Intracrine androgen biosynthesis, metabolism and action revisited

In the paper

“Both 11OHA4 and 11β-hydroxytestosterone (11OHT) may be converted to their 11-keto counterparts by the low levels of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) present in the adrenal, though peripheral HSD11B2 may make a more significant contribution (Pretorius et al., 2017, Turcu et al., 2016).”

What the sources say

• Partly supported

  Section 2 (p. 6) says low levels of adrenal 11βHSD2 convert 11OHA4 to 11KA4, and it describes 11OHT as a likely precursor to 11KT. It also suggests that 11KA4 and 11KT may form in peripheral tissues. The text does not specifically say that adrenal 11βHSD2 converts 11OHT to 11KT or that peripheral HSD11B2 makes the greater contribution. (LLM, conf=0.82)

  cites Pretorius et al., 2017 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (‘Adrenal gland production of 11oxC19 steroids’; page unavailable) identify 11-ketoandrostenedione and 11-ketotestosterone as primarily peripheral metabolites of their 11β-hydroxylated precursors. This supports the proposed conversions and a greater peripheral contribution. Our copy does not identify HSD11B2 as the enzyme or establish that it is present at low levels in the adrenal. (LLM, conf=0.85)

  cites Turcu et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“The significant levels of 11KA4 measured in the serum of healthy premenopausal woman (O'Reilly et al., 2016) supports the involvement of peripheral tissue such as the kidney, especially considering that the adrenal expresses only low levels of HSD11B2 (Coulter et al., 1999).”

What the sources say

• Supported

  Table 1 reports serum 11KA4 of 2.7 nmol/L (IQR 2.0–3.9) in healthy female controls; the Discussion identifies this study’s controls as women aged 18–40. The O’Reilly citation is attached to that measurement. The inference about kidney involvement is the citing authors’ interpretation, and the statement about adrenal HSD11B2 carries a separate citation. (LLM, conf=0.92)

  cites O'Reilly et al., 2016 source
• Not checked yetcites Coulter et al., 1999 source

In the paper

“Free T concentrations usually range around 1–2% of total T and are also age-dependent in women (Haring et al., 2012) and men (Camacho et al., 2013, Damgaard-Olesen et al., 2016).”

What the sources say

• Not checked yetcites Haring et al., 2012 source
• Not checked yetcites Camacho et al., 2013 source
• Not checked yetcites Damgaard-Olesen et al., 2016 source

In the paper

“Indeed, a recent study quantifying androgen metabolites and their sulfo- and glucoconjugates in serum, showed that T and DHT circulate predominantly in their unconjugated form, while their metabolites androsterone (AST, 5α-androstan-3α-ol-17-one), epiandrosterone (5α-androstan-3β-ol-17-one, EpiAST) and 3α-adiol (5α-androstan-3α,17β-diol) were mostly conjugated, each with specific preferences for”

What the sources say

• Not checked yetcites Zang et al., 2017 source

In the paper

“They present with a decreased DHEA/DHEAS ratio, which increases to normal levels after puberty, and a slightly increased androgen activation rate as peripheral 5α-reductase activity seems to compensate for the loss of STS function (Idkowiak et al., 2016).”

What the sources say

• Not checked yetcites Idkowiak et al., 2016 source

In the paper

“Circulating DHEA-fatty acids have been shown to account for ∼9% of total DHEA in serum (Wang et al., 2011).”

What the sources say

• Not checked yetcites Wang et al., 2011 source

In the paper

“However, while administration of DHEA yields significant increases in both DHEAS and active androgens (Arlt et al., 1998, Arlt et al., 1999b), the administration of DHEAS does not result in any increase of DHEA and downstream androgens in healthy adults (Hammer et al., 2005).”

What the sources say

• Not checked yetcites Arlt et al., 1998 source
• Not checked yetcites Arlt et al., 1999b
• Not checked yetcites Hammer et al., 2005 source

In the paper

“Clinically this results in androgen excess manifesting with premature pubarche and a phenotype in women resembling polycystic ovary syndrome (PCOS), also observed in heterozygous carriers of major loss-of-function mutations (Noordam et al., 2009, Oostdijk et al., 2015).”

What the sources say

• Not checked yetcites Noordam et al., 2009 source
• Not checked yetcites Oostdijk et al., 2015 source

In the paper

“Mutations of PAPS synthase type 2 (PAPSS2) lead to impaired PAPS synthesis and thus impaired sulfation, which results in enhanced conversion of DHEA to active androgens.”

What the sources say

• Not checked yetcites Noordam et al., 2009 source
• Not checked yetcites Oostdijk et al., 2015 source

In the paper

“It is only after adrenarche that high levels of C19 androgen precursors are available for peripheral activation and adrenarche thus represents the onset of significant intracrine androgen signalling in human life.”

In the paper

“Granulosa cells do not express CYP17A1 and their de-novo steroidogenic activity therefore stops at the stage of the C21 steroids progesterone (PROG) and pregnenolone (PREG) (Voutilainen et al., 1986).”

What the sources say

• Not checked yetcites Voutilainen et al., 1986 source

In the paper

“The adrenal thus secretes only very low amounts of active androgens, but mainly androgen precursors that are activated in peripheral tissues.”

In the paper

“These precursors diffuse into the adjacent theca cells, which express CYP17A1 and HSD3B2 (but express only low levels of CYP11A1), and serve as substrates for the production of A4 (Patel et al., 2010).”

What the sources say

• Not checked yetcites Patel et al., 2010 source

In the paper

“The presence of steroid 5α-reductase type 1 (SRD5A1), aldo-keto reductase 1C2 (AKR1C2), aldo-keto reductase 1C4 (AKR1C4) and 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6) has also been demonstrated for ovarian theca cells and some of those are required for the functioning of the backdoor pathway, which produces DHT by-passing DHEA, A4 and T, (section 5.3), (Marti et al., 2017).”

What the sources say

• Not checked yetcites Marti et al., 2017 source

In the paper

“Furthermore, the expression of HSD3B2 encoding 3β-hydroxysteroid dehydrogenase/Δ5−4-isomerase type 2 (HSD3B2) is relatively low in the zona reticularis, thereby ensuring the activity of the Δ5 pathway and the production of DHEA.”

In the paper

“In the adrenal, DHEA can further be converted to A4 by HSD3B2 and A4 can be transformed to T by the low adrenal levels of aldo-keto-reductase family 1C3 (AKR1C3, also known as 17β-hydroxysteroid dehydrogensae type 5, HSD17B5), which has 17β-hydroxysteroid dehydrogenase (17βHSD) activity (Nakamura et al., 2009b, Rainey and Nakamura, 2008, Rege et al., 2013).”

What the sources say

• Not checked yetcites Nakamura et al., 2009b
• Not checked yetcites Rainey and Nakamura, 2008
• Not checked yetcites Rege et al., 2013 source

In the paper

“It should be noted that adrenal C19 steroid production is initiated during adrenarche, a pre-pubertal event (approximately age 8 in girls and 9 in boys (Idkowiak et al., 2011)) unique to humans and higher primates (Abbott and Bird, 2009, Arlt et al., 2002, Auchus and Rainey, 2004, Miller, 2008).”

What the sources say

• Not checked yetcites Idkowiak et al., 2011 source
• Not checked yetcites Abbott and Bird, 2009
• Not checked yetcites Arlt et al., 2002 source

In the paper

“AKR1C3 can also catalyse the conversion of some DHEA to 5-diol (androst-5-ene-3β,17β-diol), which can be sulfated by SULT2A1 or converted to T by HSD3B2.”

In the paper

“Furthermore, while other rodents such as hamster (Cloutier et al., 1995) and guinea pig (Le Goascogne et al., 1991, Tremblay et al., 1995) do produce adrenal C19 steroids due to adrenal CYP17A1 expression, CYP17A1 substrate specificity in these species is significantly different from that of the human enzyme (Cloutier et al., 1997, Tremblay et al., 1995), thus limiting comparisons to human adrenal”

What the sources say

• Not checked yetcites Cloutier et al., 1995 source
• Not checked yetcites Le Goascogne et al., 1991 source
• Not checked yetcites Tremblay et al., 1995 source

In the paper

“Therefore, unlike humans, mouse and rat adrenals do not produce significant levels of androgen precursors (van Weerden et al., 1992) which can serve as substrates for intracrine action and are therefore not valid models for studies of human androgen intracrinology.”

What the sources say

• Not checked yetcites van Weerden et al., 1992 source

In the paper

“17β-hydroxysteroid dehydrogenase type 1, HSD17B1, is limited to the granulosa cells, where it activates E1 to E2 (Nelson et al., 2001).”

What the sources say

• Not checked yetcites Nelson et al., 2001 source

In the paper

“Ovarian steroidogenesis commences with puberty when the onset of hypothalamic-pituitary-gonadal signalling leads to an increase in follicle stimulating hormone and luteinizing hormone which in turn regulate steroidogenic activity (Herbison, 2016).”

What the sources say

• Not checked yetcites Herbison, 2016 source

In the paper

“Due to the ample levels of cytochrome P450 steroid 11β-hydroxylase (CYP11B1), the adrenal gives rise to 11-oxygenated C19 steroids by converting A4 and T to their 11β-hydroxyl derivatives, with 11OHA4 being the major product due to the high abundance of A4.”

In the paper

“Adrenarche is due to the development of the zona reticularis which is characterised by an increase in the expression of CYB5A (encoding cytochrome b5) and SULT2A1, and a decrease in the expression of HSD3B2, which in combination favours the biosynthesis of DHEA and DHEAS (Bird, 2012, Gell et al., 1996, Nakamura et al., 2009a).”

What the sources say

• Not checked yetcites Bird, 2012 source
• Not checked yetcites Gell et al., 1996 source
• Not checked yetcites Nakamura et al., 2009a

In the paper

“A4 can either be secreted or converted to T by AKR1C3 in the theca cells (Nelson et al., 2001), but the majority of A4 diffuses back to the granulosa cells where it is converted to estrone (E1), estradiol (E2) and E1-sulfate (E1S) (Miller and Auchus, 2011).”

What the sources say

• Not checked yetcites Nelson et al., 2001 source
• Not checked yetcites Miller and Auchus, 2011 source

In the paper

“DHEA is converted to DHEAS by DHEA sulfotransferase (sulfotransferase 2A1, SULT2A1) and as such DHEAS is the major C19 steroid secreted by the adrenal, circulating in low micromolar concentrations.”

In the paper

“The concentration of these steroids that peripheral tissue is exposed to is determined by (1) the total concentration of the respective C19 steroids in circulation, (2) whether or not the specific steroid is bound to sex hormone binding globulin (SHBG) or albumin and (3) the availability of mechanisms for cellular influx and efflux, although this is only relevant for conjugated steroids which”

What the sources say

• Not checked yetcites Giorgi and Stein, 1981

In the paper

“While ovarian steroidogenesis demonstrates a menstrual cycle-dependent profile in premenopausal women (Barbieri, 2014), the absence of ovarian follicles in the postmenopausal ovary significantly reduces the production of oestrogens (Labrie et al., 2011).”

What the sources say

• Not checked yetcites Barbieri, 2014 source
• Not checked yetcites Labrie et al., 2011 source

In the paper

“Post-natal testicular steroidogenesis is initiated by the onset of hypothalamic-pituitary-gonadal signalling during puberty.”

In the paper

“A decline of androgens in men starting in the third decade of life can be observed as aging results in a gradual development of testicular failure due to a decreased number of Leydig cells and response to hypothalamic-pituitary signalling (Beattie et al., 2015, Golan et al., 2015).”

What the sources say

• Not checked yetcites Beattie et al., 2015 source
• Not checked yetcites Golan et al., 2015 source

In the paper

“It should be noted that all C19 steroid concentrations discussed above and indicated in Table 2 refer to the total concentrations of androgens in circulation and that this is not necessarily indicative of the steroid concentration available for cellular uptake.”

In the paper

“Testicular androgen biosynthesis is carried out in the Leydig cells and, similar to the adrenal, follows the classical Δ5 pathway with only minor contribution of the Δ4 pathway (Fluck et al., 2003, Sherbet et al., 2003).”

What the sources say

• Not checked yetcites Fluck et al., 2003 source
• Not checked yetcites Sherbet et al., 2003 source

In the paper

“HSD17B3 function is essential for testicular T generation from A4 and it is the only human HSD17B isoform with an established deficiency syndrome.”

In the paper

“Although one could easily presume that most C19 steroids in circulation are produced by steroidogenic tissues, androgen metabolites released from peripheral tissue make a significant contribution to the circulating pool of C19 steroids and thus highlight the importance of local androgen activation and metabolism by intracrine mechanisms.”

In the paper

“However, the testes also express AKR1C3 and in cases of HSD17B3 deficiency the testes still produce low amounts of T via this enzyme (Werner et al., 2012).”

What the sources say

• Not checked yetcites Werner et al., 2012 source

In the paper

“Abnormal levels of SHBG and mutations altering the affinity for its ligands are associated with androgen excess and a PCOS phenotype, but have also been implicated in the pathogenesis of cancer and metabolic dysfunction (Hammond, 2016, Hogeveen et al., 2002).”

What the sources say

• Not checked yetcites Hammond, 2016 source
• Not checked yetcites Hogeveen et al., 2002 source

In the paper

“Although albumin binds all unconjugated steroids with low affinities (μmolar ranges), it makes a significant contribution to steroid binding due to its high abundance (Dunn et al., 1981).”

What the sources say

• Not checked yetcites Dunn et al., 1981 source

In the paper

“Fetal testicular T is essential for the development of the male internal genitalia, while the local conversion of testicular T to DHT is essential for the development of external genitalia taking place between 8 and 12 weeks of gestation (Krone et al., 2007, Sobel et al., 2004).”

What the sources say

• Not checked yetcites Krone et al., 2007 source
• Not checked yetcites Sobel et al., 2004 source

In the paper

“Systemic upregulation of 5α-reductase activity is observed in women with PCOS leading to enhanced glucocorticoid clearance and enhanced androgen activation in peripheral tissues (Fassnacht et al., 2003, Stewart et al., 1990, Vassiliadi et al., 2009)”

What the sources say

• Not checked yetcites Fassnacht et al., 2003 source
• Not checked yetcites Stewart et al., 1990 source
• Not checked yetcites Vassiliadi et al., 2009 source

In the paper

“mutations in human HSD3B1, which is almost exclusively expressed in peripheral tissues and placenta (Labrie et al., 1992, Simard et al., 2005), are not known, probably as they would prevent placental PROG production during pregnancy (Miller and Auchus, 2011).”

What the sources say

• Not checked yetcites Miller and Auchus, 2011 source

In the paper

“STS is a membrane-bound enzyme on the luminal side of the endoplasmic reticulum (Ghosh, 2007) and ubiquitously expressed in all human tissues (Reed et al., 2005).”

What the sources say

• Not checked yetcites Ghosh, 2007 source
• Not checked yetcites Reed et al., 2005 source

In the paper

“While unconjugated steroids can freely diffuse across the membrane due to their hydrophobic nature, steroid conjugates (sulfates and glucuronides) are hydrophilic and require active transport mechanisms by transmembrane proteins (Giorgi and Stein, 1981).”

What the sources say

• Not checked yetcites Giorgi and Stein, 1981

In the paper

“AKR1C3 is also overexpressed in prostate cancer, presumably promoting cancer progression by increasing intratumoral androgen levels (Adeniji et al., 2013, Fung et al., 2006).”

What the sources say

• Not checked yetcites Adeniji et al., 2013 source
• Not checked yetcites Fung et al., 2006 source

In the paper

“However, STS activity is upregulated in several types of cancer (reviewed in (Mueller et al., 2015)) and has been proposed as drug target in hormone-dependent breast, prostate and endometrial cancers to prevent local oestrogen (including 5-diol, which has oestrogenic effects) and androgen formation from estrone sulfate, DHEAS and 5-diol-sufate.”

What the sources say

• Not checked yetcites Mueller et al., 2015 source

In the paper

“Organic anion-transporting polypeptides (OATPs) belong to the solute carrier organic anion (SLCO) transporter gene superfamily and are the primary transporters for the influx of conjugated steroids, while multi drug resistant (MDR) proteins belonging to the ATP-binding cassette (ABC) transporters are the primary transporters for the efflux of conjugated steroids (Deeley et al., 2006, Mueller et al”

What the sources say

• Not checked yetcites Deeley et al., 2006 source
• Not checked yetcites Mueller et al., 2015 source

In the paper

“Once transported across the plasma membrane, a steroid sulfate ester is hydrolysed by steroid sulfatase (STS), with maintenance of stereo configuration yielding the respective hydroxysteroid that is subsequently accessible for enzymatic conversions or can exert biological functions (Hobkirk, 1993).”

What the sources say

• Not checked yetcites Hobkirk, 1993 source

In the paper

“AKR1C3 (HSD17B5) has been suggested to make the major contribution to peripheral A4 activation by conversion to T (Miller and Auchus, 2011).”

What the sources say

• Not checked yetcites Miller and Auchus, 2011 source

In the paper

“It should again be noted that care should be taken when using animal models to study intracrinology as the enzyme isoforms vary greatly between species.”

What the sources say

• Not checked yetcites de Launoit et al., 1992 source
• Not checked yetcites Payne et al., 1995 source
• Not checked yetcites Simard et al., 1995 source

In the paper

“It is mainly expressed in the liver (Charbonneau and The, 2001, Wu et al., 2009) and 5β-reduction therefore plays only a minor role in other tissues.”

What the sources say

• Not checked yetcites Charbonneau and The, 2001
• Not checked yetcites Wu et al., 2009

In the paper

“5α-reduced metabolites are therefore conclusively more indicative for peripheral androgen metabolism than 5β-reduced metabolites, which are more likely to be of hepatic origin (Chen and Penning, 2014).”

What the sources say

• Not checked yetcites Chen and Penning, 2014

In the paper

“The activation of androgens within adipocytes has been shown to regulate proliferation and differentiation, insulin sensitivity, adipokine signalling and lipid metabolism (O'Reilly et al., 2014a).”

What the sources say

• Not checked yetcites O'Reilly et al., 2014a

In the paper

“This metabolism prevents the over-activation of the AR as well as the release of significant amounts of the activated androgens back into circulation (Labrie, 1991).”

What the sources say

• Not checked yetcites Labrie, 1991 source

In the paper

“However, the classical pathway via T plays only a minor role in the generation of DHT from inactive C19 precursors.”

In the paper

“This pathway is not present in the adrenal or gonads, but plays the major role for peripheral DHT generation from circulating precursors other than T (Luu-The and Labrie, 2010).”

What the sources say

• Not checked yetcites Luu-The and Labrie, 2010

In the paper

“As opposed to sulfation, glucuronidation is irreversible and ultimately inactivates the androgen and initiates its renal excretion by increasing polarity and water solubility of the molecule (Belanger et al., 2003).”

What the sources say

• Not checked yetcites Belanger et al., 2003 source

In the paper

“While 11OHT and 11OHDHT represent partial AR agonists, 11KT and 11KDHT are full agonists with the same AR activating potential as T and DHT, respectively (Pretorius et al., 2016, Storbeck et al., 2013).”

What the sources say

• Not checked yetcites Pretorius et al., 2016 source
• Not checked yetcites Storbeck et al., 2013 source

In the paper

“The production of T from A4 by AKR1C3 has been proposed to be the essential step of androgen activation in muscle (Lin et al., 1997, Longcope and Fineberg, 1985, Luu-The and Labrie, 2010), with the further conversion of T to DHT seeming to play only a minor role as there is no clarity regarding the expression of SRD5A isoforms (Luu-The and Labrie, 2010).”

What the sources say

• Not checked yetcites Lin et al., 1997
• Not checked yetcites Longcope and Fineberg, 1985
• Not checked yetcites Luu-The and Labrie, 2010

In the paper

“The liver has high levels of the 5β-reductase AKR1D1 and primarily produces 5β-reduced androgens (e.g. etiochonanolone, 5β-androstan-3α-ol-17-one, ETIO) in contrast to peripheral tissue which produce 5α-reduced species (Charbonneau and The, 2001, Chen and Penning, 2014, Penning, 2010).”

What the sources say

• Not checked yetcites Charbonneau and The, 2001
• Not checked yetcites Chen and Penning, 2014
• Not checked yetcites Penning, 2010

In the paper

“This data supports the AKR1C3 catalysed conversion of A4 to T within adipose tissue and further suggests that not all T produced within adipocytes is inactivated, but that a portion of the T is also released in circulation.”

In the paper

“Mutations of AKR1D1 lead to severely reduced to completely absent urinary 5β-reduced steroid excretion and hepatic failure, as AKR1D1 is essentially involved in hepatic bile acid synthesis, but no other clinical manifestations (Gonzales et al., 2004, Lemonde et al., 2003, Palermo et al., 2008).”

What the sources say

• Not checked yetcites Gonzales et al., 2004 source
• Not checked yetcites Lemonde et al., 2003 source
• Not checked yetcites Palermo et al., 2008 source

In the paper

“CYP3A4 is the most abundant P450 in the liver (∼30%) (Shimada et al., 1994) and predominantly, though not exclusively, catalyses the 6β-hydroxylation of T and the 16α- and 7α-hydroxylation of DHEA (Niwa et al., 2015).”

What the sources say

• Not checked yetcites Shimada et al., 1994 source
• Not checked yetcites Niwa et al., 2015 source

In the paper

“The formation of androgen linked di-glucuronides (second glucuronidation occurs on the first glucuronosyl moiety) is also possible (Murai et al., 2005, Murai et al., 2006).”

What the sources say

• Not checked yetcites Murai et al., 2005 source
• Not checked yetcites Murai et al., 2006 source

In the paper

“While aromatase activity increases during decidualisation leading to an increased estrogen secretion (Gibson et al., 2013)”

What the sources say

• Not checked yetcites Gibson et al., 2013 source

In the paper

“The formation of distinct di-sulfates is described for the synthetic androgen tibolone (Falany et al., 2004) and cholesterol (Cook et al., 2009).”

What the sources say

• Not checked yetcites Falany et al., 2004 source
• Not checked yetcites Cook et al., 2009 source

In the paper

“Breast cancer tissue has STS, 3βHSD, reductive 17βHSD, 5α-reductase and aromatase activities (Labrie et al., 2003, McNamara and Sasano, 2015b, Suzuki et al., 2005) as well as 3αHSD, UGT, and SULT activity (McNamara et al., 2013).”

What the sources say

• Not checked yetcites Labrie et al., 2003 source
• Not checked yetcites McNamara and Sasano, 2015b
• Not checked yetcites Suzuki et al., 2005 source

In the paper

“Interestingly, the concentration of 17-keto metabolites in circulation is higher than that of the 17β-hydroxy metabolites with AST-glucuronide and -sulfate being the most abundant (see (Kalogera et al., 2013) for a review of LC-MS/MS based studies of circulating androgen and their glucuronides).”

What the sources say

• Not checked yetcites Kalogera et al., 2013 source

In the paper

“11KA4 is then preferentially converted to 11KT by AKR1C3 and 11KT can then be 5α-reduced to yield 11KDHT (Pretorius et al., 2017) (Fig. 6).”

What the sources say

• Not checked yetcites Pretorius et al., 2017 source

In the paper

“Because of the ability of prostate cancer cells to convert 3α-adiol back to DHT its glucuronidation is of particular importance for androgen inactivation and the regulation of cancer progression (Chouinard et al., 2007).”

What the sources say

• Not checked yetcites Chouinard et al., 2007 source

In the paper

“The placenta expresses CYP11A1 and catalyses StAR-independent (Sugawara et al., 1995) de-novo steroidogenesis probably facilitated by MLN64 with StAR-like activity (Bose et al., 2000).”

What the sources say

• Not checked yetcites Sugawara et al., 1995 source
• Not checked yetcites Bose et al., 2000 source

In the paper

“The presence of SRD5A1 allows for the local production of DHT (Luu-The et al., 1994), with the 5α-dione pathway bypassing T being the preferred route (Samson et al., 2010, Sugimoto et al., 1995) (Fig. 6).”

What the sources say

• Not checked yetcites Luu-The et al., 1994 source
• Not checked yetcites Samson et al., 2010 source
• Not checked yetcites Sugimoto et al., 1995 source

In the paper

“and 5α-reductase inhibitors are an established treatment for male pattern alopecia (Kaufman and Dawber, 1999).”

What the sources say

• Not checked yetcites Kaufman and Dawber, 1999

In the paper

“However, CYP17A1 activity is sufficient for the production of T, E1 and E2, as has been demonstrated for trophoblasts (Escobar et al., 2011).”

What the sources say

• Not checked yetcites Escobar et al., 2011 source

In the paper

“a reductive 17αHSD (product of AKR1C21) has been isolated from the mouse and has been shown to convert 17-keto steroids to their 17α-hydroxyl, thus suggesting that A4 could be the direct precursor to EpiT.”

What the sources say

• Not checked yetcites Bellemare et al., 2005 source

In the paper

“UGTs and SULTs are expressed and may contribute to phase 2 metabolism (Slominski et al., 2013).”

What the sources say

• Not checked yetcites Slominski et al., 2013 source

In the paper

“Renal excretion of conjugates takes advantage of (1) the hydrophilic water-soluble nature of steroid conjugates and (2) the fact that their transport across the cell membrane requires active transport mechanisms which allow for the concentration of the molecules on one side of the membrane (Pritchard and Miller, 1996, VanWert et al., 2010).”

What the sources say

• Not checked yetcites Pritchard and Miller, 1996
• Not checked yetcites VanWert et al., 2010 source

In the paper

“Steroid measurements in saliva can be superior to that of serum as they rely on a non-invasive, cheap collection technique and are representative of the bioavailable, non-protein bound, levels of the steroid that can passively diffuse from circulation into saliva in the salivary glands (Vining et al., 1983).”

What the sources say

• Not checked yetcites Vining et al., 1983 source

In the paper

“DHEA could be further metabolised to T, via A4 or 5α-dione, and the resulting T could be 5α-reduced to DHT.”

What the sources say

• Not checked yetcites Quinkler et al., 2003 source

In the paper

“and therefore while the kidney inactivates glucocorticoids it may play a vital role in activating 11-oxygenated androgens.”

In the paper

“In the skin, A4 and T can be aromatised to oestrogens, which induce beneficial effect on keratinocyte proliferation, production of extracellular matrix components and wound healing (Kanda and Watanabe, 2004a, Kanda and Watanabe, 2004b, Raine-Fenning et al., 2003).”

What the sources say

• Not checked yetcites Kanda and Watanabe, 2004a
• Not checked yetcites Kanda and Watanabe, 2004b
• Not checked yetcites Raine-Fenning et al., 2003 source

In the paper

“Sulfo- and glucoconjugates are excreted in different ratios for every androgen, while the excretion of free forms is negligible (Buiarelli et al., 2004).”

What the sources say

• Not checked yetcites Buiarelli et al., 2004 source

In the paper

“The ratio of urinary T and EpiT-glucuronide is used as an indicator of exogenous T administration in doping analysis (Mareck et al., 2010, Shackleton et al., 1997a, Shackleton et al., 1997b, Wada, 2015).”

What the sources say

• Not checked yetcites Mareck et al., 2010 source
• Not checked yetcites Shackleton et al., 1997a
• Not checked yetcites Shackleton et al., 1997b

In the paper

“EpiT circulates with low nM concentrations and EpiT/T ratios are between 0.1 for women and up to 1 in men as measured in serum of healthy subjects by immunoassay (Havlikova et al., 2002).”

What the sources say

• Not checked yetcites Havlikova et al., 2002 source

In the paper

“Organic anion transporters are highly expressed in renal epithelia (Emami Riedmaier et al., 2012).”

What the sources say

• Not checked yetcites Emami Riedmaier et al., 2012 source

In the paper

“A range of liquid chromatography tandem mass spectrometry assays for salivary cortisol/cortisone and salivary androgens have thus been developed and implemented in routine clinical laboratories (Keevil, 2016).”

What the sources say

• Not checked yetcites Keevil, 2016 source

In the paper

“In addition, DHEA can be 7α-hydroxylated by CYP7B1, which is expressed in the skin (Hennebert et al., 2007), thereby preventing its metabolism to active androgens.”

What the sources say

• Not checked yetcites Hennebert et al., 2007 source

In the paper

“Salivary glands express STS, SULT2B1, HSD3B1, AKR1C3, SRD5A1 and CYP19A1 and the activity of the encoded enzymes allows for the conversion of circulating DHEAS and DHEA to DHT and oestrogens (Spaan et al., 2009).”

What the sources say

• Not checked yetcites Spaan et al., 2009 source

In the paper

“While urinary 11-oxygenated ETIO is predominantly a product of glucocorticoid metabolism, urinary 11-oxygenated AST results mainly from 11-oxygenated androgens (Jones et al., 2016, Shackleton et al., 2008).”

What the sources say

• Not checked yetcites Jones et al., 2016 source
• Not checked yetcites Shackleton et al., 2008 source

In the paper

“Urinary 11-oxygenated AST and 11-oxygenated ETIO originate from androgen and glucocorticoid metabolism, however in different ratios.”

What the sources say

• Not checked yetcites Jones et al., 2016 source
• Not checked yetcites Shackleton et al., 2008 source

In the paper

“Besides the classical conjugates, T metabolites conjugated with cysteine have been detected in urine and plasma (Fabregat et al., 2013).”

What the sources say

• Not checked yetcites Fabregat et al., 2013 source

In the paper

“Also, the reverse co-regulation of androgen and glucocorticoid action (SRD5A enzymes and HSD11B2 activate androgens, but inactivate glucocorticoids) is a striking phenomenon”

In the paper

“As intracrine androgen activation takes place in the cell and may start with the uptake of an androgen precursor and end with the efflux of an inactive androgen metabolite, circulating levels of active androgens are not a valid reflection of total body androgen action (O'Reilly et al., 2014b).”

What the sources say

• Not checked yetcites O'Reilly et al., 2014b

In the paper

“AST and ETIO are measured as representatives of active androgens, while DHEA and 16αOH-DHEA are measured as representatives of direct androgen precursors (Arlt et al., 2011, Krone et al., 2010).”

What the sources say

• Not checked yetcites Arlt et al., 2011 source
• Not checked yetcites Krone et al., 2010 source

In the paper

“The urinary steroid metabolome represents the total of all steroid biosynthetic and metabolising pathways and has proven to be a specific and sensitive biomarker for the diagnosis of steroidogenic disease (Arlt et al., 2011).”

What the sources say

• Not checked yetcites Arlt et al., 2011 source

In the paper

“De-conjugation by β-glucuronidase is time-consuming and may lead to imprecision due to variability in hydrolysis efficiency (Trabert et al., 2016)”

What the sources say

• Not checked yetcites Trabert et al., 2016 source