Wikipedia

Androgen backdoor pathway

The androgen backdoor pathway is responsible for the synthesis of physiologically relevant androgens. This process starts with 21-carbon (C
21) steroids, also known as pregnanes, and involves a step called "5α-reduction". Notably, this pathway does not require the intermediate formation of testosterone, hence the term "bypassing testosterone" is sometimes used in medical literature as the hallmark feature of this way of androgen biosynthesis. This feature is a key distinction from the conventional, canonical androgenic pathway, which necessitates the involvement of testosterone as an intermediate in the synthesis of androgens.

Figure 1. Schematic diagram of the canonical (left), backdoor (middle), and 11-oxy backdoor (right) pathways of androgen biosynthesis

These alternate androgen pathways play a crucial role in early male sexual development. In individuals with congenital adrenal hyperplasia due to enzyme deficiencies like 21-hydroxylase or cytochrome P450 oxidoreductase deficiency, these pathways can activate at any age with increased levels of precursors like progesterone or 17α-hydroxyprogesterone.[citation needed] This activation can lead to symptoms of hyperandrogenism such as acne, hirsutism, polycystic ovarian syndrome, or prostate enlargement.

In the canonical pathway, dihydrotestosterone is directly synthesized from testosterone by the enzyme 5α-reductase, primarily in tissues like the prostate gland, hair follicles, and skin. Both pathways rely on 5α-reductase, but in the androgen backdoor pathway, this enzyme acts on C
21 steroids (pregnanes), initiating a series of chemical reactions that eventually lead to dihydrotestosterone production. In contrast, in the canonical pathway, 5α-reductase targets the 4,5-double bond in testosterone, producing dihydrotestosterone directly.

The backdoor pathway was initially described as a biosynthetic route where 5α-reduction of 17α-hydroxyprogesterone ultimately leads to dihydrotestosterone. Since then, several other pathways have been discovered that lead to 11-oxygenated androgens which are also physiologically significant.

Function

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Androgens that bind to and activate the androgen receptor have numerous physiological functions which can broadly divided into androgenic (male sexual development) and anabolic (building muscle and bone). The anabolic effects are important in both males and females, although females have lower circulating levels of androgens. The physiologically most important androgens are testosterone (T) and dihydrotestosterone (DHT), which are considered classical androgens because their role in human health was discovered in 1930s.[1] However, much later, in 2010s,[2] the role in human health of 11-oxygenated androgens was established, namely, of 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT), that both bind and activate the human androgen receptor with affinities, potencies, and efficacies that are similar to that of testosterone (T) and DHT, respectively,[3][2][4] although 11-oxygenated androgens were long known to be principal androgens in teleost fishes.[2]

The main biochemical route to T and DHT is the canonical (classical) pathway that proceeds from pregnenolone (P5). Alternatively, DHT but not T can be produced through a backdoor pathway that proceeds from 17α-hydroxyprogesterone (17OHP) or progesterone (P4).[citation needed] The function of androgen backdoor pathways is to produce physiologically significant androgens in normal conditions where the conventional pathway is insufficient, such as in male early sexual differentiation.[5][3] Sexual differentiation is a process by which hormones determine anatomic phenotype, mainly the development of the reproductive organs.[6] DHT is the most important androgenic hormone and is a product of both canonical and backdoor pathways.[7] Additionally, 11KDHT but not 11KT can be biosynthesized from the C11-oxy backdoor pathway starting from progesterone (P4).[citation needed] These C11-oxy androgens can contribute to the pathology of congenital adrenal hyperplasia, polycystic ovarian syndrome, and prostate cancer.[7][8]

The androgen backdoor route is activated during normal prenatal development and leads to early male sexual differentiation.[5][9][10] 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.[11] 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.[12][5][13] 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.[12][6] 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.[14]

The backdoor pathway of DHT biosynthesis from 17OHP to DHT was first described in the marsupials and later confirmed in humans.[15][16][6] 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 17α-hydroxyprogesterone (17OHP) or progesterone (P4) to DHT lead to undervirilization in male fetuses because placental P4 is the precursor of DHT via the backdoor pathway.[12]

In 21-hydroxylase deficiency[17] or cytochrome P450 oxidoreductase deficiency,[18] even a mild increase in circulating 17-OHP levels may activate this pathway, regardless of the patient's age and sex.[19][20]

Mechanism

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Androgen signaling

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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 response elements.[21] 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).[22][23]

Different androgens have different effects on androgen receptors because they have different degrees of binding and activating the receptors. Physiologically significant androgens are those androgens that have a strong influence on the development and functioning of male sexual characteristics, unlike physiologically insignificant androgens, which have low biological activity or are quickly metabolized into other steroids. Physiologically 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.[24]

Androgen biosynthesis

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Figure 2. Numbering of carbon atoms in a prototypical steroid nucleus[3]

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,[25] 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.[26] The androgen backdoor pathways occur without the involvement of testosterone (T) and/or androstenedione (A4), which are part of the conventional, canonical (classic)[27][28][11] androgenic pathway.[15]

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).[27][15][29] 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 2) in the steroid molecule is replaced to the single bond in a chemical reaction catalyzed by the SRD5A1 enzyme (see examples on the § Figure 3 denoted by arrows marked by "SRD5A1" in the square box).[3]

The androgen backdoor pathways can be also activated in pathologic conditions (diseases), such as congenital adrenal hyperplasia (CAH), leading to hyperandrogenism.[25][8]

Biochemistry

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Canonical biosynthesis

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Figure 3. Canonical (left) vs backdoor (right) pathways of androgen biosynthesis.[6] Key 5α-reduction steps (catalyzed by SRD5A1/2/3) highlighted in pink.
See also: Testosterone § Biosynthesis, and Dihydrotestosterone § Biosynthesis

In the canonical androgen biosynthesis pathway, dihydrotestosterone (DHT) is synthesized irreversibly from testosterone (T) by the enzyme 5α-reductase,[25][30][31] while T is synthesized from androstenediol (A5) or androstenedione (A4), which all are C
19 steroids (androgens).[25] The 5α-reduction of T occurs in various tissues including the genitals (penis, scrotum, clitoris, labia majora),[32] prostate gland, skin, hair follicles, liver, and brain.[30] Around 5 to 7% of T undergoes 5α-reduction into DHT in male adults.[33][34] Most DHT is produced in peripheral tissues like the skin and liver (called target tissues), whereas most circulating DHT originates specifically from the liver. The testes and prostate gland contribute relatively little to concentrations of DHT in circulation.[30]

Backdoor biosynthesis

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Enzymes involved in canonical and backdoor DHT biosynthesis[6]
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

What distinguishes the androgen backdoor from the classical pathway is whether 5α-reduction initiates or terminates the pathway. In the backdoor pathway, 5α-reduction of progesterone (P4) or 17α-hydroxyprogesterone (17OHP) occurs at or near the beginning of the pathway respectively.[35][25][17] Conversely, in the classical pathway, 5α-reduction is the final step, where testosterone is converted into dihydrotestosterone (DHT).[3]

The backdoor pathway splits into two subpathways at P4, proceeding through either 17OHP or 5α-DHP before merging again at 5α-Pdiol. The biosynthetic intermediate 5α-Pdiol in turn is converted into DHT in two chemical steps.

17OHP subpathway

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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).[3] The reaction is catalyzed by SRD5A1.[36] 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)[37][15][38] or HSD17B6, that also has 3α-reduction activity.[39][40] The pathway then proceeds from 5α-Pdiol the same way as the pathway that starts from P4, i.e. 5α-Pdiol → AST → 3α-diol → DHT.[25]

The pathway can be summarized as: 17OHP → 17OHDHP → 5α-Pdiol → AST → 3α-diol → DHT.[25][3]

5α-DHP subpathway

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The pathway from progesterone (P4) to DHT is similar to that described above from 17OHP to DHT, but the initial substrate for 5α-reductase 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.[37][15][38]

The first step in this pathway is 5α-reduction of P4 toward 5α-dihydroprogesterone (5α-DHP) by SRD5A1.[37][15][38] 5α-DHP is then converted to allopregnanolone (AlloP5) via 3α-reduction by AKR1C2 or AKR1C4.[25][3] AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1.[37][15][38] 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17OH-allopregnanolone.[41][42][12] 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 C
21 steroid (a pregnane) to a C
19 steroid (an androstane or androgen).[25][3] 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, HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9. This oxidation is not required in the classical androgen pathway.[43][44][25] The pathway can be summarized as: P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT.[25]

11-Oxygenated androgen backdoor biosynthesis

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Figure 4. The backdoor pathways from progesterone or 17α-hydroxyprogesterone to 11-ketodihydrotestosterone (rose background). The two groups of steroids are distinguished by the carbon 17 substituent configuration associated with four distinct precursors.[3] 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 (gray box) are omitted for clarity. Δ5 compounds that are transformed to Δ4 compounds are also omitted for clarity.[3]

There are two known physiologically and 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.[4][3]

As for 11β-hydroxytestosterone (11OHT) and 11β-hydroxydihydrotestosterone (11OHDHT), the androgenicity of these steroids is a point of research. Although some studies[45][8][4][22] 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.[2][46][4][47]

Still, of all physiologically and clinically significant 11-oxygenated androgens, only 11KDHT (but not 11KT) is biosynthesized via a backdoor pathway.[48][49][19]

The backdoor pathways to 11-oxygenated androgens can be broadly defined as two Δ4 steroid entry points (17OHP and P4, see Figure 4) that can undergo a common sequence of several transformations:[48][19]

  • 11β-hydroxylation of 17OHP or P4 by CYP11B1 in the adrenal cortex into 21dF or 11OHP4, respectively,[48][19]
  • 5α-reduction by SRD5A1/SRD5A2,[48][19]
  • cleavage of a side-chain (C17-C20 bond) from the steroid nucleus by 17,20-lyase activity of CYP17A1 which converts a C
    21     steroid to a C
    19     steroid,[48][19]
  • 17β-reduction by AKR1C3 (an oxo (=O) functional group in position 17β replaced to the hydroxyl (−OH) functional group),[48][19]
  • reversible 11β-reduction/oxidation of the ketone/alcohol (an oxo (=O) functional group or hydroxyl (−OH) functional group, respectively) by HSD11B1/HSD11B2.[48][19]
  • reversible 3β-reduction/oxidation of the ketone/alcohol (an oxo (=O) functional group or hydroxyl (−OH) functional group, respectively) by AKR1C2 or AKR1C4.[48][50][19]

Clinical significance

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Congenital adrenal hyperplasia

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See also: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

In congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase or cytochrome P450 oxidoreductase (POR),[19][51][12] the associated elevated 17OHP levels result in flux through the backdoor pathway to DHT that begins with 5α-reduction of 17OHP.[3] This pathway may be activated regardless of age and sex and cause symptoms of androgen excess[52] In adult females, excess androgens can cause hirsutism (excessive hair growth), alopecia (hair loss), menstrual irregularities, infertility, and polycystic ovarian syndrome.[8][53] 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.[53] 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.[38][54][55][56] P4 levels may also be elevated in CAH,[56] leading to androgen excess via the backdoor pathway from P4 to DHT.[57] 17OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.[49][3]

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.[58]

Serum levels of the C
21 11-oxygenated steroids: 21-deoxycorticosterone, also known as 11β-hydroxyprogesterone (11OHP4) and 21-deoxycortisol (21dF), have been known to be elevated in both non-classical and classical forms of CAH,[59][60][61] and liquid chromatography–mass spectrometry profiles that include these steroids have been proposed for clinical applications,[62][63] including newborn screening.[19] Classical CAH patients receiving glucocorticoid therapy had C
19 11-oxygenated steroid serum levels that were elevated compared to healthy controls.[56][64][65] 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.[65][64][56] In males with CAH, 11-oxygenated androgen levels may indicate the presence of testicular adrenal rest tumors.[66][56]

Development of the reproductive system

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See also: Development of the gonads

In order for the male genitalia to develop properly in humans, both the classical and backdoor pathways are essential as means of DHT biosynthesis.[5][12] Deficiencies in the backdoor pathway that converts 17OHP or P4 into DHT can result in undervirilization of the male fetus.[67][68] 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.[36]

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.[69] These conditions may impact fertility, sexual function, and can also affect an individual's overall gender identity later in life.[70]

A case study 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 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. However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.[71] This case study highlights the role of AKR1C2/4 in the alternative androgen pathways.[71][6][3]

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.[67] This rare deficiency can lead to DSD in both sexes, with affected girls being asymptomatic until puberty, when they show amenorrhea.[71]

11-oxygenated androgens may play important roles in DSDs.[72][54][27] 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 (virilization).[72][19]

Benign prostatic hyperplasia and prostatitis

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See also: Benign prostatic hyperplasia and Chronic prostatitis/chronic pelvic pain syndrome

Androgens are known to play a crucial role in prostate-related conditions such as benign prostatic hyperplasia (BPH), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and prostate cancer.[73] In BPH, C
21 11-oxygenated steroids (pregnanes) have been identified are precursors to androgens.[74] Specifically, steroids like 11β-hydroxyprogesterone (11OHP4) and 11-ketoprogesterone (11KP4) can be converted to 11-ketodihydrotestosterone (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.[75][76][77]

Prostate cancer

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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.[78][4][7]

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.[79] 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).[79]

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.[79] However, in some cases, metastatic tumors can develop into castration-resistant prostate cancer (CRPC).[80] 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.[73] 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.[81][45][4] These 11-oxygenated androgens contribute greatly to reactivating androgen signaling in patients with CRPC.[79][29] 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.[79]

History

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The backdoor pathway to DHT biosynthesis was discovered in early 2000s in the marsupials and later confirmed in humans.[15] That's why the backdoor pathway of DHT biosynthesis from 17OHP can be called a marsupial pathway.[6] This pathway is also present in other mammals,[82][83] such as rats, and are studied in the other mammals as a way to better understand these pathways in humans.[25][82][36]

Marsupials, and in particular, tammar wallabies (Notamacropus eugenii)[84] are especially useful for studying the processes of sexual differentiation and development in the context of androgen biosynthesis,[6][85] 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.[86][87][88]

The discovery of the backdoor pathway to DHT biosynthesis in tammar wallaby pouch young 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.[6][84] Over the following two decades, several other distinct pathways have been discovered: the pathways that lead to the synthesis of 11-oxygenated androgens.[4][48][89]

Below is a brief selection of key events in the history of androgen backdoor pathway research:[3]

  • In 2000, Shaw et al.[9] demonstrated that circulating 3α-diol mediates prostate development in tammar wallaby pouch young via conversion to DHT in target tissues.[16] 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.[88][90] While 3α-diol's androgen receptor binding affinity is five orders of magnitude lower than DHT (3α-diol is generally described as inactive to the androgen receptor), it was known that 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.[91][92][93]
  • In 2003, Wilson et al.[84] demonstrated that 5α-reductase expression in target tissues enabled a novel pathway from 17OHP to 3α-diol without T or A4 as an intermediate.[84]
  • In 2004, Mahendroo et al.[10] demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby.[16][93][94][95]
  • The term "backdoor pathway" was coined by Auchus in 2004[25] 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 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.[96] 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.[5][97][98]
  • The clinical relevance of the results published by Auchus in 2004 was demonstrated in 2012 for the first time when Kamrath et al.[17] 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.[99][100][101][5]
  • Barnard et al.[48] 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.[102][49][3]

List of figures

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  1. Schematic diagram of the canonical, backdoor, and 11-oxy backdoor pathways of androgen biosynthesis
  2. Numbering of carbon atoms in a steroid molecule
  3. The backdoor pathways from progesterone or 17α-hydroxyprogesterone to dihydrotestosterone
  4. The backdoor pathways from progesterone or 17α-hydroxyprogesterone to 11-oxygenated androgens

See also

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References

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  1. ^ Nieschlag E, Nieschlag S (June 2019). "Endocrine history: The history of discovery, synthesis and development of testosterone for clinical use". secondary. Eur J Endocrinol. 180 (6): R201–R212. doi:10.1530/EJE-19-0071. PMID 30986385.
  2. ^ a b c d Pretorius E, Arlt W, Storbeck KH (February 2017). "A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids" (PDF). secondary. Mol Cell Endocrinol. 441: 76–85. doi:10.1016/j.mce.2016.08.014. PMID 27519632. S2CID 4079662. Archived (PDF) from the original on 9 February 2021. Retrieved 26 February 2024.
  3. ^ a b c d e f g h i j k l m n o p q Masiutin MM, Yadav MK (3 April 2023). "Alternative androgen pathways" (PDF). WikiJournal of Medicine. 10: 29. doi:10.15347/WJM/2023.003. S2CID 257943362. Archived (PDF) from the original on 24 October 2023. Retrieved 10 April 2024.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  4. ^ a b c d e f g Snaterse G, Hofland J, Lapauw B (January 2023). "The role of 11-oxygenated androgens in prostate cancer". secondary. Endocr Oncol. 3 (1): e220072. doi:10.1530/EO-22-0072. PMC 10305623. PMID 37434644.
  5. ^ a b c d e f Miller WL, Auchus RJ (April 2019). "The "backdoor pathway" of androgen synthesis in human male sexual development". secondary. PLOS Biol. 17 (4): e3000198. doi:10.1371/journal.pbio.3000198. PMC 6464227. PMID 30943210.
  6. ^ a b c d e f g h i Biason-Lauber A, Pandey AV, Miller WL, Flück CE (January 2014). "Marsupial pathway in humans.". In New MI, Lekarev O, Parsa A, Yuen TT, O'Malley B, Hammer GD (eds.). Genetic Steroid Disorders. secondary. Academic Press. pp. 215–224. doi:10.1016/B978-0-12-416006-4.00015-6. ISBN 978-0-12-416006-4. Archived from the original on 1 January 2024. Retrieved 1 January 2024.
  7. ^ a b c Turcu AF, Rege J, Auchus RJ, Rainey WE (May 2020). "11-Oxygenated androgens in health and disease". secondary. Nature Reviews. Endocrinology. 16 (5): 284–296. doi:10.1038/s41574-020-0336-x. PMC 7881526. PMID 32203405.
  8. ^ a b c d Wang K, Li Y, Chen Y (2023). "Androgen excess: a hallmark of polycystic ovary syndrome". secondary. Front Endocrinol (Lausanne). 14: 1273542. doi:10.3389/fendo.2023.1273542. PMC 10751361. PMID 38152131.
  9. ^ a b Shaw G, Renfree MB, Leihy MW, Shackleton CH, Roitman E, Wilson JD (October 2000). "Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol". primary. Proceedings of the National Academy of Sciences of the United States of America. 97 (22): 12256–12259. Bibcode:2000PNAS...9712256S. doi:10.1073/pnas.220412297. PMC 17328. PMID 11035809.
  10. ^ a b Mahendroo M, Wilson JD, Richardson JA, Auchus RJ (July 2004). "Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways". primary. Molecular and Cellular Endocrinology. 222 (1–2): 113–120. doi:10.1016/j.mce.2004.04.009. PMID 15249131. S2CID 54297812.
  11. ^ a b Burris-Hiday SD, Scott EE (May 2021). "Steroidogenic cytochrome P450 17A1 structure and function". secondary. Mol Cell Endocrinol. 528: 111261. doi:10.1016/j.mce.2021.111261. PMC 8087655. PMID 33781841.
  12. ^ a b c d e f Lee HG, Kim CJ (June 2022). "Classic and backdoor pathways of androgen biosynthesis in human sexual development". secondary. Annals of Pediatric Endocrinology & Metabolism. 27 (2): 83–89. doi:10.6065/apem.2244124.062. PMC 9260366. PMID 35793998. S2CID 250155674.
  13. ^ Sharpe RM (August 2020). "Androgens and the masculinization programming window: human-rodent differences". secondary. Biochemical Society Transactions. 48 (4): 1725–1735. doi:10.1042/BST20200200. PMC 7458408. PMID 32779695.
  14. ^ Josso N (May 2004). "The undervirilized male child: endocrine aspects". secondary. BJU Int. 93 (Suppl 3): 3–5. doi:10.1111/j.1464-410X.2004.04702.x. PMID 15086435. S2CID 35565574.
  15. ^ a b c d e f g h Lawrence BM, O'Donnell L, Smith LB, Rebourcet D (December 2022). "New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice". secondary. International Journal of Molecular Sciences. 23 (24): 15555. doi:10.3390/ijms232415555. PMC 9779265. PMID 36555196.
  16. ^ a b c Connan-Perrot S, Léger T, Lelandais P, Desdoits-Lethimonier C, David A, Fowler PA, et al. (June 2021). "Six Decades of Research on Human Fetal Gonadal Steroids". secondary. Int J Mol Sci. 22 (13): 6681. doi:10.3390/ijms22136681. PMC 8268622. PMID 34206462.
  17. ^ a b c Kamrath C, Hochberg Z, Hartmann MF, Remer T, Wudy SA (March 2012). "Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis". primary. The Journal of Clinical Endocrinology and Metabolism. 97 (3): E367–E375. doi:10.1210/jc.2011-1997. PMID 22170725. S2CID 3162065.
  18. ^ Reisch N, Taylor AE, Nogueira EF, Asby DJ, Dhir V, Berry A, et al. (October 2019). "Alternative pathway androgen biosynthesis and human fetal female virilization". secondary. Proc Natl Acad Sci U S A. 116 (44): 22294–22299. Bibcode:2019PNAS..11622294R. doi:10.1073/pnas.1906623116. PMC 6825302. PMID 31611378.
  19. ^ a b c d e f g h i j k l de Hora M, Heather N, Webster D, Albert B, Hofman P (2023). "The use of liquid chromatography-tandem mass spectrometry in newborn screening for congenital adrenal hyperplasia: improvements and future perspectives". secondary. Frontiers in Endocrinology. 14: 1226284. doi:10.3389/fendo.2023.1226284. PMC 10578435. PMID 37850096. In 2004, a "backdoor" pathway was described with a metabolic route from 17OHP to DHT that does not involve A4 or T. In CAH, accumulating 17OHP is 5α- and 3α- reduced before being converted to androsterone by CYP17A1 with subsequent reduction and oxidation steps yielding DHT (44). Urinary steroid profiles in babies with CAH revealed that this pathway is active in CAH in the newborn period (45). The backdoor pathway may also make further contributions to the total androgen pool in CAH in the newborn period. In vitro studies have demonstrated that 11-hydroxylated corticosteroids such as 21DF, 21-deoxycortisone (21DE) and 11β-hydroxyprogesterone (11βOHP) can be converted by backdoor pathway enzymes to yield 11-ketodihydrotestosterone (11KDHT) (46), an androgen with a similar potency to DHT ( Figure 1 ). Almost 60 years ago, Jailer and colleagues demonstrated that 21DF and not 17OHP dosing resulted in increased 11-hydroxyandrosterone (11OHAST) excretion, an indication that 21DF is an androgen precursor (47). Whether the route is via the backdoor pathway or by the direct conversion of 21DF to 11OHA4 via CYP17A1, 21DF may be an important contributor to the androgen pool in CAH.
  20. ^ Sumińska M, Bogusz-Górna K, Wegner D, Fichna M (June 2020). "Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report". secondary. International Journal of Molecular Sciences. 21 (13): 4622. doi:10.3390/ijms21134622. PMC 7369945. PMID 32610579.
  21. ^ Van-Duyne G, Blair IA, Sprenger C, Moiseenkova-Bell V, Plymate S, Penning TM (2023). "The androgen receptor". Vitamins and Hormones. secondary. Vol. 123. pp. 439–481. doi:10.1016/bs.vh.2023.01.001. ISBN 978-0-443-13455-5. PMID 37717994.
  22. ^ a b Alemany M (October 2022). "The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health". secondary. International Journal of Molecular Sciences. 23 (19): 11952. doi:10.3390/ijms231911952. PMC 9569951. PMID 36233256.
  23. ^ Ceruti JM, Leirós GJ, Balañá ME (April 2018). "Androgens and androgen receptor action in skin and hair follicles". secondary. Molecular and Cellular Endocrinology. 465: 122–133. doi:10.1016/j.mce.2017.09.009. hdl:11336/88192. PMID 28912032. S2CID 3951518.
  24. ^ Cussen L, McDonnell T, Bennett G, Thompson CJ, Sherlock M, O'Reilly MW (August 2022). "Approach to androgen excess in women: Clinical and biochemical insights". secondary. Clin Endocrinol (Oxf). 97 (2): 174–186. doi:10.1111/cen.14710. PMC 9541126. PMID 35349173.
  25. ^ a b c d e f g h i j k l m Auchus RJ (November 2004). "The backdoor pathway to dihydrotestosterone". secondary. Trends in Endocrinology and Metabolism. 15 (9): 432–438. doi:10.1016/j.tem.2004.09.004. PMID 15519890. S2CID 10631647. 21-carbon steroids can be converted to 19-carbon steroids by a third pathway. The unique feature of the pathway is the 5a-reduction of the 21-carbon precursors, which leads to 19-carbon products that are 5a-reduced. We call this the backdoor pathway to DHT because AD and T are not intermediates to DHT
  26. ^ "Progesterone". secondary. National Library of Medicine. Archived from the original on 21 December 2023. Retrieved 1 January 2024.
  27. ^ a b c Kater CE, Giorgi RB, Costa-Barbosa FA (March 2022). "Classic and current concepts in adrenal steroidogenesis: a reappraisal". secondary. Archives of Endocrinology and Metabolism. 66 (1): 77–87. doi:10.20945/2359-3997000000438. PMC 9991025. PMID 35263051.
  28. ^ Naamneh Elzenaty R, du Toit T, Flück CE (July 2022). "Basics of androgen synthesis and action". secondary. Best Pract Res Clin Endocrinol Metab. 36 (4): 101665. doi:10.1016/j.beem.2022.101665. PMID 35595638. S2CID 248624649. Archived from the original on 15 February 2024. Retrieved 15 February 2024.
  29. ^ a b c Storbeck KH, Mostaghel EA (2019). "Canonical and Noncanonical Androgen Metabolism and Activity". Prostate Cancer. secondary. Advances in Experimental Medicine and Biology. Vol. 1210. Springer. pp. 239–277. doi:10.1007/978-3-030-32656-2_11. ISBN 978-3-030-32655-5. PMID 31900912. S2CID 209748543.
  30. ^ a b c Melmed S (2016). Williams Textbook of Endocrinology. secondary. Elsevier Health Sciences. pp. 621, 711. ISBN 978-0-323-29738-7.
  31. ^ Blume-Peytavi U, Whiting DA, Trüeb RM (2008). Hair Growth and Disorders. secondary. Springer Science & Business Media. pp. 161–62. ISBN 978-3-540-46911-7. Archived from the original on 11 January 2023. Retrieved 5 February 2024.
  32. ^ Rhoades RA, Bell DR (2012). Medical Physiology: Principles for Clinical Medicine. secondary. Lippincott Williams & Wilkins. pp. 690–. ISBN 978-1-60913-427-3.
  33. ^ Rakel D (2012). Integrative Medicine E-Book. secondary. Elsevier Health Sciences. pp. 321–. ISBN 978-1-4557-2503-8.
  34. ^ Morrison MF (2000). Hormones, Gender and the Aging Brain: The Endocrine Basis of Geriatric Psychiatry. secondary. Cambridge University Press. pp. 17–. ISBN 978-1-139-42645-9.
  35. ^ Kinter KJ, Anekar AA (2021). Biochemistry, Dihydrotestosterone. secondary. StatPearls. PMID 32491566. NCBI NBK557634.
  36. ^ a b c Fukami M, Homma K, Hasegawa T, Ogata T (April 2013). "Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development". secondary. Developmental Dynamics. 242 (4): 320–329. doi:10.1002/dvdy.23892. PMID 23073980. S2CID 44702659.
  37. ^ a b c d Bhattacharya I, Dey S (2022). "Emerging concepts on Leydig cell development in fetal and adult testis". secondary. Front Endocrinol (Lausanne). 13: 1086276. doi:10.3389/fendo.2022.1086276. PMC 9851038. PMID 36686449.
  38. ^ a b c d e Pignatti E, du Toit T, Flück CE (February 2023). "Development and function of the fetal adrenal". secondary. Rev Endocr Metab Disord. 24 (1): 5–21. doi:10.1007/s11154-022-09756-3. PMC 9884658. PMID 36255414.
  39. ^ Biswas MG, Russell DW (June 1997). "Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate". secondary. The Journal of Biological Chemistry. 272 (25): 15959–15966. doi:10.1074/jbc.272.25.15959. PMID 9188497.
  40. ^ Muthusamy S, Andersson S, Kim HJ, Butler R, Waage L, Bergerheim U, et al. (December 2011). "Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer". secondary. Proceedings of the National Academy of Sciences of the United States of America. 108 (50): 20090–20094. Bibcode:2011PNAS..10820090M. doi:10.1073/pnas.1117772108. PMC 3250130. PMID 22114194.
  41. ^ Wu Y, Tang L, Azabdaftari G, Pop E, Smith GJ (April 2019). "Adrenal androgens rescue prostatic dihydrotestosterone production and growth of prostate cancer cells after castration". secondary. Mol Cell Endocrinol. 486: 79–88. doi:10.1016/j.mce.2019.02.018. PMC 6438375. PMID 30807787.
  42. ^ Merke DP, Poppas DP (December 2013). "Management of adolescents with congenital adrenal hyperplasia". secondary. Lancet Diabetes Endocrinol. 1 (4): 341–52. doi:10.1016/S2213-8587(13)70138-4. PMC 4163910. PMID 24622419.
  43. ^ Li S, Lee W, Heo W, Son HY, Her Y, Kim JI, et al. (February 2023). "AKR1C2 Promotes Metastasis and Regulates the Molecular Features of Luminal Androgen Receptor Subtype in Triple Negative Breast Cancer Cells". secondary. J Breast Cancer. 26 (1): 60–76. doi:10.4048/jbc.2023.26.e1. PMC 9981988. PMID 36762781.
  44. ^ Mantel A, Carpenter-Mendini AB, Vanbuskirk JB, De Benedetto A, Beck LA, Pentland AP (April 2012). "Aldo-keto reductase 1C3 is expressed in differentiated human epidermis, affects keratinocyte differentiation, and is upregulated in atopic dermatitis". secondary. J Invest Dermatol. 132 (4): 1103–10. doi:10.1038/jid.2011.412. PMC 3305848. PMID 22170488.
  45. ^ a b Snaterse G, Mies R, van Weerden WM, French PJ, Jonker JW, Houtsmuller AB, et al. (June 2023). "Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids". secondary (Meta-Analysis). Prostate Cancer and Prostatic Diseases. 26 (2): 293–301. doi:10.1038/s41391-022-00491-z. PMID 35046557. S2CID 246040148. Archived from the original on 24 February 2024. Retrieved 19 October 2023.
  46. ^ Yin L, Qi S, Zhu Z (2023). "Advances in mitochondria-centered mechanism behind the roles of androgens and androgen receptor in the regulation of glucose and lipid metabolism". secondary. Front Endocrinol (Lausanne). 14: 1267170. doi:10.3389/fendo.2023.1267170. PMC 10613047. PMID 37900128.
  47. ^ Fukami M (2022). "11-Oxyandrogens from the viewpoint of pediatric endocrinology". secondary. Clin Pediatr Endocrinol. 31 (3): 110–115. doi:10.1297/cpe.2022-0029. PMC 9297174. PMID 35928376.
  48. ^ a b c d e f g h i j Barnard L, Gent R, van Rooyen D, Swart AC (November 2017). "Adrenal C11-oxy C
    21     steroids contribute to the C11-oxy C
    19     steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone". secondary. The Journal of Steroid Biochemistry and Molecular Biology. 174: 86–95. doi:10.1016/j.jsbmb.2017.07.034. PMID 28774496. S2CID 24071400. The downstream metabolism of 21dF and 21dE by the enzymes in the backdoor pathway, SRD5A and AKR1C2, was investigated and the resulting novel C11‐oxy C21 steroids, 5α‐pregnan-3α,11β,17-triol-20-one (11OHPdiol) and 5α-pregnan-3α,17-diol-11,20-dione (11KPdiol), were shown to be suitable substrates for the lyase activity of CYP17A1, resulting in the production of C11-oxy C19 steroid metabolites 11β‐hydroxyandrosterone (11OHAST) and 11‐ketoandrosterone (11KAST) [...] The interconversion of 21dF and 21dE by 11βHSD yielded two C11-oxy C21 steroids which our in vitro assays showed are metabolised by steroidogenic enzymes in the backdoor pathway to yield C11-oxy C19 androgens. [...] the backdoor pathway may include the 5α-reduction of 21dF and 21dE in these patients and, as a consequence, the production of potent androgens, 11OHDHT and 11KDHT.    C
    21     steroids contribute to the C11-oxy C
    19     steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone&rft.volume=174&rft.pages=86-95&rft.date=2017-11&rft_id=https://api.semanticscholar.org/CorpusID:24071400#id-name=S2CID&rft_id=info:pmid/28774496&rft_id=info:doi/10.1016/j.jsbmb.2017.07.034&rft.aulast=Barnard&rft.aufirst=L&rft.au=Gent, R&rft.au=van Rooyen, D&rft.au=Swart, AC&rfr_id=info:sid/en.wikipedia.org:Androgen backdoor pathway" class="Z3988">
  49. ^ a b c van Rooyen D, Yadav R, Scott EE, Swart AC (May 2020). "CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway". primary. The Journal of Steroid Biochemistry and Molecular Biology. 199: 105614. doi:10.1016/j.jsbmb.2020.105614. PMID 32007561. S2CID 210955834. [...] steroidogenic research has focused on the metabolism of the C11-oxy C21 steroids in backdoor pathway yielding potent androgens (Fig. 1). Increased activation of the pathway and elevated enzyme expression levels are more frequently reported in the human fetus and ovaries and in clinical conditions which include 21OHD and adrenocortical tumours. [...] The detection of C11-oxy steroids in clinical conditions associated with increased backdoor pathway activity led us to investigate the catalytic activity of CYP17A1 towards the C11-oxy C21 steroids potentially contributing to the androgen pool.
  50. ^ Turcu AF, Nanba AT, Auchus RJ (2018). "The Rise, Fall, and Resurrection of 11-Oxygenated Androgens in Human Physiology and Disease". secondary. Hormone Research in Paediatrics. 89 (5): 284–291. doi:10.1159/000486036. PMC 6031471. PMID 29742491.
  51. ^ Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, et al. (January 2022). "Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management". secondary. Endocr Rev. 43 (1): 91–159. doi:10.1210/endrev/bnab016. PMC 8755999. PMID 33961029.
  52. ^ Turcu AF, Auchus RJ (June 2015). "Adrenal steroidogenesis and congenital adrenal hyperplasia". secondary. Endocrinology and Metabolism Clinics of North America. 44 (2). Elsevier BV: 275–296. doi:10.1016/j.ecl.2015.02.002. PMC 4506691. PMID 26038201.
  53. ^ a b Bacila IA, Elder C, Krone N (December 2019). "Update on adrenal steroid hormone biosynthesis and clinical implications" (PDF). secondary. Arch Dis Child. 104 (12): 1223–1228. doi:10.1136/archdischild-2017-313873. PMID 31175123. S2CID 182950024. Archived (PDF) from the original on 13 December 2023. Retrieved 13 December 2023.
  54. ^ a b Finkielstain GP, Vieites A, Bergadá I, Rey RA (2021). "Disorders of Sex Development of Adrenal Origin". secondary. Frontiers in Endocrinology. 12: 770782. doi:10.3389/fendo.2021.770782. PMC 8720965. PMID 34987475.
  55. ^ Inkster AM, Fernández-Boyano I, Robinson WP (July 2021). "Sex Differences Are Here to Stay: Relevance to Prenatal Care". secondary. J Clin Med. 10 (13): 3000. doi:10.3390/jcm10133000. PMC 8268816. PMID 34279482.
  56. ^ a b c d e Sarafoglou K, Merke DP, Reisch N, Claahsen-van der Grinten H, Falhammar H, Auchus RJ (August 2023). "Interpretation of Steroid Biomarkers in 21-Hydroxylase Deficiency and Their Use in Disease Management". secondary. J Clin Endocrinol Metab. 108 (9): 2154–2175. doi:10.1210/clinem/dgad134. PMC 10438890. PMID 36950738.
  57. ^ Ntali G, Charisis S, Kylafi CF, Vogiatzi E, Michala L (July 2021). "The way toward adulthood for females with nonclassic congenital adrenal hyperplasia". secondary. Endocrine. 73 (1): 16–30. doi:10.1007/s12020-021-02715-z. PMID 33855677. S2CID 233237454.
  58. ^ Schardein JL (1980). "Congenital abnormalities and hormones during pregnancy: a clinical review". secondary. Teratology. 22 (3): 251–70. doi:10.1002/tera.1420220302. PMID 7015547.
  59. ^ Di Cosola M, Spirito F, Zhurakivska K, Nocini R, Lovero R, Sembronio S, et al. (2022). "Congenital adrenal hyperplasia. Role of dentist in early diagnosis". secondary. Open Med (Wars). 17 (1): 1699–1704. doi:10.1515/med-2022-0524. PMC 9616050. PMID 36382053.
  60. ^ Adriaansen BP, Schröder MA, Span PN, Sweep FC, van Herwaarden AE, Claahsen-van der Grinten HL (2022). "Challenges in treatment of patients with non-classic congenital adrenal hyperplasia". secondary. Front Endocrinol (Lausanne). 13: 1064024. doi:10.3389/fendo.2022.1064024. PMC 9791115. PMID 36578966.
  61. ^ Falhammar H, Nordenström A (September 2015). "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome". secondary. Endocrine. 50 (1): 32–50. doi:10.1007/s12020-015-0656-0. PMID 26082286. S2CID 23469344.
  62. ^ French D (April 2023). "Clinical utility of laboratory developed mass spectrometry assays for steroid hormone testing". secondary. J Mass Spectrom Adv Clin Lab. 28: 13–19. doi:10.1016/j.jmsacl.2023.01.006. PMC 9900367. PMID 36756146.
  63. ^ Falhammar H, Thorén M (June 2012). "Clinical outcomes in the management of congenital adrenal hyperplasia". secondary. Endocrine. 41 (3): 355–73. doi:10.1007/s12020-011-9591-x. PMID 22228497. S2CID 22387824.
  64. ^ a b Itonaga T, Hasegawa Y (2023). "Monitoring treatment in pediatric patients with 21-hydroxylase deficiency". Front Endocrinol (Lausanne). 14: 1102741. doi:10.3389/fendo.2023.1102741. PMC 9945343. PMID 36843618.
  65. ^ a b Mallappa A, Merke DP (June 2022). "Management challenges and therapeutic advances in congenital adrenal hyperplasia". secondary. Nat Rev Endocrinol. 18 (6): 337–352. doi:10.1038/s41574-022-00655-w. PMC 8999997. PMID 35411073.
  66. ^ Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, et al. (August 2017). "11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency". primary. The Journal of Clinical Endocrinology and Metabolism. 102 (8): 2701–2710. doi:10.1210/jc.2016-3989. PMC 5546849. PMID 28472487.
  67. ^ a b Flück CE, Pandey AV (May 2014). "Steroidogenesis of the testis – new genes and pathways". secondary. Annales d'Endocrinologie. 75 (2): 40–47. doi:10.1016/j.ando.2014.03.002. PMID 24793988.
  68. ^ Stratakis CA, Bossis I (March 2004). "Genetics of the adrenal gland". secondary. Rev Endocr Metab Disord. 5 (1): 53–68. doi:10.1023/B:REMD.0000016124.44064.8f. PMID 14966389. S2CID 22128921.
  69. ^ Batista RL, Mendonca BB (2022). "The Molecular Basis of 5α-Reductase Type 2 Deficiency". secondary. Sex Dev. 16 (2–3): 171–183. doi:10.1159/000525119. PMID 35793650. S2CID 250337336.
  70. ^ Sultan C, Lumbroso S, Paris F, Jeandel C, Terouanne B, Belon C, et al. (August 2002). "Disorders of androgen action". secondary. Semin Reprod Med. 20 (3): 217–28. doi:10.1055/s-2002-35386. PMID 12428202. S2CID 41205149.
  71. ^ a b c Boettcher C, Flück CE (January 2022). "Rare forms of genetic steroidogenic defects affecting the gonads and adrenals" (PDF). secondary. Best Practice & Research. Clinical Endocrinology & Metabolism. 36 (1): 101593. doi:10.1016/j.beem.2021.101593. PMID 34711511. S2CID 242536877. Archived (PDF) from the original on 3 December 2023. Retrieved 2 February 2024.
  72. ^ a b du Toit T, Swart AC (September 2021). "Turning the spotlight on the C11-oxy androgens in human fetal development". secondary. The Journal of Steroid Biochemistry and Molecular Biology. 212: 108636. doi:10.1016/j.jsbmb.2021.108636. PMID 34171490. S2CID 235603586.
  73. ^ a b Luu-The V, Bélanger A, Labrie F (2008). "Androgen biosynthetic pathways in the human prostate". secondary. Best Practice & Research. Clinical Endocrinology & Metabolism. 22 (2). Elsevier BV: 207–221. doi:10.1016/j.beem.2008.01.008. ISSN 1521-690X. PMID 18471780.
  74. ^ Pena VN, Engel N, Gabrielson AT, Rabinowitz MJ, Herati AS (October 2021). "Diagnostic and Management Strategies for Patients with Chronic Prostatitis and Chronic Pelvic Pain Syndrome". secondary. Drugs Aging. 38 (10): 845–886. doi:10.1007/s40266-021-00890-2. PMID 34586623. S2CID 238208708.
  75. ^ du Toit T, Swart AC (2020). "The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone". secondary. The Journal of Steroid Biochemistry and Molecular Biology. 196: 105497. doi:10.1016/j.jsbmb.2019.105497. PMID 31626910. S2CID 204734045.
  76. ^ Masiutin MG, Yadav MK (2022). "Letter to the editor regarding the article "Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome"". secondary. Urology. 169: 273. doi:10.1016/j.urology.2022.07.051. ISSN 0090-4295. PMID 35987379. S2CID 251657694. Archived from the original on 30 June 2023. Retrieved 1 January 2024.
  77. ^ Dimitrakoff J, Nickel JC (2022). "Author reply". secondary. Urology. 169: 273–274. doi:10.1016/j.urology.2022.07.049. ISSN 0090-4295. PMID 35985522. S2CID 251658492. Archived from the original on 30 June 2023. Retrieved 1 January 2024.
  78. ^ Gent R, Van Rooyen D, Atkin SL, Swart AC (December 2023). "C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors". Int J Mol Sci. 25 (1): 101. doi:10.3390/ijms25010101. PMC 10778819. PMID 38203272.
  79. ^ a b c d e du Toit T, Swart AC (February 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. S2CID 6335125.
  80. ^ Krishnan S, Kanthaje S, Punchappady DR, Mujeeburahiman M, Ratnacaram CK (March 2023). "Circulating metabolite biomarkers: a game changer in the human prostate cancer diagnosis". J Cancer Res Clin Oncol. 149 (3): 951–967. doi:10.1007/s00432-022-04113-y. PMID 35764700. S2CID 250094257.
  81. ^ Dai C, Dehm SM, Sharifi N (September 2023). "Targeting the Androgen Signaling Axis in Prostate Cancer". J Clin Oncol. 41 (26): 4267–4278. doi:10.1200/JCO.23.00433. PMC 10852396. PMID 37429011.
  82. ^ a b Renfree MB, Shaw G (September 2023). "The alternate pathway of androgen metabolism and window of sensitivity". primary. J Endocrinol. 258 (3). doi:10.1530/JOE-22-0296. PMID 37343228. S2CID 259222117.
  83. ^ Draskau MK, Svingen T (2022). "Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development". secondary. Front Toxicol. 4: 883254. doi:10.3389/ftox.2022.883254. PMC 9097791. PMID 35573275.
  84. ^ a b c d Wilson JD (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". primary. Endocrinology. 144 (2): 575–80. doi:10.1210/en.2002-220721. PMID 12538619. S2CID 84765868.
  85. ^ Biason-Lauber A, Miller WL, Pandey AV, Flück CE (May 2013). "Of marsupials and men: "Backdoor" dihydrotestosterone synthesis in male sexual differentiation". secondary. Mol Cell Endocrinol. 371 (1–2): 124–32. doi:10.1016/j.mce.2013.01.017. PMID 23376007. S2CID 3102436.
  86. ^ Leihy MW, Shaw G, Wilson JD, Renfree MB (July 2004). "Penile development is initiated in the tammar wallaby pouch young during the period when 5alpha-androstane-3alpha,17beta-diol is secreted by the testes". primary. Endocrinology. 145 (7): 3346–52. doi:10.1210/en.2004-0150. PMID 15059957.
  87. ^ Glickman SE, Short RV, Renfree MB (November 2005). "Sexual differentiation in three unconventional mammals: spotted hyenas, elephants and tammar wallabies". secondary. Horm Behav. 48 (4): 403–17. doi:10.1016/j.yhbeh.2005.07.013. PMID 16197946. S2CID 46344114.
  88. ^ a b Chen Y, Renfree MB (January 2020). "Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby". secondary. Genes. 11 (1): 106. doi:10.3390/genes11010106. PMC 7017150. PMID 31963388.
  89. ^ Turcu AF, Auchus RJ (June 2017). "Clinical significance of 11-oxygenated androgens". secondary. Curr Opin Endocrinol Diabetes Obes. 24 (3): 252–259. doi:10.1097/MED.0000000000000334. PMC 5819755. PMID 28234803.
  90. ^ Asby DJ, Arlt W, Hanley NA (March 2009). "The adrenal cortex and sexual differentiation during early human development". Rev Endocr Metab Disord. 10 (1): 43–9. doi:10.1007/s11154-008-9098-9. PMID 18670886. S2CID 20475488.
  91. ^ Penning TM (June 1997). "Molecular endocrinology of hydroxysteroid dehydrogenases". secondary. Endocrine Reviews. 18 (3): 281–305. doi:10.1210/edrv.18.3.0302. PMID 9183566. S2CID 29607473.
  92. ^ Schiffer L, Barnard L, Baranowski ES, Gilligan LC, Taylor AE, Arlt W, et al. (November 2019). "Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review". J Steroid Biochem Mol Biol. 194: 105439. doi:10.1016/j.jsbmb.2019.105439. PMC 6857441. PMID 31362062.
  93. ^ a b Penning TM, Wangtrakuldee P, Auchus RJ (April 2019). "Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes". Endocr Rev. 40 (2): 447–475. doi:10.1210/er.2018-00089. PMC 6405412. PMID 30137266.
  94. ^ Baranowski ES, Arlt W, Idkowiak J (2018). "Monogenic Disorders of Adrenal Steroidogenesis". Horm Res Paediatr. 89 (5): 292–310. doi:10.1159/000488034. PMC 6067656. PMID 29874650.
  95. ^ Schiffer L, Kempegowda P, Arlt W, O'Reilly MW (September 2017). "MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease". Eur J Endocrinol. 177 (3): R125–R143. doi:10.1530/EJE-17-0124. PMC 5510573. PMID 28566439.
  96. ^ Eckstein B, Borut A, Cohen S (April 1987). "Metabolic pathways for androstanediol formation in immature rat testis microsomes". primary. Biochimica et Biophysica Acta (BBA) - General Subjects. 924 (1): 1–6. doi:10.1016/0304-4165(87)90063-8. PMID 3828389.
  97. ^ Jeong HR (June 2022). "Commentary on "Classic and backdoor pathways of androgen biosynthesis in human sexual development"". Ann Pediatr Endocrinol Metab. 27 (2): 81–82. doi:10.6065/apem.2222057edi01. PMC 9260375. PMID 35793997.
  98. ^ Balsamo A, Baronio F, Ortolano R, Menabo S, Baldazzi L, Di Natale V, et al. (2020). "Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant". Front Pediatr. 8: 593315. doi:10.3389/fped.2020.593315. PMC 7783414. PMID 33415088.
  99. ^ "21-hydroxylase deficiency - About the Disease - Genetic and Rare Diseases Information Center". Archived from the original on 30 July 2023. Retrieved 13 March 2024.
  100. ^ Merke DP, Auchus RJ (2020). "Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency". New England Journal of Medicine. 383 (13): 1248–1261. doi:10.1056/NEJMra1909786. PMID 32966723. S2CID 221884108. Archived from the original on 12 October 2022. Retrieved 13 March 2024.
  101. ^ Auchus RJ (2015). "The Classic and Nonclassic Concenital Adrenal Hyperplasias". Endocrine Practice. 21 (4): 383–389. doi:10.4158/EP14474.RA. PMID 25536973.
  102. ^ van Rooyen D, Gent R, Barnard L, Swart AC (April 2018). "The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway". primary. The Journal of Steroid Biochemistry and Molecular Biology. 178: 203–212. doi:10.1016/j.jsbmb.2017.12.014. PMID 29277707. S2CID 3700135.

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