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Cited by 217Hormonal and reproductive studiesAdrenal Hormones and DisordersSexual Differentiation and Disorders

Intracrine androgen biosynthesis, metabolism and action revisited

Open access
Schiffer, Lina, Arlt, Wiebke, Storbeck, Karl-Heinz·2018·Molecular and Cellular Endocrinology
DOI 10.1016/j.mce.2017.08.016PMC PMC6565845
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Abstract

Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone. However, the intracellular or intracrine activation of C 19 androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates. In this review we provide an overview of human C 19 steroid biosynthesis including the production of 11-oxygenated androgens, their transport in circulation and uptake into peripheral tissues. We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen metabolites and conjugates to assess intracrine androgen production is discussed.

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Written from the paper’s full text.

TL;DR

This review argues that intracrine activation of C19 androgen precursors in peripheral tissues is central to androgen action in both sexes, with 11-oxygenated androgens contributing substantially. It synthesizes human C19 steroid biosynthesis, transport, tissue-specific activation/inactivation, and analytical implications for assessing androgen burden.

Key findings

  • Adrenal vein sampling in healthy women showed secretion of DHEAS (low micromolar range) ≫ DHEA, 11OHA4, A4 (medium nanomolar ranges) > 5-diol, 11KA4, T, 11OHT, 11KT and DHT (low nanomolar ranges), indicating the adrenal secretes mainly androgen precursors rather than active androgens.
  • In healthy premenopausal women, circulating 11KT levels were 3–4-fold higher than T; 11KT and 11KDHT are full AR agonists with the same AR-activating potential as T and DHT, respectively, whereas 11OHT and 11OHDHT are partial AR agonists.
  • Testicular venous blood concentrations in healthy individuals were T (high nanomolar–low micromolar) ≫ A4, DHEA (medium nanomolar), making the testes the only steroidogenic organ secreting significant amounts of an active androgen.
  • Peripheral DHT generation can proceed via the alternate 5α-dione pathway bypassing T, and in castration-resistant prostate cancer this pathway is important for intratumoral DHT production; 11KT and 11KDHT were inactivated more slowly than T and DHT in prostate cancer cell lines.

Methods

  • Narrative review of human C19 steroid biosynthesis, circulation, uptake, intracrine activation/inactivation, and tissue-specific pathways, including adipose tissue, skeletal muscle, liver, breast/endometrium, prostate, placenta, skin, salivary gland, and kidney.
  • Data are drawn from cited literature; no primary cohort, systematic search strategy, or quantitative synthesis is stated. Tables summarize enzymes, serum C19 steroids by LC-MS/MS, and urinary C19 metabolites by GC-MS after de-conjugation.
  • Main analysis is conceptual synthesis of intracrinology principles and pathways, with selected reported concentrations and tissue enzyme activities used as illustrative evidence.

Limitations

  • The paper states that rodent and non-human primate models differ substantially from humans in adrenal C19 steroidogenesis, enzyme isoforms, substrate specificity, and tissue distribution, limiting their use for studying human intracrinology.
  • The paper states that binding of 11-oxygenated androgens to SHBG and albumin has not been investigated, so the free 11KT fraction relative to T is unknown.
  • Evident from the text: as a narrative review, it lacks stated systematic search/selection criteria; some cited evidence comes from small or non-physiological samples, such as kidney tissue from tumour nephrectomies and prostate cancer tissue from two patients.

Model-written summary. Check it against the paper before relying on it.

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Registry

Crossref · 10.1016/j.mce.2017.08.016

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation

    Adrenal vein sampling of healthy women has shown that the adrenal secretes DHEAS (low micromolar range) >> DHEA, 11OHA4, A4 (medium nanomolar ranges) > 5-diol, 11KA4, T, 11OHT, 11KT and DHT (low nanomolar ranges).

    “Adrenal vein sampling of healthy women has shown that the adrenal secretes DHEAS (low micromolar range) » DHEA, 11OHA4, A4 (medium nanomolar ranges) > 5-diol, 11-ketoandrostenedione (11KA4), T, 11OHT, 11-ketotestosterone (11KT) and DHT (low nanomolar ranges) (Rege et al., 2013).”
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  • Findingcitation

    Concentrations of androgen in testicular venous blood of healthy individuals are T (high nanomolar-low micromolar) >> A4, DHEA (medium nanomolar).

    “Concentrations of androgen in testicular venous blood of healthy individuals are T (high nanomolar-low micromolar) » A4, DHEA (medium nanomolar) (Hammond et al., 1977, Ishida et al., 1990, Weinstein et al., 1974).”
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  • Findingcitation

    This results in a decline of circulating T concentrations of approximately 0.1 nmol/L per year.

    “This results in a decline of circulating T concentrations of approximately 0.1 nmol/L per year (Camacho et al., 2013).”
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    • cites Camacho et al., 2013 source

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  • Findingcitation

    The circulating levels of the active androgen 11KT were 3-4fold higher than that of T in healthy premenopausal women.

    “Significantly, our study in healthy and PCOS women showed for the first time that the circulating levels of the active androgen 11KT were 3–4fold higher than that of T in healthy premenopausal women (O'Reilly et al., 2016), highlighting the important contribution of the 11-oxygenated androgens to the circulating androgen pool in women.”
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    • cites O'Reilly et al., 2016 source

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  • Findingcitation

    The 11-oxygenated androgens were the predominant C19 steroids in women with PCOS.

    “For example, we recently profiled classical and 11-oxygenated androgens in serum of healthy premenopausal women and premenopausal women with PCOS. We found that the 11-oxygenated androgens were the predominant C19 steroids in women with PCOS (O'Reilly et al., 2016).”
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    Findingcitation

    Free T concentrations usually range around 1-2% of total T and are also age-dependent in women and men.

    “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).”
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    Findingcitation

    T and DHT circulate predominantly in their unconjugated form, while their metabolites androsterone (AST), epiandrosterone (EpiAST) and 3α-adiol were mostly conjugated, each with specific preferences for sulfation or glucuronidation.

    “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”
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    • cites Zang et al., 2017 source

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    Findingcitation

    STS deficiency patients 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.

    “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).”
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    Findingcitation

    Circulating DHEA-fatty acids have been shown to account for ∼9% of total DHEA in serum.

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

    Administration of DHEA yields significant increases in both DHEAS and active androgens, while administration of DHEAS does not result in any increase of DHEA and downstream androgens in healthy adults.

    “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).”
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    • cites Arlt et al., 1998 source

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    • cites Arlt et al., 1999b

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    • cites Hammer et al., 2005 source

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    Premisereasoning

    PAPSS2 mutations clinically result 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.

    “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).”
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    Premisereasoning

    Mutations of PAPSS2 lead to impaired PAPS synthesis and thus impaired sulfation, which results in enhanced conversion of DHEA to active androgens.

    “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.”
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    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

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    Premisecitation

    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).

    “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).”
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    Interpretationcitation

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

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

    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.

    “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).”
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    Premisecitation

    The presence of SRD5A1, AKR1C2, AKR1C4 and HSD17B6 has 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.

    “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).”
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    • cites Marti et al., 2017 source

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    Premisereasoning

    The expression of HSD3B2 is relatively low in the zona reticularis, thereby ensuring the activity of the Δ5 pathway and the production of DHEA.

    “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.”
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    Premisecitation

    In the adrenal, DHEA can be converted to A4 by HSD3B2 and A4 can be transformed to T by AKR1C3.

    “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).”
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    • cites Nakamura et al., 2009b

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    • cites Rainey and Nakamura, 2008

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    • cites Rege et al., 2013 source

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    Premisecitation

    Adrenal C19 steroid production is initiated during adrenarche, a pre-pubertal event approximately age 8 in girls and 9 in boys, unique to humans and higher primates.

    “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).”
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    • cites Idkowiak et al., 2011 source

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    • cites Abbott and Bird, 2009

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    • cites Arlt et al., 2002 source

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    Premisecitation

    Both 11OHA4 and 11OHT may be converted to their 11-keto counterparts by the low levels of HSD11B2 present in the adrenal, though peripheral HSD11B2 may make a more significant contribution.

    “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).”
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    • cites Turcu et al., 2016 source

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    Premisenone given

    AKR1C3 can catalyse the conversion of some DHEA to 5-diol, which can be sulfated by SULT2A1 or converted to T by HSD3B2.

    “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.”
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    Premisecitation

    Other rodents such as hamster and guinea pig do produce adrenal C19 steroids due to adrenal CYP17A1 expression, but CYP17A1 substrate specificity in these species is significantly different from that of the human enzyme, thus limiting comparisons to human adrenal steroidogenesis.

    “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”
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    Interpretationcitation

    Unlike humans, mouse and rat adrenals do not produce significant levels of androgen precursors which can serve as substrates for intracrine action and are therefore not valid models for studies of human androgen intracrinology.

    “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.”
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    Premisecitation

    HSD17B1 is limited to the granulosa cells, where it activates E1 to E2.

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

    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.

    “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).”
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    Premisereasoning

    Due to ample levels of 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.

    “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.”
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    Premisecitation

    Adrenarche is due to the development of the zona reticularis, which is characterised by an increase in the expression of CYB5A and SULT2A1, and a decrease in the expression of HSD3B2, which in combination favours the biosynthesis of DHEA and DHEAS.

    “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).”
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    • cites Nakamura et al., 2009a

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    Premisecitation

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

    “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).”
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    Premisereasoning

    DHEAS is the major C19 steroid secreted by the adrenal, circulating in low micromolar concentrations.

    “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.”
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    Premisecitation

    The concentration of C19 steroids that peripheral tissue is exposed to is determined by the total concentration of the respective C19 steroids in circulation, whether or not the specific steroid is bound to SHBG or albumin, and the availability of mechanisms for cellular influx and efflux, although this is only relevant for conjugated steroids which require active transport across the cell膜.

    “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”
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    • cites Giorgi and Stein, 1981

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    Premisecitation

    While ovarian steroidogenesis demonstrates a menstrual cycle-dependent profile in premenopausal women, the absence of ovarian follicles in the postmenopausal ovary significantly reduces the production of oestrogens.

    “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).”
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    Premisenone given

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

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

    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.

    “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).”
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    Premisereasoning

    All C19 steroid concentrations discussed above and indicated in Table 2 refer to the total concentrations of androgens in circulation and this is not necessarily indicative of the steroid concentration available for cellular uptake.

    “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.”
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    Premisecitation

    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.

    “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).”
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    • cites Fluck et al., 2003 source

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    • cites Sherbet et al., 2003 source

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    Premisenone given

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

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

    Androgen metabolites released from peripheral tissue make a significant contribution to the circulating pool of C19 steroids, highlighting the importance of local androgen activation and metabolism by intracrine mechanisms.

    “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.”
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    Premisecitation

    The testes also express AKR1C3 and in cases of HSD17B3 deficiency the testes still produce low amounts of T via this enzyme.

    “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).”
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    • cites Werner et al., 2012 source

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    Premisecitation

    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.

    “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).”
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    • cites Hammond, 2016 source

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    Premisecitation

    Albumin binds all unconjugated steroids with low affinities (μmolar ranges) but makes a significant contribution to steroid binding due to its high abundance.

    “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).”
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    • cites Dunn et al., 1981 source

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    Premisecitation

    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.

    “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).”
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    • cites Krone et al., 2007 source

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    • cites Sobel et al., 2004 source

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    Premisecitation

    Systemic upregulation of 5α-reductase activity is observed in women with PCOS leading to enhanced glucocorticoid clearance and enhanced androgen activation in peripheral tissues.

    “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)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Fassnacht et al., 2003 source

      Not checked in the free run.

    • cites Stewart et al., 1990 source

      Not checked in the free run.

    • cites Vassiliadi et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in human HSD3B1 are not known, probably because they would prevent placental PROG production during pregnancy.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miller and Auchus, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    STS is a membrane-bound enzyme on the luminal side of the endoplasmic reticulum and ubiquitously expressed in all human tissues.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ghosh, 2007 source

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    • cites Reed et al., 2005 source

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  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Giorgi and Stein, 1981

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C3 is overexpressed in prostate cancer, presumably promoting cancer progression by increasing intratumoral androgen levels.

    “AKR1C3 is also overexpressed in prostate cancer, presumably promoting cancer progression by increasing intratumoral androgen levels (Adeniji et al., 2013, Fung et al., 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Adeniji et al., 2013 source

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    • cites Fung et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    STS activity is upregulated in several types of cancer and has been proposed as drug target in hormone-dependent breast, prostate and endometrial cancers to prevent local oestrogen and androgen formation from estrone sulfate, DHEAS and 5-diol-sufate.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mueller et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OATPs belong to the SLCO transporter gene superfamily and are the primary transporters for the influx of conjugated steroids, while MDR proteins belonging to the ABC transporters are the primary transporters for the efflux of conjugated steroids.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Deeley et al., 2006 source

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    • cites Mueller et al., 2015 source

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  • May combine two claims.

    Premisecitation

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

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hobkirk, 1993 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AKR1C3 (HSD17B5) has been suggested to make the major contribution to peripheral A4 activation by conversion to T.

    “AKR1C3 (HSD17B5) has been suggested to make the major contribution to peripheral A4 activation by conversion to T (Miller and Auchus, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miller and Auchus, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enzyme isoforms vary greatly between species, so care should be taken when using animal models to study intracrinology.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites de Launoit et al., 1992 source

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    • cites Payne et al., 1995 source

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    • cites Simard et al., 1995 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1D1 is mainly expressed in the liver and 5β-reduction therefore plays only a minor role in other tissues.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Charbonneau and The, 2001

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    • cites Wu et al., 2009

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  • May combine two claims.

    Interpretationreasoning

    5α-reduced metabolites are more indicative for peripheral androgen metabolism than 5β-reduced metabolites, which are more likely to be of hepatic origin.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen and Penning, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The activation of androgens within adipocytes regulates proliferation and differentiation, insulin sensitivity, adipokine signalling and lipid metabolism.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites O'Reilly et al., 2014a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metabolism of activated androgens prevents over-activation of the AR and the release of significant amounts of activated androgens back into circulation.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Labrie, 1991 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The classical pathway via T plays only a minor role in the generation of DHT from inactive C19 precursors.

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

  • May combine two claims.

    Premisecitation

    The 5α-dione pathway is not present in the adrenal or gonads, but plays the major role for peripheral DHT generation from circulating precursors other than T.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Luu-The and Labrie, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As opposed to sulfation, glucuronidation is irreversible and ultimately inactivates the androgen and initiates its renal excretion by increasing polarity and water solubility.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Belanger et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    11KT and 11KDHT are full AR agonists with the same AR activating potential as T and DHT, respectively.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pretorius et al., 2016 source

      Not checked in the free run.

    • cites Storbeck et al., 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The production of T from A4 by AKR1C3 has been proposed to be the essential step of androgen activation in muscle, with further conversion of T to DHT seeming to play only a minor role.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Lin et al., 1997

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    • cites Longcope and Fineberg, 1985

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    • cites Luu-The and Labrie, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The liver has high levels of the 5β-reductase AKR1D1 and primarily produces 5β-reduced androgens, in contrast to peripheral tissue which produces 5α-reduced species.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Charbonneau and The, 2001

      Not checked in the free run.

    • cites Chen and Penning, 2014

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    • cites Penning, 2010

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The correlation of serum T with BMI supports the AKR1C3-catalysed conversion of A4 to T within adipose tissue and suggests that not all T produced within adipocytes is inactivated, but that a portion is released into circulation.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gonzales et al., 2004 source

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    • cites Lemonde et al., 2003 source

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    • cites Palermo et al., 2008 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CYP3A4 is the most abundant P450 in the liver and predominantly, though not exclusively, catalyses the 6β-hydroxylation of T and the 16α- and 7α-hydroxylation of DHEA.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Shimada et al., 1994 source

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    • cites Niwa et al., 2015 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The formation of androgen-linked di-glucuronides, in which a second glucuronidation occurs on the first glucuronosyl moiety, is possible.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Murai et al., 2005 source

      Not checked in the free run.

    • cites Murai et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aromatase activity increases during decidualisation, leading to increased estrogen secretion.

    “While aromatase activity increases during decidualisation leading to an increased estrogen secretion (Gibson et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gibson et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The formation of distinct di-sulfates is described for the synthetic androgen tibolone and cholesterol.

    “The formation of distinct di-sulfates is described for the synthetic androgen tibolone (Falany et al., 2004) and cholesterol (Cook et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Falany et al., 2004 source

      Not checked in the free run.

    • cites Cook et al., 2009 source

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  • May combine two claims.

    Premisecitation

    Breast cancer tissue has STS, 3βHSD, reductive 17βHSD, 5α-reductase, aromatase, 3αHSD, UGT, and SULT activities.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Labrie et al., 2003 source

      Not checked in the free run.

    • cites McNamara and Sasano, 2015b

      Not checked in the free run.

    • cites Suzuki et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kalogera et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    11KA4 is preferentially converted to 11KT by AKR1C3 and 11KT can then be 5α-reduced to yield 11KDHT.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pretorius et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Glucuronidation of 3α-adiol is of particular importance for androgen inactivation and regulation of cancer progression because prostate cancer cells can convert 3α-adiol back to DHT.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chouinard et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The placenta expresses CYP11A1 and catalyses StAR-independent de-novo steroidogenesis probably facilitated by MLN64 with StAR-like activity.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sugawara et al., 1995 source

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    • cites Bose et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The presence of SRD5A1 allows for local production of DHT, with the 5α-dione pathway bypassing T being the preferred route.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Luu-The et al., 1994 source

      Not checked in the free run.

    • cites Samson et al., 2010 source

      Not checked in the free run.

    • cites Sugimoto et al., 1995 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    5α-reductase inhibitors are an established treatment for male pattern alopecia.

    “and 5α-reductase inhibitors are an established treatment for male pattern alopecia (Kaufman and Dawber, 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kaufman and Dawber, 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP17A1 activity is sufficient for the production of T, E1 and E2, as demonstrated for trophoblasts.

    “However, CYP17A1 activity is sufficient for the production of T, E1 and E2, as has been demonstrated for trophoblasts (Escobar et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Escobar et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bellemare et al., 2005 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    UGTs and SULTs are expressed in the skin and may contribute to phase 2 metabolism.

    “UGTs and SULTs are expressed and may contribute to phase 2 metabolism (Slominski et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Slominski et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Renal excretion of conjugates takes advantage of the hydrophilic water-soluble nature of steroid conjugates and 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.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pritchard and Miller, 1996

      Not checked in the free run.

    • cites VanWert et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Steroids can passively diffuse from circulation into saliva in the salivary glands, so salivary levels represent bioavailable, non-protein bound levels.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vining et al., 1983 source

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  • May combine two claims.

    Interpretationcitation

    Significant levels of 11KA4 measured in serum of healthy premenopausal women support the involvement of peripheral tissue such as the kidney, especially considering that the adrenal expresses only low levels of HSD11B2.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites O'Reilly et al., 2016 source

      Not checked in the free run.

    • cites Coulter et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “DHEA could be further metabolised to T, via A4 or 5α-dione, and the resulting T could be 5α-reduced to DHT.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Quinkler et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While the kidney inactivates glucocorticoids, it may play a vital role in activating 11-oxygenated androgens.

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

  • May combine two claims.

    Premisecitation

    In the skin, A4 and T can be aromatised to oestrogens, which induce beneficial effects on keratinocyte proliferation, production of extracellular matrix components and wound healing.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kanda and Watanabe, 2004a

      Not checked in the free run.

    • cites Kanda and Watanabe, 2004b

      Not checked in the free run.

    • cites Raine-Fenning et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sulfo- and glucoconjugates are excreted in different ratios for every androgen, while the excretion of free forms is negligible.

    “Sulfo- and glucoconjugates are excreted in different ratios for every androgen, while the excretion of free forms is negligible (Buiarelli et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Buiarelli et al., 2004 source

      Not checked in the free run.

    • Rests on an assumption: Steroid sulfates are generally excreted at a lower rate than their glucuronidated counterparts as STS catalyses their desulfation.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ratio of urinary T and EpiT-glucuronide is used as an indicator of exogenous T administration in doping analysis.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mareck et al., 2010 source

      Not checked in the free run.

    • cites Shackleton et al., 1997a

      Not checked in the free run.

    • cites Shackleton et al., 1997b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Havlikova et al., 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Organic anion transporters are highly expressed in renal epithelia.

    “Organic anion transporters are highly expressed in renal epithelia (Emami Riedmaier et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Emami Riedmaier et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A range of liquid chromatography tandem mass spectrometry assays for salivary cortisol/cortisone and salivary androgens have been developed and implemented in routine clinical laboratories.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Keevil, 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA can be 7α-hydroxylated by CYP7B1, which is expressed in the skin, thereby preventing its metabolism to active androgens.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hennebert et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Spaan et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Urinary 11-oxygenated ETIO is predominantly a product of glucocorticoid metabolism, while urinary 11-oxygenated AST results mainly from 11-oxygenated androgens.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jones et al., 2016 source

      Not checked in the free run.

    • cites Shackleton et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “Urinary 11-oxygenated AST and 11-oxygenated ETIO originate from androgen and glucocorticoid metabolism, however in different ratios.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jones et al., 2016 source

      Not checked in the free run.

    • cites Shackleton et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Besides the classical conjugates, T metabolites conjugated with cysteine have been detected in urine and plasma.

    “Besides the classical conjugates, T metabolites conjugated with cysteine have been detected in urine and plasma (Fabregat et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fabregat et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    SRD5A enzymes and HSD11B2 activate androgens, but inactivate glucocorticoids.

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

  • May combine two claims.

    Interpretationcitation

    Circulating levels of active androgens are not a valid reflection of total body androgen action because 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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites O'Reilly et al., 2014b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AST and ETIO are measured as representatives of active androgens, while DHEA and 16αOH-DHEA are measured as representatives of direct androgen precursors.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Arlt et al., 2011 source

      Not checked in the free run.

    • cites Krone et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Arlt et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    De-conjugation by β-glucuronidase is time-consuming and may lead to imprecision due to variability in hydrolysis efficiency.

    “De-conjugation by β-glucuronidase is time-consuming and may lead to imprecision due to variability in hydrolysis efficiency (Trabert et al., 2016)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Trabert et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5β-reduction (→ ETIO) is indicative of hepatic metabolism, while 5α-reduction (→ AST) takes place in most peripheral tissues.

    “As previously mentioned, 5β-reduction (→ ETIO) is indicative of hepatic metabolism (Chen and Penning, 2014), while 5α-reduction (→ AST) takes place in most peripheral tissues (Russell and Wilson, 1994).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chen and Penning, 2014

      Not checked in the free run.

    • cites Russell and Wilson, 1994 source

      Not checked in the free run.

95 of 95

  • The paper relies on this without support.

    Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone.

    “Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone.”

  • The paper relies on this without support.

    Intracrine pathways play the major role for peripheral androgen action.

    “It should be noted that while intracrine pathways play the major role for peripheral androgen action, active androgens such as T are produced by the testes and the adrenal, albeit only low levels, and these do not require activation in target tissue.”

  • The paper relies on this without support.

    The liver expresses AR, making it a target tissue for classical androgen action.

    “Although the liver is traditionally considered only in terms of phase 1 and phase 2 metabolism, the liver also expresses AR turning it into a target tissue for classical androgen action.”

  • The paper relies on this without support.

    De-novo steroidogenesis in the placenta yields mainly PREG and PROG due to low levels of CYP17A1.

    “De-novo steroidogenesis in the placenta yields mainly PREG and PROG due to low levels of CYP17A1.”

  • The paper relies on this without support.

    5α-reduced androgens cannot be aromatised.

    “However, 5α-reduced androgens cannot be aromatised and therefore can transfer from fetus to mother unhindered by the placenta, which is observed e.g. in aromatase deficiency and PORD.”

  • The paper relies on this without support.

    Local androgen availability in the skin is necessary to stimulate sebum secretion and hair growth.

    “Local androgen availability in the skin is necessary to stimulate sebum secretion and hair growth.”

  • The paper relies on this without support.

    Acne vulgaris and androgenic alopecia are associated with local androgen hyperproduction.

    “Acne vulgaris and androgenic alopecia are associated with local androgen hyperproduction.”

  • The paper relies on this without support.

    Steroid sulfates are generally excreted at a lower rate than their glucuronidated counterparts as STS catalyses their desulfation.

    “Steroid sulfates are generally excreted at a lower rate than their glucuronidated counterparts as STS catalyse their desulfation.”

  • The paper relies on this without support.

    Significant differences in adrenal development, C19 steroidogenesis and subsequent metabolism exist between humans and common animal models, i.e. rodent and non-human primates.

    “significant differences in adrenal development, C19 steroidogenesis and subsequent metabolism between humans and common animal models, i.e. rodent and non-human primates, must be taken into account.”

  • The paper relies on this without support.

    Less is known about androgen action in non-classical target tissues, such as the liver and skeletal muscle, than in reproductive tissues.

    “While androgen metabolism in reproductive tissues is well studied, less is known to date about androgen action in non-classical target tissues, such as the liver and skeletal muscle, which are major compartments responsible for metabolic regulation and metabolic health.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • DHT is described as retaining a double bond that its formation removes

    Minor

    The paper says all active androgens, including DHT and 11KDHT, share a 3-keto-Δ4 motif. It also says that producing DHT and 11KDHT involves reducing the Δ4 double bond, so those products cannot retain that motif.

  • HSD11B1 reaction is called both oxidative and reductive

    Minor

    The liver section calls conversion of an 11-keto steroid to its 11β-hydroxyl form oxidation, whereas Table 1 identifies HSD11B1 as predominantly reductive.

2 of 2

Cites

Flagged first, then by citations

19 of the 349 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Mendonca, 1999, 17Beta-hydroxysteroid dehydrogenase 3 deficiency in women, J. Clin. Endocrinol. Metab., 84, 802

Cited by

Sorted by citations

Related

Authors
Schiffer, L., Arlt, W., & Storbeck, K.-H.
Affiliations
  • University of Birmingham (GB)
  • Stellenbosch University (ZA)
Corresponding author
Arlt, Wiebke
ORCID
Venue
Molecular and Cellular Endocrinology
Publisher
Elsevier BV
Published
2018-04
Volume
465
Pages
4-26
ISSN
0303-7207 (ISSN-L)
DOI
10.1016/j.mce.2017.08.016
PMC
PMC6565845
OpenAlex
W2752706152
Semantic Scholar
9d8d894b81455769f4a5eb82ce3b04e7d865f8a1
Cited by
217
References
349
Citations by year
2026: 22 · 2025: 24 · 2024: 30 · 2023: 33 · 2022: 27 · 2021: 29 · 2020: 24 · 2019: 19 · 2018: 9
FWCI
2.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular and Cellular Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc-nd)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (092283)
  • Academy of Medical Science
  • National Research Foundation of South Africa (98886)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
androgen production, androgen metabolism, androgen receptor, androgen transport, liver, kidney, renal excretion, testosterone, dihydrotestosterone
MeSH terms
Androgens, Animals, Humans, Organ Specificity, Reproduction, Steroids, Biosynthetic Pathways

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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