasing the production of P4, which can then serve as a substrate for the backdoor pathway. One of the main drawbacks of this increased production of P4 leads to an increase in DHT levels, which fuel the growth of prostate cancer cells. This increased production of P4 and DHT can result in the cancer becoming resistant to ADT and continuing to grow and spread. Additionally, the increased levels of P4 can also cause side effects such as weight gain, fatigue, and mood swings (extreme or rapid changes in mood).[66]

In prostate cancer, removal of testicular T through castration (surgical or chemical removal or inactivation of testicles) helps eliminate the growth-promoting effects of androgens.[66] However, in some cases, metastatic tumors can develop into castration-resistant prostate cancer (CRPC).[67] While castration reduces serum T levels by 90-95%, it only decreases DHT in the prostate gland by 50%. This difference between the magnitude of androgen levels confirms that the prostate has enzymes capable of producing DHT even without testicular T.[61] In addition to DHT production within the prostate, researchers found that 11-oxygenated androgens play a role in maintaining total circulating androgen pool levels which are relevant to the amounts of clinically significant androgens in the body.[68] These 11-oxygenated androgens contribute greatly to reactivating androgen signaling in patients with CRPC.[66][29] Serum levels of 11KT, one type of 11-oxygenated androgen, are higher than any other androgen in approximately 97% of CRPC patients. In fact, 11-oxygenated androgens make up around 60% of the total active androgen pool in such patients. Unlike T or DHT, these levels of 11-oxygenated androgens remain unaffected by castration therapy.[66]


History

In the early 2000s, the 5α-reduction of 17α-hydroxyprogesterone was described in medical literature as the start of the backdoor pathway to DHT biosynthesis. This pathway was first described in the marsupials and later confirmed in humans.[23] That's why the backdoor pathway of DHT biosynthesis from 17OHP can be called a marsupial pathway.[11] This pathway is also present in other mammals,[69][70] such as rats, and are studied in the other mammals as a way to better understand these pathways in humans.[4][69][26]

Marsupials, and in particular, tammar wallabies (Notamacropus eugenii)[71] are especially useful for studying the processes of sexual differentiation and development in the context of androgen biosynthesis,[11][72] because sexual differentiation in these species occurs only after birth, with testes beginning to form two days after birth and ovaries only on the eighth day after birth. This feature of post-natal early sexual differentiation allows scholars to study the influence of hormones on the body from the very beginning of the process of sexual differentiation, as well as the pathways of biosynthesis of these hormones. Tammar wallabies are particularly interesting due to the fact that all these hormones, pathways, and the ways in which hormones affect body features and growth of different organs can be studied when the organism is already born, unlike in other mammals such as rats, where sexual differentiation in a fetus occurs inside the placenta before birth.[73][74][75]

The discovery of the backdoor pathway to DHT biosynthesis in tammar wallaby pouch young in 2003 prompted research into identifying and characterizing similar pathways in humans, leading to a better understanding of the regulation, metabolism, and therapeutic targeting of androgen biosynthesis in human health and diseases related to excessive or insufficient androgen biosynthesis when the classical androgen pathway could not fully explain the observed conditions in patients.[11][71] Over the following two decades, several other distinct pathways have been discovered: the pathways that lead to the synthesis of 11-oxygenated androgens.[31] [21][76]

In 2000, Shaw et al.[16] demonstrated that circulating 3α-diol mediates prostate development in tammar wallaby pouch young via conversion to DHT in target tissues. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development which suggests that another androgenization mechanism was responsible. While 3α-diol's androgen receptor binding affinity is five orders of magnitude lower than DHT (generally described as AR inactive), it was known that 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.[77]

In 2003, Wilson et al.[71] demonstrated that 5α-reductase expression in this tissue enabled a novel pathway from 17OHP to 3α-diol without T as an intermediate.[71]

In 2004, Mahendroo et al.[17] demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby.[17]

The term "backdoor pathway" was coined by Auchus in 2004[4] and was described as 5α-reduction of 17α-hydroxyprogesterone (17OHP) which is a first step in a pathway that ultimately leads to the production of 5α-dihydrotestosterone (DHT). and defined as a route to DHT that: (1) bypasses conventional intermediates androstenedione (A4) and T; (2) involves 5α-reduction of C
21 pregnanes to C
19 androstanes; and (3) involves the 3α-oxidation of 3α-diol to DHT.[78] The backdoor pathway explains how androgens are produced under certain normal and pathological conditions in humans when the classical androgen pathway cannot fully explain the observed consequences.[4]

The clinical relevance of the results published by Auchus in 2004 was demonstrated in 2012 for the first time when Kamrath et al.[15] attributed the urinary metabolites to the androgen backdoor pathway from 17OHP to DHT in patients with steroid 21-hydroxylase (encoded by the gene CYP21A2) enzyme deficiency.[15]

Barnard et al.[21] in 2017 demonstrated metabolic pathways from C
21 steroids to 11KDHT that bypasses A4 and T, an aspect that is similar to that of the backdoor pathway to DHT. These newly discovered pathways to 11-oxygenated androgens were also described as "backdoor" pathways due to this similarity, and were further characterized in subsequent studies.[79][42]

Note

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

List of figures

  1. Numbering of carbon atoms in a steroid molecule
  2. The backdoor pathways from progesterone or 17α-hydroxyprogesterone to 5α-dihydrotestosterone
  3. The backdoor pathways from progesterone or 17α-hydroxyprogesterone to 11-oxygenated androgens

See also

References

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