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Cited by 450Metabolomics and Mass Spectrometry StudiesAdrenal Hormones and DisordersSteroid Chemistry and Biochemistry

Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review

Open access
Schiffer, Lina, Barnard, Lise, Baranowski, Elizabeth S., Gilligan, Lorna C., Taylor, Angela E., Arlt, Wiebke, Shackleton, Cedric H.L., Storbeck, Karl-Heinz·2019·The Journal of Steroid Biochemistry and Molecular Biology
DOI 10.1016/j.jsbmb.2019.105439PMC PMC6857441
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Abstract

Advances in technology have allowed for the sensitive, specific, and simultaneous quantitative profiling of steroid precursors, bioactive steroids and inactive metabolites, facilitating comprehensive characterization of the serum and urine steroid metabolomes. The quantification of steroid panels is therefore gaining favor over quantification of single marker metabolites in the clinical and research laboratories. However, although the biochemical pathways for the biosynthesis and metabolism of steroid hormones are now well defined, a gulf still exists between this knowledge and its application to the measured steroid profiles. In this review, we present an overview of steroid hormone biosynthesis and metabolism by the liver and peripheral tissues, specifically highlighting the pathways linking and differentiating the serum and urine steroid metabolomes. A brief overview of the methodology used in steroid profiling is also provided.

AI snapshot

Written from the paper’s full text.

TL;DR

This comprehensive review describes human steroid biosynthesis, phase 1/2 metabolism, and excretion, contrasting serum and urine steroid metabolomes. It emphasizes that serum and urine profiles reflect different metabolic stages and that mass spectrometry-based steroid metabolomics requires careful pathway interpretation.

Key findings

  • Serum and urine steroid metabolomes are differentially informative: serum mainly reflects circulating precursors and active hormones, while urine predominantly reflects downstream conjugated metabolites after phase 1 and phase 2 metabolism.
  • DHEAS is the most abundant circulating steroid and the only human steroid circulating in micromolar concentrations; cortisol circulates at 100–600 nM, cortisone at 30–100 nM, and glucocorticoid precursors such as progesterone, 17OHP, and 11-deoxycortisol are ≤10 nM.
  • Urine excretion accounts for approximately 80% of excretion following exogenous steroid administration, while unconjugated steroids account for only 5–10% of the total urine steroid pool; androgen metabolites are excreted with a 17-keto/17β-hydroxy ratio of approximately 10:1, chiefly as androsterone and etiocholanolone.
  • Steroid metabolomics combines mass spectrometry-based profiling with machine learning; the review cites automated differentiation of adrenocortical carcinoma from benign adrenocortical tumors via a “malignant steroid fingerprint” as an example.

Methods

  • Narrative comprehensive review of current knowledge on human steroid biosynthesis, metabolism, and excretion, with no primary cohort or experimental data reported.
  • Synthesizes enzymatic pathways and serum/urine metabolomes across mineralocorticoids, glucocorticoids, androgens, estrogens, and progestogens, including tables of circulating steroids and targeted urine steroid metabolite concentration ranges.
  • Discusses analytical approaches including GC-MS, UHPLC-MS/MS, UHPSFC-MS/MS, and HRAM mass spectrometry, and defines steroid metabolomics as mass spectrometry profiling plus computational machine learning.

Limitations

  • Stated in the paper: mass spectrometry methods require cross-validation; differences in sample work-up, instrumentation, and settings can produce reference ranges that vary between laboratories, and no reference ranges have been established for 11-oxygenated androgens due to significant variation in reported levels.
  • Stated in the paper: several pathways remain incompletely understood, including the metabolism of 11KT, the human enzyme(s) responsible for 20β-hydroxy isomers of cortols/cortolones, and the enzymes responsible for certain neonatal hydroxylations.
  • Evident from the text: this is a narrative review without a described systematic search or formal quality appraisal, and it explicitly excludes neurosteroids from scope.

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

Integrity signals

Registry

Crossref · 10.1016/j.jsbmb.2019.105439

Cites

363 of 363 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    All three primary steroidogenic organs (adrenal cortex, gonads, placenta) can biosynthesize cholesterol de novo under regulation of tropic hormones.

    “All three primary steroidogenic organs, namely the adrenal cortex, gonads and placenta, can biosynthesize cholesterol de novo under the regulation of tropic hormones and plasma lipoproteins are widely accepted as the principal source of cholesterol used for steroid biosynthesis [[5], [6], [7], [8]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Gwynne J.T. Strauss J.F. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands Endocr. Rev. 3 1982 299 329 6288367 source

      Not checked in the free run.

    • cites [6] Azhar S. Reaven E. Scavenger receptor class BI and selective cholesteryl ester uptake: partners in the regulation of steroidogenesis Mol. Cell. Endocrinol. 195 2002 1 26 12354669 source

      Not checked in the free run.

    • cites [7] Azhar S. Leers-Sucheta S. Reaven E. Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and “selective” pathway connection Front. Biosci. 8 2003 998 1029 http://www.ncbi.nlm.nih.gov/pubmed/12957864 12957864 source

      Not checked in the free run.

  • Interpretationcitation

    Lack of CYP17A1 expression in zona glomerulosa together with abundant expression of HSD3B2 ensures that all steroid intermediates are directed towards aldosterone biosynthesis.

    “The lack of CYP17A1 expression in the zona glomerulosa [25] together with the abundant expression of HSD3B2 ensures that all steroid intermediates are directed towards aldosterone biosynthesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Suzuki T. Sasano H. Takeyama J. Kaneko C. Freije W.A. Carr B.R. Rainey W.E. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies Clin. Endocrinol. (Oxf.) 2000 739 748 11155097 source

      Not checked in the free run.

  • Premisereasoning

    DHEAS is the most abundant steroid in circulation.

    “This results in significant DHEAS output and accounts for DHEAS being the most abundant steroid in circulation (Table 2) [39,41].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Rege J. Nakamura Y. Satoh F. Morimoto R. Kennedy M.R. Layman L.C. Honma S. Sasano H. Rainey W.E. Liquid chromatography – tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation J. Clin. Endocrinol. Metab. 98 2013 1182 1188 23386646 PMC3590473 source

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    • cites [41] O’Reilly M.W. Kempegowda P. Jenkinson C. Taylor A.E. Quanson J.L. Storbeck K.-H.H. Arlt W. O’Reilly M.W. Kempegowda P. Jenkinson C. Taylor A.E. Quanson J.L. Storbeck K.-H.H. Arlt W. 11-Oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome J. Clin. Endocrinol. Metab. 102 2017 840 848 27901631 PMC5460696 source

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  • Premisecitation

    Other Δ5 steroids, e.g. pregnenolone, 17α-hydroxypregnenolone and androstenediol, can also be released in their respective sulfated form.

    “Other Δ5 steroids, e.g. pregnenolone, 17α-hydroxypregnenolone and androstenediol, can also be released in their respective sulfated form [[42], [43], [44]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Strott C.A. Sulfonation and molecular action Endocr. Rev. 23 2002 703 732 12372849 source

      Not checked in the free run.

    • cites [43] Rege J. Nanba A.T. Auchus R.J. Ren J. Peng H.-M. Rainey W.E. Turcu A.F. Adrenocorticotropin acutely regulates pregnenolone sulfate production by the human adrenal in vivo and in vitro J. Clin. Endocrinol. Metab. 103 2018 320 327 29126147 PMC5761485 source

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    • cites [44] Rege J. Karashima S. Lerario A.M. Smith J.M. Auchus R.J. Kasa-Vubu J.Z. Sasano H. Nakamura Y. White P.C. Rainey W.E. Age-dependent increases in adrenal cytochrome b5 and serum 5-androstenediol-3-sulfate J. Clin. Endocrinol. Metab. 101 2016 4585 4593 27623070 PMC5155691 source

      Not checked in the free run.

  • Premisecitation

    HSD3B1 and HSD3B2 have dual catalytic activity: they transform the hydroxy group on carbon 3 to a keto group and isomerize the double bond from Δ5 to Δ4.

    “These enzymes have dual catalytic activity and not only transform the hydroxy group on carbon 3 to a keto group but additionally isomerize the double bond from Δ5 to Δ4 [[15], [16], [17], [18]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Luu-The V. Takahashi M. de Launoit Y. Dumont M. Lachance Y. Labrie F. Evidence for distinct dehydrogenase and isomerase sites within a single 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase protein Biochemistry 30 1991 8861 8865 1832298 source

      Not checked in the free run.

    • cites [16] Thomas J.L. Frieden C. Nash W.E. Strickler R.C. An NADH-induced conformational change that mediates the sequential 3β-hydroxysteroid dehydrogenase/isomerase activities Is supported by affinity labeling and the time-dependent activation of isomerase J. Biol. Chem. 270 1995 21003 21008 7673125 source

      Not checked in the free run.

    • cites [17] Thomas J.L. Berko E.A. Faustino A. Myers R.P. Strickler R.C. Human placental 3β-hydroxy-5-ene-steroid dehydrogenase and steroid 5→4-ene-isomerase: purification from microsomes, substrate kinetics and inhibition by product steroids J. Steroid Biochem. 31 1988 785 793 3199818 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 68
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    17,20-lyase activity of CYP17A1 is dependent on augmentation by cytochrome b5 (CYB5A) in addition to electron transfer from POR.

    “It should be noted that the 17,20-lyase activity of CYP17A1 is dependent on augmentation by cytochrome b5 (CYB5A) in addition to electron transfer from POR [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Auchus R.J. Lee T.C. Miller W.L. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer J. Biol. Chem. 273 1998 3158 3165 http://www.ncbi.nlm.nih.gov/pubmed/9452426 9452426 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Majority of DHEA is efficiently sulfated by SULT2A1, which is abundantly expressed in zona reticularis.

    “However, the majority of DHEA is efficiently sulfated by the major DHEA sulfotransferase (SULT2A1), which is abundantly expressed in the zona reticularis [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Mueller J.W. Gilligan L.C. Idkowiak J. Arlt W. Foster P.A. The regulation of steroid action by sulfation and desulfation Endocr. Rev. 36 2015 526 563 26213785 PMC4591525 source

      Not checked in the free run.

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

    Premisecitation

    Gonadal steroidogenesis is active during minipuberty, a short period of hypothalamic-pituitary-gonadal axis activation during neonatal period.

    “Gonadal steroidogenesis is also active during ‘minipuberty’, a short period of hypothalamic-pituitary-gonadal axis activation during the neonatal period [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Lanciotti L. Cofini M. Leonardi A. Penta L. Esposito S. Up-to-date review about minipuberty and overview on hypothalamic-pituitary-gonadal axis activation in fetal and neonatal life Front. Endocrinol. (Lausanne) 9 2018 410 30093882 PMC6070773 source

      Not checked in the free run.

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

    Premisecitation

    Plasma lipoproteins are widely accepted as the principal source of cholesterol used for steroid biosynthesis.

    “All three primary steroidogenic organs, namely the adrenal cortex, gonads and placenta, can biosynthesize cholesterol de novo under the regulation of tropic hormones and plasma lipoproteins are widely accepted as the principal source of cholesterol used for steroid biosynthesis [[5], [6], [7], [8]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Gwynne J.T. Strauss J.F. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands Endocr. Rev. 3 1982 299 329 6288367 source

      Not checked in the free run.

    • cites [6] Azhar S. Reaven E. Scavenger receptor class BI and selective cholesteryl ester uptake: partners in the regulation of steroidogenesis Mol. Cell. Endocrinol. 195 2002 1 26 12354669 source

      Not checked in the free run.

    • cites [7] Azhar S. Leers-Sucheta S. Reaven E. Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and “selective” pathway connection Front. Biosci. 8 2003 998 1029 http://www.ncbi.nlm.nih.gov/pubmed/12957864 12957864 source

      Not checked in the free run.

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

    Premisecitation

    Hypothalamus produces CRH that stimulates corticotrope cells in anterior pituitary to biosynthesize and release ACTH that in turn stimulates adrenal gland to produce steroid hormones, specifically DHEA and cortisol.

    “In short, the hypothalamus produces corticotropin-releasing hormone (CRH) that stimulates corticotrope cells in the anterior pituitary to biosynthesize and release adrenocorticotropic hormone (ACTH) that in turn stimulates the adrenal gland to produce steroid hormones, specifically DHEA and cortisol [21,22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Xing Y. Edwards M.A. Ahlem C.N. Kennedy M. Cohen A. Gomez-sanchez C.E. Rainey W.E. The effects of ACTH on steroid metabolomic profiles in human adrenal cells J. Endocrinol. 209 2011 327 335 21429963 PMC3774117 source

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    • cites [22] Simpson E.R. Waterman M.R. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH Annu. Rev. Physiol. 50 1988 427 440 2837136 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some DHEA is converted to androstenediol by AKR1C3, which exhibits minor expression in zona reticularis.

    “Some of the resulting DHEA is converted to androstenediol by AKR1C3, which exhibits minor expression in the zona reticularis [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Rege J. Nakamura Y. Satoh F. Morimoto R. Kennedy M.R. Layman L.C. Honma S. Sasano H. Rainey W.E. Liquid chromatography – tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation J. Clin. Endocrinol. Metab. 98 2013 1182 1188 23386646 PMC3590473 source

      Not checked in the free run.

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

    Premisecitation

    Androgens and estrogens provide negative feedback at hypothalamus and pituitary level to suppress LH in men and women, respectively.

    “Androgens and estrogens provide negative feedback at the hypothalamus and pituitary level to suppress LH in men and women, respectively [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Handa R.J. Weiser M.J. Gonadal steroid hormones and the hypothalamo – pituitary – adrenal axis Front. Neuroendocrinol. 35 2014 197 220 24246855 PMC5802971 source

      Not checked in the free run.

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

    Premisecitation

    Adrenal cortex is responsible for biosynthesis of mineralocorticoids and glucocorticoids, as well as production of adrenal androgen precursors and androgens, a function unique to higher primates.

    “The cortex of the adrenal gland is responsible for the biosynthesis of mineralocorticoids and glucocorticoids, as well as the production of adrenal androgen precursors and androgens, a function unique to higher primates [19,20].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Cutler G.B. Glenn M. Bush M. Hodgen G.D. Graham C.E. Loriaux D.L. Adrenarche: a survey of rodents, domestic animals, and primates Endocrinology 103 1978 2112 2118 155005 source

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    • cites [20] Arlt W. Martens J.W.M. Song M. Wang J.T. Auchus R.J. Miller W.L. Molecular evolution of adrenarche: structural and functional analysis of p450c17 from four primate species Endocrinology 143 2002 4665 4672 12446594 source

      Not checked in the free run.

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

    Premisecitation

    Progesterone is converted to 11-deoxycorticosterone (DOC) by CYP21A2, which is abundantly expressed in ER of zona glomerulosa.

    “Progesterone is subsequently converted to 11-deoxycorticosterone (DOC) by CYP21A2, which is abundantly expressed in the ER of the zona glomerulosa [26,27].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Pezzi V. Mathis J.M. Rainey W.E. Carr B.R. Profiling transcript levels for steroidogenic enzymes in fetal tissues J. Steroid Biochem. Mol. Biol. 87 2003 181 189 14672738 source

      Not checked in the free run.

    • cites [27] Coulter C.L. Jaffe R.B. Functional maturation of the primate fetal adrenal in vivo: 3. specific zonal localization and developmental regulation of CYP21A2 (P450c21) and CYP11B1/CYP11B2 (P450c11/aldosterone synthase) lead to integrated concept of zonal and temporal steroi Endocrinology 139 1998 5144 5150 9832454 source

      Not checked in the free run.

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

    Premisecitation

    HSD3B1 and HSD3B2 catalyze an irreversible reaction directly linked to isomerization of the Δ5 double bond.

    “An exception to this rule are the two HSD3B isoforms, HSD3B1 and HSD3B2, which catalyze an irreversible reaction, directly linked to the isomerization of the Δ5 double bond.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Luu-The V. Takahashi M. de Launoit Y. Dumont M. Lachance Y. Labrie F. Evidence for distinct dehydrogenase and isomerase sites within a single 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase protein Biochemistry 30 1991 8861 8865 1832298 source

      Not checked in the free run.

    • cites [16] Thomas J.L. Frieden C. Nash W.E. Strickler R.C. An NADH-induced conformational change that mediates the sequential 3β-hydroxysteroid dehydrogenase/isomerase activities Is supported by affinity labeling and the time-dependent activation of isomerase J. Biol. Chem. 270 1995 21003 21008 7673125 source

      Not checked in the free run.

    • cites [17] Thomas J.L. Berko E.A. Faustino A. Myers R.P. Strickler R.C. Human placental 3β-hydroxy-5-ene-steroid dehydrogenase and steroid 5→4-ene-isomerase: purification from microsomes, substrate kinetics and inhibition by product steroids J. Steroid Biochem. 31 1988 785 793 3199818 source

      Not checked in the free run.

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

    Premisecitation

    HSD enzymes catalyze conversion of a given hydroxysteroid to its corresponding ketosteroid counterpart and vice versa, and in doing so regulate activity of the steroid at specific steroid receptors.

    “The function of the HSD enzymes from both families is to catalyze the conversion of a given hydroxysteroid to its corresponding ketosteroid counterpart and vice versa, and in doing so, regulate the activity of the steroid at specific steroid receptors [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Penning T.M. Molecular endocrinology of hydroxysteroid dehydrogenases Endocr. Rev. 18 1997 281 305 9183566

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two isoforms of CYP11B are expressed in zona glomerulosa, both with ability to catalyze 11β-hydroxylation of DOC yielding corticosterone.

    “Two isoforms of CYP11B are expressed in the zona glomerulosa, both with the ability to catalyze the 11β-hydroxylation of DOC yielding corticosterone.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Pezzi V. Mathis J.M. Rainey W.E. Carr B.R. Profiling transcript levels for steroidogenic enzymes in fetal tissues J. Steroid Biochem. Mol. Biol. 87 2003 181 189 14672738 source

      Not checked in the free run.

    • cites [28] Kawamoto T. Mitsuuchi Y. Toda K. Yokoyama Y. Miyahara K. Miura S. Ohnishi T. Ichikawa Y. Makao K. Mura H. Ulick S. Shizuta Y. Role of steroid 11β-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans Proc. Natl. Acad. Sci. U. S. A. 89 1992 1458 1462 1741400 PMC48470 source

      Not checked in the free run.

    • cites [29] Kawamoto T. Mitsuuchi Y. Ohnishi T. Ichikawa Y. Yokoyama Y. Sumimoto H. Toda K. Miyahara K. Kuribayashi I. Nakao K. Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism Biochem. Biophys. Res. Commun. 173 1990 309 316 2256920 source

      Not checked in the free run.

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

    Premisecitation

    A4 can serve as additional substrate for AKR1C3, yielding testosterone.

    “A4 can serve as an additional substrate for AKR1C3, yielding testosterone [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Schiffer L. Arlt W. Storbeck K.H. Intracrine androgen biosynthesis, metabolism and action revisited Mol. Cell. Endocrinol. 465 2018 4 26 28865807 PMC6565845 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In adrenal zona glomerulosa, CYP11A1 converts cholesterol to pregnenolone, followed by HSD3B2-catalyzed conversion of pregnenolone to progesterone.

    “CYP11A1 converts cholesterol to pregnenolone, followed by the HSD3B2-catalyzed conversion of pregnenolone to the Δ4 steroid, progesterone.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Suzuki T. Sasano H. Takeyama J. Kaneko C. Freije W.A. Carr B.R. Rainey W.E. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies Clin. Endocrinol. (Oxf.) 2000 739 748 11155097 source

      Not checked in the free run.

    • cites [26] Pezzi V. Mathis J.M. Rainey W.E. Carr B.R. Profiling transcript levels for steroidogenic enzymes in fetal tissues J. Steroid Biochem. Mol. Biol. 87 2003 181 189 14672738 source

      Not checked in the free run.

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

    Premisecitation

    HSD3B2 is present in both mitochondria and ER of zona glomerulosa cells.

    “HSD3B2 is present in both the mitochondria and ER of zona glomerulosa cells [25,26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Suzuki T. Sasano H. Takeyama J. Kaneko C. Freije W.A. Carr B.R. Rainey W.E. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies Clin. Endocrinol. (Oxf.) 2000 739 748 11155097 source

      Not checked in the free run.

    • cites [26] Pezzi V. Mathis J.M. Rainey W.E. Carr B.R. Profiling transcript levels for steroidogenic enzymes in fetal tissues J. Steroid Biochem. Mol. Biol. 87 2003 181 189 14672738 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP17A1-catalyzed 17α-hydroxylation of pregnenolone yields 17α-hydroxypregnenolone, which serves as preferred substrate for 17,20-lyase activity of CYP17A1, producing C19 steroids from C21 precursors.

    “The CYP17A1-catalyzed 17α-hydroxylation of pregnenolone yields 17α-hydroxypregnenolone, which serves as the preferred substrate for the 17,20-lyase activity of CYP17A1, producing C19 steroids from C21 precursors [[30], [31], [32]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Gupta M.K. Guryev O.L. Auchus R.J. 5α-reduced C21 steroids are substrates for human cytochrome P450c17 Arch. Biochem. Biophys. 418 2003 151 160 14522586 source

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    • cites [31] Petrunak E.M. DeVore N.M. Porubsky P.R. Scott E.E. Structures of human steroidogenic cytochrome P450 17A1 with substrates J. Biol. Chem. 289 2014 32952 32964 25301938 PMC4239641 source

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    • cites [32] Gregory M.C. Denisov I.G. Grinkova Y.V. Khatri Y. Sligar S.G. Kinetic solvent isotope effect in human P450 CYP17A1-mediated androgen formation: evidence for a reactive peroxoanion intermediate J. Am. Chem. Soc. 135 2013 16245 16247 24160919 PMC3867208 source

      Not checked in the free run.

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

    Premisecitation

    CYP11B2 (aldosterone synthase) exhibits 18-hydroxylase and 18-methyl oxidase activity required to convert corticosterone to aldosterone via 18-hydroxycorticosterone intermediate.

    “CYP11B2, which is also known as aldosterone synthase, additionally exhibits 18-hydroxylase and 18-methyl oxidase activity, which are required to convert corticosterone to aldosterone via the 18-hydroxycorticosterone intermediate [26,28,29].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Pezzi V. Mathis J.M. Rainey W.E. Carr B.R. Profiling transcript levels for steroidogenic enzymes in fetal tissues J. Steroid Biochem. Mol. Biol. 87 2003 181 189 14672738 source

      Not checked in the free run.

    • cites [28] Kawamoto T. Mitsuuchi Y. Toda K. Yokoyama Y. Miyahara K. Miura S. Ohnishi T. Ichikawa Y. Makao K. Mura H. Ulick S. Shizuta Y. Role of steroid 11β-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans Proc. Natl. Acad. Sci. U. S. A. 89 1992 1458 1462 1741400 PMC48470 source

      Not checked in the free run.

    • cites [29] Kawamoto T. Mitsuuchi Y. Ohnishi T. Ichikawa Y. Yokoyama Y. Sumimoto H. Toda K. Miyahara K. Kuribayashi I. Nakao K. Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism Biochem. Biophys. Res. Commun. 173 1990 309 316 2256920 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alternate 5α-androstanedione pathway is favored in tissues with predominant SRD5A1 expression and in conditions such as castration-resistant prostate cancer in which SRD5A1 is upregulated and SRD5A2 is downregulated.

    “This so called “alternate 5α-androstanedione” pathway is favored in tissues with predominant SRD5A1 expression and in conditions such as castration-resistant prostate cancer in which the expression of SRD5A1 is upregulated and that of SRD5A2 is downregulated [55,58].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Sharifi N. The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer J. Invest. Med. 60 2012 504 507 PMC3262939 22064602 source

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    Premisecitation

    Activation/inactivation of glucocorticoids and 11-oxygenated androgens work in antiparallel manner, with 11β-hydroxy derivative being active glucocorticoid, while 11-keto androgens are more potent than their 11β-hydroxy counterparts.

    “Interestingly, activation/inactivation of glucocorticoids and 11-oxygenated androgens work in an antiparallel manner, with the 11β-hydroxy derivative being the active glucocorticoid [74,75], while the 11-keto androgens are more potent than their 11β-hydroxy counterparts [76].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Gathercole L.L. Lavery G.G. Morgan S.A. Cooper M.S. Sinclair A.J. Tomlinson J.W. Stewart P.M. 11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects Endocr. Rev. 34 2013 525 555 23612224 source

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    • cites [75] Grossmann C. Scholz T. Rochel M. Bumke-Vogt C. Oelkers W. Pfeiffer A.F.H. Diederich S. Bähr V. Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties Eur. J. Endocrinol. 151 3 2004 397 406 15362971 source

      Not checked in the free run.

    • cites [76] Storbeck K.-H. Bloem L.M. Africander D.J. Schloms L. Swart P. Swart A.C. 11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? Mol. Cell. Endocrinol. 377 2013 135 146 23856005 source

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  • May combine two claims.

    Premisecitation

    Androgen secretion by theca cells surpasses secretion of estrogens, while progesterone is primary progestogen produced.

    “Indeed, androgen secretion by the theca cells surpasses the secretion of estrogens, while progesterone is the primary progestogen produced [85].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] McNatty K.P. Makris A. DeGrazia C. Osathanondh R. Ryan K.J. The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro* J. Clin. Endocrinol. Metab. 49 1979 687 699 489711 source

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

    Premisecitation

    Peripheral cell specific activation and inactivation is known as pre- and post-receptor steroid metabolism or steroid intracrinology.

    “This process of peripheral cell specific activation and inactivation is known as pre- and post-receptor steroid metabolism or steroid ” intracrinology” [45,[59], [60], [61]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Schiffer L. Arlt W. Storbeck K.H. Intracrine androgen biosynthesis, metabolism and action revisited Mol. Cell. Endocrinol. 465 2018 4 26 28865807 PMC6565845 source

      Not checked in the free run.

    • cites [59] Labrie F. Intracrinology Mol. Cell. Endocrinol. 78 1991 13 18 1838082 source

      Not checked in the free run.

    • cites [60] Labrie F. Bélanger A. Simard J. Luu-The V. Labrie C. DHEA and peripheral androgen and estrogen formation: intracrinology Ann. N. Y. Acad. Sci. 774 1995 16 28 8597456 source

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  • May combine two claims.

    Premisecitation

    In Leydig cells, DHEA is converted to testosterone via A4 or androstenediol through action of HSD3B2 and HSD17B3, with HSD17B3 playing key role in testicular androgen biosynthesis.

    “DHEA is then converted to testosterone via A4 or androstenediol through the action of HSD3B2 and HSD17B3, respectively, with HSD17B3 playing a key role in testicular androgen biosynthesis [47,48].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Geissler W.M. Davis D.L. Wu L. Bradshaw K.D. Patel S. Mendonca B.B. Elliston K.O. Wilson J.D. Russell D.W. Andersson S. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3 Nat. Genet. 7 1994 34 39 8075637 source

      Not checked in the free run.

    • cites [48] Andersson S. Geissler W.M. Wu L. Davis D.L. Grumbach M.M. New M.I. Schwarz H.P. Blethen S.L. Mendonca B.B. Bloise W. Witchel S.F. Cutler G.B. Griffin J.E. Wilson J.D. Russell D.W. Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency J. Clin. Endocrinol. Metab. 81 1996 130 136 8550739

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  • May combine two claims.

    Premisecitation

    Subsequent 5α-reduction of testosterone yields more potent androgen DHT, serving as target-specific amplification of androgen signal, a pre-receptor activation of testosterone to DHT.

    “Subsequent 5α-reduction of testosterone yields the more potent androgen 5α-dihydrotestosterone (DHT), with this step therefore serving as a target-specific amplification of the androgen signal, a pre-receptor activation of testosterone to DHT [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Schiffer L. Arlt W. Storbeck K.H. Intracrine androgen biosynthesis, metabolism and action revisited Mol. Cell. Endocrinol. 465 2018 4 26 28865807 PMC6565845 source

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  • May combine two claims.

    Premisecitation

    Adrenopause reaches minimum by age 70, with only about 5-10% of peak levels observed in young adulthood.

    “This reaches a minimum by the age of 70, with only about 5–10% of the peak levels observed in young adulthood [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Papierska L. Adrenopause – does it really exist? Menopausal Rev. 2 2017 57 60 PMC5509973 28721131 source

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  • May combine two claims.

    Premisecitation

    AKR1C3 catalyzes conversion of 11KA4 to 11KT with an 8-fold higher efficiency than that of A4 to testosterone, which may account for higher levels of peripheral activation.

    “Indeed, a recent study has shown that AKR1C3 catalyzes the conversion of 11KA4 to 11KT with an 8-fold higher efficiency than that of A4 to testosterone, which may account for higher levels of peripheral activation [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Barnard M. Quanson J.L. Mostaghel E. Pretorius E. Snoep J.L. Storbeck K.-H. 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): implications for castration resistant prostate cancer J. Steroid Biochem. Mol. Biol. 183 2018 192 201 29936123 PMC6283102 source

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  • May combine two claims.

    Premisecitation

    Within adrenal, A4 can serve as substrate for CYP11B1, yielding 11OHA4, with conversion of testosterone to 11OHT also occurring.

    “Within the adrenal, A4 can serve as a substrate for CYP11B1, yielding the 11-oxygenated androgen precursor, 11OHA4 [67], with conversion of testosterone to 11β-hydroxytestosterone (11OHT), also occurring (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Swart A.C. Schloms L. Storbeck K.-H. Bloem L.M. Du Toit T. Quanson J.L. Rainey W.E. Swart P. 11β-Hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione J. Steroid Biochem. Mol. Biol. 138 2013 132 142 23685396 source

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  • May combine two claims.

    Premisecitation

    11KA4 serves as substrate for AKR1C3 expressed in peripheral tissues such as adipose tissue, yielding 11KT, which binds and activates human androgen receptor with affinity and potency similar to testosterone.

    “11KA4 in turn serves as a substrate for AKR1C3 expressed in peripheral tissues such as adipose tissue, yielding 11KT, which binds and activates the human androgen receptor with an affinity and potency similar to that of testosterone [45,[70], [71], [72]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Schiffer L. Arlt W. Storbeck K.H. Intracrine androgen biosynthesis, metabolism and action revisited Mol. Cell. Endocrinol. 465 2018 4 26 28865807 PMC6565845 source

      Not checked in the free run.

    • cites [70] Pretorius E. Arlt W. Storbeck K.-H. A new dawn for androgens: novel lessons from 11-oxygenated C19 steroids Mol. Cell. Endocrinol. 441 2017 76 85 27519632 source

      Not checked in the free run.

    • cites [71] Pretorius E. Africander D.J. Vlok M. Perkins M.S. Quanson J.L. Storbeck K.-H. 11-Ketotestosterone and 11-ketodihydrotestosterone in castration resistant prostate cancer: potent androgens which can no longer be ignored PLoS One 11 2016 e0159867 PMC4956299 27442248 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low levels of 11KA4 and 11KT have been reported in adrenal vein samples and are suggested to result from some HSD11B2 activity in adrenal.

    “Low levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) have also been reported in adrenal vein samples and are suggested to result from some HSD11B2 activity in the adrenal [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Rege J. Nakamura Y. Satoh F. Morimoto R. Kennedy M.R. Layman L.C. Honma S. Sasano H. Rainey W.E. Liquid chromatography – tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation J. Clin. Endocrinol. Metab. 98 2013 1182 1188 23386646 PMC3590473 source

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  • May combine two claims.

    Premisecitation

    11OHA4 is by far predominant product due to significantly higher levels of A4 produced in zona reticularis.

    “However, 11OHA4 is by far the predominant product due to the significantly higher levels of A4 produced in the zona reticularis [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Rege J. Nakamura Y. Satoh F. Morimoto R. Kennedy M.R. Layman L.C. Honma S. Sasano H. Rainey W.E. Liquid chromatography – tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation J. Clin. Endocrinol. Metab. 98 2013 1182 1188 23386646 PMC3590473 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Allopregnanolone can be converted to 17α-hydroxyallopregnanolone, which serves as excellent substrate for 17,20-lyase activity of CYP17A1, yielding androsterone.

    “Allopregnanolone can then be converted to 17α-hydroxyallopregnanolone, which serves as an excellent substrate for the 17,20-lyase activity of CYP17A1 [30], yielding androsterone.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Gupta M.K. Guryev O.L. Auchus R.J. 5α-reduced C21 steroids are substrates for human cytochrome P450c17 Arch. Biochem. Biophys. 418 2003 151 160 14522586 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testicular steroid output is predominantly testosterone, with lower levels of A4 and DHEA also being released into circulation.

    “Testicular steroid output is predominantly testosterone, with lower levels of A4 and DHEA also being released into circulation [[51], [52], [53]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [51] Weinstein R.L. Kelch R.P. Jenner M.R. Kaplan S.L. Grumbach M.M. Secretion of unconjugated androgens and estrogens by the normal and abnormal human testis before and after human chorionic gonadotropin J. Clin. Invest. 53 1974 1 6 4271572 PMC301431 source

      Not checked in the free run.

    • cites [52] Hammond G.L. Ruokonen A. Kontturi M. Koskela E. Vihko R. The simultaneous radioimmunoassay of seven steroids in human spermatic and peripheral venous blood J. Clin. Endocrinol. Metab. 45 1977 16 24 874062 source

      Not checked in the free run.

    • cites [53] Ishida H. Tashiro H. Watanabe M. Fujii N. Yoshida H. Imamura K. Minowada S. Shinohara M. Fukutani K. Aso Y. Kretser D.M.D.E. Measurement of inhibin concentrations in men: study of changes after castration and comparison with androgen levels in testicular tissue, spermatic venous blood, and peripheral venous blood J. Clin. Endocrinol. Metab. 70 2015 1019 1022 2318932 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ovarian steroid output varies considerably during menstrual cycle - 17β-estradiol is primary steroid produced during follicular phase, while progesterone is principal steroid during luteal phase.

    “Ovarian steroid output varies considerably during the course of the menstrual cycle – 17β-estradiol is the primary steroid produced during the follicular phase, while progesterone is the principal steroid during the luteal phase [[77], [78], [79]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [77] Short R.V. Steroids in the follicular fluid and the corpus luteum of the mare. A “two-cell type” theory of ovarian steroid synthesis J. Endocrinol. 24 1962 59 63 13912279 source

      Not checked in the free run.

    • cites [78] Mikhail G. Hormone secretion by the human ovaries Gynecol. Obstet. Invest. 1 1970 5 20 5481651 source

      Not checked in the free run.

    • cites [79] Baird D.T. The endocrinology of ovarian steroid secretion Eur. J. Obstet. Gynecol. Reprod. Biol. 1974 31 39 4607188 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA can be converted to A4 by peripheral HSD3B1, with A4 serving as substrate for production of testosterone by AKR1C3.

    “More specifically, DHEA can be converted to A4 by peripheral HSD3B1, with A4 serving as the substrate for the production of testosterone by AKR1C3 [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Penning T.M. Wangtrakuldee P. Auchus R.J. Structural and functional biology of aldo-keto reductase steroid transforming enzymes Endocr. Rev. 40 2 2018 447 475 PMC6405412 30137266 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Theca cells express high levels of estrogen sulfotransferase SULT1E1, which preferentially sulfates estrone yielding relatively abundant estrone sulfate measured in circulation.

    “Theca cells also express high levels of the estrogen sulfotransferase enzyme SULT1E1, which preferentially sulfates estrone yielding the relatively abundant estrone sulfate measured in circulation [[82], [83], [84]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [82] Noel T. Noel C.T. Reed M.J. Jacobs H.S. James V.H.T. The plasma concentration of oestrone sulphate in postmenopausal women: lack of diurnal variation, effect of ovariectomy, age and weight J. Steroid Biochem. 14 1981 1101 1105 7198170 source

      Not checked in the free run.

    • cites [83] Rezvanpour A. Don-Wauchope A.C. Critical reviews in clinical laboratory sciences clinical implications of estrone sulfate measurement in laboratory medicine clinical implications of estrone sulfate measurement in laboratory medicine * Crit. Rev. Clin. Lab. Sci. 0 2016 000 27960570

      Not checked in the free run.

    • cites [84] Mungenast F. Aust S. Vergote I. Vanderstichele A. Sehouli J. Braicu E. Mahner S. Cacsire D.A.N. Tong C. Zeillinger R. Thalhammer T. Clinical significance of the estrogen-modifying enzymes steroid sulfatase and estrogen sulfotransferase in epithelial ovarian cancer Oncol. Lett. 13 2017 4047 4054 28588698 PMC5452883 source

      Not checked in the free run.

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

    Premisecitation

    AKR1C3 expression has been reported in Leydig cells and may also contribute to testosterone production.

    “AKR1C3 expression has been reported in Leydig cells and may also contribute to testosterone production [49,50].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Pelletier G. Luu-The V. Têtu B. Labrie F. Immunocytochemical localization of type 5 17β-hydroxysteroid dehydrogenase in human reproductive tissues J. Histochem. Cytochem. 47 1999 731 737 10330449 source

      Not checked in the free run.

    • cites [50] Werner R. Kulle A. Sommerfeld I. Riepe F.G. Wudy S. Hartmann M.F. Merz H. Döhnert U. Bertelloni S. Holterhus P.M. Hiort O. Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency Sex. Dev. 6 2012 161 168 22398356 source

      Not checked in the free run.

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

    Premisecitation

    Placental progesterone has been suggested to serve as substrate for androsterone biosynthesis in male fetus via alternative pathway which occurs across several non-gonadal fetal tissues.

    “Interestingly, placental progesterone has been suggested to serve as substrate for androsterone biosynthesis in the male fetus via the alternative pathway which occurs across several non-gonadal fetal tissues [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] O’Shaughnessy P.J. Antignac J.P. Le Bizec B. Morvan M.L. Svechnikov K. Söder O. Savchuk I. Monteiro A. Soffientini U. Johnstonid Z.C. Bellingham M. Hough D. Walker N. Filis P. Fowler P.A. Alternative (backdoor) androgen production and masculinization in the human fetus PLoS Biol. 17 2 2019 e3000002 PMC6375548 30763313 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addition of exogenous testosterone does not lead to increased 11-oxygenated androgen output, confirming that only locally produced substrates (primarily A4) can be 11β-hydroxylated.

    “Notably, the addition of exogenous testosterone does not lead to increased 11-oxygenated androgen output, thereby confirming that only locally produced substrates (primarily A4) can be 11β-hydroxylated [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Davis S.R. Turcu A.F. Robinson P.J. Bell R.J. Exogenous testosterone does not influence 11-oxygenated C19 steroid concentrations in healthy postmenopausal women J. Endocr. Soc. 3 2019 670 677 30842991 PMC6397421 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Suppression of adrenal androgen output by dexamethasone in healthy, young women with regular menstrual cycle leads to 90% decrease in DHEA(S) output, but also reduces circulating testosterone and DHT concentrations to one third of their respective baseline concentrations.

    “Suppression of adrenal androgen output by dexamethasone in healthy, young women with a regular menstrual cycle leads to a 90% decrease in DHEA(S) output, but also reduces circulating testosterone and DHT concentrations to one third of their respective baseline concentrations [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Arlt W. Justl H.-G. Callies F. Reincke M. Hübler D. Oettel M. Ernst M. Schulte H.M. Allolio B. Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression J. Clin. Endocrinol. Metab. 83 1998 1928 1934 9626121 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSD11B1 is a bidirectional enzyme but primarily catalyzes the reduction of 11-ketosteroids in vivo.

    “HSD11B1 is a bidirectional enzyme, but primarily catalyzes the reduction of 11-ketosteroids in vivo”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Bujalska I.J. Draper N. Michailidou Z. Tomlinson J.W. White P.C. Chapman K.E. a Walker E. Stewart P.M. Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1 J. Mol. Endocrinol. 34 2005 675 684 15956339 source

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

    Premisecitation

    Disruption of SRD5A2 leads to disordered sex development in 46,XY individuals.

    “with its disruption leading to disordered sex development in 46,XY individuals [95]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Wilson J.D. Griffin J.E. Russell D.W. Steroid 5 alpha-reductase 2 deficiency Endocr. Rev. 14 1993 577 593 8262007

      Not checked in the free run.

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

    Premisenone given

    Only SRD5A1 and SRD5A2 function as genuine steroid 5α-reductases.

    “only two of these, SRD5A1 and SRD5A2, function as genuine steroid 5α-reductases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AKR1C enzymes are multifunctional and also function as 20α- and 17β-HSDs, with different efficiencies, stereoselectivities and tissue specific expression.

    “AKR1C enzymes are multifunctional and also function as 20α- and 17β-HSDs, with different efficiencies, stereoselectivities and tissue specific expression [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Penning T.M. Burczynski M.E. Jez J.M. Hung C.F. Lin H.K. Ma H. Moore M. Palackal N. Ratnam K. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones Biochem. J. 351 2000 67 77 10998348 PMC1221336 source

      Not checked in the free run.

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

    Premisenone given

    SRD5A3 has only minor steroid 5α-reductase activity.

    “SRD5A3 appears to have only minor steroid 5α-reductase activity”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    AKR1C4 is thought to be a liver-specific enzyme which works in concert with AKR1D1, yielding 5β,3α-metabolites.

    “AKR1C4 is thought to be a liver-specific enzyme which works in concert with AKR1D1, yielding 5β,3α-metabolites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    5α-reduced steroids can be converted to both their 3α- or 3β-hydroxy epimers, with 3α-reduction generally being more efficient.

    “5α-reduced steroids can be converted to both their 3α- or 3β-hydroxy epimers (with the 3α-reduction generally being more efficient)”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Direct 20α-reduction of progesterone terminates its progestogenic activity.

    “the direct 20α-reduction of progesterone terminates its progestogenic activity”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Penning T.M. Burczynski M.E. Jez J.M. Hung C.F. Lin H.K. Ma H. Moore M. Palackal N. Ratnam K. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones Biochem. J. 351 2000 67 77 10998348 PMC1221336 source

      Not checked in the free run.

    • cites [115] Rižner T.L. Šmuc T. Rupreht R. Šinkovec J. Penning T.M. AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer Mol. Cell. Endocrinol. 248 2006 126 135 16338060 source

      Not checked in the free run.

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

    Premisecitation

    SRD5A2 is expressed mainly in male reproductive and genital tissues.

    “SRD5A2 is expressed mainly in male reproductive and genital tissues”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Wilson J.D. Griffin J.E. Russell D.W. Steroid 5 alpha-reductase 2 deficiency Endocr. Rev. 14 1993 577 593 8262007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5α/β-reduction is irreversible, with stereochemistry playing important role in regulating biological activity of androgens.

    “Importantly, 5α/β-reduction is irreversible, with the stereochemistry of this reduction playing an important role in regulating the biological activity of androgens (Section 4.3.2) [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Chen M. Penning T.M. 5β-Reduced steroids and human Δ4-3-ketosteroid 5β-reductase (AKR1D1) Steroids 83 2014 17 26 24513054 PMC3971473 source

      Not checked in the free run.

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

    Premisecitation

    A-ring reduction consists of two sequential reductions, namely reduction of Δ4-double bond followed by reduction of 3-keto group to hydroxy group.

    “A-ring reduction consists of two sequential reductions, namely the reduction of the Δ4-double bond followed by the reduction of the 3-keto group to a hydroxy group [92] (Fig. 4(a)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Penning T.M. New frontiers in androgen biosynthesis and metabolism Curr. Opin. Endocrinol. Diab. Obes. 17 2010 233 239 PMC3206266 20186052 source

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

    Premisecitation

    AKR1D1 is the only human enzyme catalyzing the 5β-reduction of 3-keto-Δ4 steroids and bile acids.

    “It is the only human enzyme catalyzing the 5β-reduction of 3-keto-Δ4 steroids and bile acids [100].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Chen M. Drury J.E. Penning T.M. Substrate specificity and inhibitor analyses of human steroid 5beta-reductase (AKR1D1) Steroids 76 2011 484 490 21255593 PMC3056882 source

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

    Premisecitation

    SRD5A3 plays an important role in N-linked protein glycosylation.

    “has been shown to play an important role in N-linked protein glycosylation [[96], [97], [98]]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [96] Uemura M. Tamura K. Chung S. Honma S. Okuyama A. Nakamura Y. Nakagawa H. Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer Cancer Sci. 99 2008 81 86 17986282 PMC11158902 source

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    • cites [97] Stiles A.R. Russell D.W. SRD5A3: a surprising role in glycosylation Cell 142 2010 196 198 20655462 PMC3104503 source

      Not checked in the free run.

    • cites [98] Cantagrel V. Lefeber D.J. Ng B.G. Guan Z. Silhavy J.L. Bielas S.L. Lehle L. Hombauer H. Adamowicz M. Swiezewska E. De Brouwer A.P. Blümel P. Sykut-Cegielska J. Houliston S. Swistun D. Ali B.R. Dobyns W.B. Babovic-Vuksanovic D. van Bokhoven H. Wevers R.A. Raetz C.R.H. Freeze H.H. Morava É. Al-Gazali L. Gleeson J.G. SRD5A3 Is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder Cell 142 2 2010 203 217 20637498 PMC2940322 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These enzymes are multi-functional and often have overlapping substrate specificities and expression patterns, allowing redundant enzymes to cover in case of deficiency of another enzyme.

    “Generally, these enzymes are multi-functional and often have overlapping substrate specificities and expression patterns, allowing for redundant enzymes to cover in case of deficiency of another enzyme [107,114].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] Marchais-Oberwinkler S. Henn C. Moller G. Klein T. Negri M. Oster A. Spadaro A. Werth R. Wetzel M. Xu K. Frotscher M. Hartmann R.W. Adamski J. 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development J. Steroid Biochem. Mol. Biol. 125 2011 66 82 21193039 source

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    • cites [114] Moeller G. Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases Mol. Cell. Endocrinol. 301 2009 7 19 19027824 source

      Not checked in the free run.

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

    Premisecitation

    Steroid 5β-reduction is catalyzed by AKR1D1, which is primarily expressed in the liver.

    “Steroid 5β-reduction is catalyzed by the aldo-keto-reductase (AKR) family member AKR1D1, which is primarily expressed in the liver.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    To date, 14 human enzymes with 17β-HSD/oxoreductase activities have been identified.

    “To date, 14 human enzymes with 17β-HSD/oxoreductase activities have been identified [105,106,113].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [105] Mindnich R. Möller G. Adamski J. The role of 17 beta-hydroxysteroid dehydrogenases Mol. Cell. Endocrinol. 218 2004 7 20 15130507 source

      Not checked in the free run.

    • cites [106] Moeller G. Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases Mol. Cell. Endocrinol. 301 2009 7 19 19027824 source

      Not checked in the free run.

    • cites [113] Miller W.L. Auchus R.J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders Endocr. Rev. 32 2011 81 151 21051590 PMC3365799 source

      Not checked in the free run.

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

    Premisecitation

    SRD5A1 is mainly expressed in the liver and peripheral tissues.

    “SRD5A1 is mainly expressed in the liver and peripheral tissues [94]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Thigpen A.E. Silver R.I. Guileyardo J.M. Casey M.L. McConnell J.D. Russell D.W. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression J. Clin. Invest. 92 1993 903 910 7688765 PMC294929 source

      Not checked in the free run.

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

    Premisecitation

    HSD11B1 mainly activates cortisone to cortisol.

    “mainly activating cortisone to cortisol [109]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Bujalska I.J. Draper N. Michailidou Z. Tomlinson J.W. White P.C. Chapman K.E. a Walker E. Stewart P.M. Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1 J. Mol. Endocrinol. 34 2005 675 684 15956339 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    5α-reduced metabolites inform about global metabolism while 5β-reduced metabolites predominantly reflect hepatic reduction only.

    “5α-reduced metabolites inform about global metabolism while 5β-reduced metabolites predominantly reflect hepatic reduction only.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Steroid metabolism is traditionally divided into two sequential stages, phase 1 and phase 2 reactions.

    “This metabolism is traditionally divided into two sequential stages, namely phase 1 and phase 2 reactions [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Williams R.T. Detoxication Mechanisms; the Metabolism and Detoxication of Drugs, Toxic Substances, and Other Organic Compounds 1959 Wiley New York

      Not checked in the free run.

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

    Premisecitation

    AKR1C1 is the most important isoform for the formation of the 3β-hydroxyepimer.

    “AKR1C1 is the most important isoform for the formation of the 3β-hydroxyepimer [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Steckelbroeck S. Jin Y. Gopishetty S. Oyesanmi B. Penning T.M. Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action J. Biol. Chem. 279 2004 10784 10795 14672942 source

      Not checked in the free run.

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

    Premisenone given

    5α-Reduction is catalyzed by steroid 5α-reductase (SRD5A) enzymes, of which there are three main isozymes.

    “5α-Reduction is catalyzed by steroid 5α-reductase (SRD5A) enzymes of which there are three main isozymes.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    HSD11B1 functions as an epimerase interconverting the 7α- and 7β-hydroxy-stereoisomers via a 7-keto-intermediate.

    “HSD11B1 functions as an epimerase interconverting the 7α- and 7β-hydroxy-stereoisomers via a 7-keto-intermediate”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Hennebert O. Montes M. Favre-Reguillon A. Chermette H. Ferroud C. Morfin R. Epimerase activity of the human 11beta-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids J. Steroid Biochem. Mol. Biol. 114 2009 57 63 19167490 source

      Not checked in the free run.

    • cites [111] Muller C. Pompon D. Urban P. Morfin R. Inter-conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone by the human 11beta-hydroxysteroid dehydrogenase type 1 J. Steroid Biochem. Mol. Biol. 99 2006 215 222 16603347 source

      Not checked in the free run.

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

    Premisenone given

    The second step of A-ring reduction is the reduction of the 3-keto group to a hydroxy group.

    “The second step of the A-ring reduction is the reduction of the 3-keto group to a hydroxy group.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    HSD11B2 functions exclusively as an oxidative enzyme, inactivating cortisol to cortisone.

    “HSD11B2 functions exclusively as an oxidative enzyme, inactivating cortisol to cortisone [108].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Tomlinson J.W. Walker E.A. Bujalska I.J. Draper N. Lavery G.G. Cooper M.S. Hewison M. Stewart P.M. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response Endocr. Rev. 25 2004 831 866 15466942 source

      Not checked in the free run.

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

    Premisecitation

    Colocalized H6PDH regenerates NADPH required for HSD11B1 cortisone reductase activity.

    “as colocalized hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH required for its cortisone reductase activity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Bujalska I.J. Draper N. Michailidou Z. Tomlinson J.W. White P.C. Chapman K.E. a Walker E. Stewart P.M. Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1 J. Mol. Endocrinol. 34 2005 675 684 15956339 source

      Not checked in the free run.

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

    Premisecitation

    While phase 1 and phase 2 reactions are classically believed to be sequential, more recent studies have shown metabolism of conjugated steroids by phase 1 enzymes.

    “While phase 1 and phase 2 reactions are classically believed to be sequential, more recent studies have shown the metabolism of conjugated steroids by phase 1 enzymes [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Jin Y. Duan L. Lee S.H. Kloosterboer H.J. Blair I.A. Penning T.M. Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J. Biol. Chem. 284 2009 10013 10022 19218247 PMC2665056 source

      Not checked in the free run.

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

    Premisecitation

    O-methylation of catechols plays an important role in the phase 2 metabolism of estrogens and is catalyzed by catechol-O-methyltransferase (COMT).

    “The O-methylation of catechols plays an important role in the phase 2 metabolism of estrogens (Section 4.4.1) and is catalyzed by the enzyme catechol-O-methyltransferase (COMT) [179]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Axelrod J. Tomchick R. Enzymatic O-methylation of epinephrine and other catechols J Biol Chem. 233 1958 702 705 13575440 source

      Not checked in the free run.

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

    Premisenone given

    Hydroxylation by hepatic CYPs inactivates steroids and increases their polarity and water solubility.

    “The hydroxylation by hepatic CYPs inactivates the steroids and increases their polarity and water solubility.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    At least 17 hepatic CYPs potentially participate in the metabolism of steroids.

    “with at least 17 hepatic CYPs potentially participating in the metabolism of steroids [[116], [117], [118]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [116] Niwa T. Murayama N. Imagawa Y. Yamazaki H. Regioselective hydroxylation of steroid hormones by human cytochromes P450 Drug Metab Rev. 47 2015 89 110 25678418 source

      Not checked in the free run.

    • cites [117] Waxman D.J. Interactions of hepatic cytochromes P-450 with steroid hormones: regioselectivity and stereospecificity of steroid metabolism and hormonal regulation of rat P-450 enzyme expression Biochem. Pharmacol. 37 1988 71 84 3276320 source

      Not checked in the free run.

    • cites [118] You L. Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes Chem. Biol. Interact. 147 2004 233 246 15135080 source

      Not checked in the free run.

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

    Premisenone given

    CYP3A7 differs from CYP3A4 in terms of expression and function.

    “and differs from CYP3A4 in terms of expression and function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Estrogens seem to undergo higher biliary excretion than other steroids, but also higher reabsorption leading to low fecal excretion.

    “estrogens seem to undergo higher biliary excretion than other steroids, but also higher reabsorption leading to low fecal excretion [194,206].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [194] van Kammen E. Thijssen J.H. Donker G.H. Schwarz F. The excretion of metabolites of testosterone and of estradiol in male patients with chronic renal failure Steroids 26 1975 508 515 1202665 source

      Not checked in the free run.

    • cites [206] Sandberg A.A. Slaunwhite W.R. Studies on Phenolic Steroids in Human Subjects. II. The Metabolic Fate and Hepato-Biliary-Enteric Circulation of C14-Estrone and C14-Estradiol in Women Clin Invest 36 8 1957 1266 1278 PMC1072719 13463090 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For Δ5 steroids such as DHEA, 16α-hydroxylation is the most frequent hydroxylation detected in adults, followed by 7α-hydroxylation.

    “In terms of Δ5 steroids, e.g. DHEA, 16α-hydroxylation is the most frequent hydroxylation detected in adults followed by 7α-hydroxylation”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [133] Shackleton C.H. Taylor N.F. Identification of the androstenetriolones and androstenetetrols present in the urine of infants J Steroid Biochem. 6 1975 1393 1399 1052839 source

      Not checked in the free run.

    • cites [134] Stárka L. The origin of 7α-hydroxy-dehydroepiandrosterone and its physiological role: a history of discoveries Physiol. Res. 66 2017 285 294 28948812 source

      Not checked in the free run.

    • cites [135] Stárka L. Hill M. Kolatorova L. Dušková M. Androst-5-ene-3β,7α/β,17β-triols, their plasma levels and dependence on the hypothalamic–pituitary–adrenal axis Steroids 134 2018 88 95 29477344 source

      Not checked in the free run.

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

    Premisecitation

    CYP3A5 catalyzes a comparable range of reactions as CYP3A4.

    “CYP3A5 catalyzes a comparable range of reactions as CYP3A4”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [123] Williams J.A. Ring B.J. Cantrell V.E. Jones D.R. Eckstein J. Ruterbories K. Hamman M.A. Hall S.D. Wrighton S.A. Kitada M. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7 Drug Metab Dispos. 30 2002 883 891 12124305 source

      Not checked in the free run.

    • cites [124] Westlind-Johnsson A. Malmebo S. Johansson A. Otter C. Andersson T.B. Johansson I. Edwards R.J. Boobis A.R. Ingelman-Sundberg M. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism Drug Metab. Dispos. 31 2003 755 761 12756208 source

      Not checked in the free run.

    • cites [125] Hakkola J. Raunio H. Purkunen R. Saarikoski S. Vahakangas K. Pelkonen O. Edwards R.J. Boobis A.R. Pasanen M. Cytochrome P450 3A expression in the human fetal liver: evidence that CYP3A5 is expressed in only a limited number of fetal livers Biol. Neonate 80 2001 193 201 11585982 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sulfation is reversible and unconjugated bioactive steroids can be regenerated from their sulfates by STS, which is ubiquitously expressed in all tissues.

    “sulfation is reversible and unconjugated bioactive steroids can be regenerated from their sulfates by STS, which is ubiquitously expressed in all tissues [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Mueller J.W. Gilligan L.C. Idkowiak J. Arlt W. Foster P.A. The regulation of steroid action by sulfation and desulfation Endocr. Rev. 36 2015 526 563 26213785 PMC4591525 source

      Not checked in the free run.

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

    Premisenone given

    CYP3A4-catalyzed 6β-hydroxylation is the most common hydroxylation for Δ4 steroids, e.g. cortisol.

    “CYP3A4-catalyzed 6β-hydroxylation is the most common hydroxylation for Δ4 steroids, e.g. cortisol”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Steroid metabolism by gut bacteria is influenced by the administration of antibiotics.

    “steroid metabolism by gut bacteria has been shown to be influenced by the administration of antibiotics [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Adlercreutz H. Pulkkinen M.O. Hamalainen E.K. Korpela J.T. Studies on the role of intestinal bacteria in metabolism of synthetic and natural steroid hormones J Steroid Biochem. 20 1984 217 229 6231418 source

      Not checked in the free run.

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

    Premisecitation

    CYP3A4 is the most abundant CYP expressed in the adult liver.

    “CYP3A4 is the most abundant CYP expressed in the adult liver [121,122]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [121] Imaoka S. Yamada T. Hiroi T. Hayashi K. Sakaki T. Yabusaki Y. Funae Y. Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Systematic characterization and comparison with those of the rat Biochem. Pharmacol. 51 1996 1041 1050 8866826 source

      Not checked in the free run.

    • cites [122] Shimada T. Yamazaki H. Mimura M. Inui Y. Guengerich F.P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians J. Pharmacol. Exp. Ther. 270 1994 414 423 8035341 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Clearance of steroid glucuronides generally proceeds faster than clearance of steroid sulfates, presumably due to the irreversible nature of glucuronidation in humans.

    “The clearance of steroid glucuronides generally proceeds faster than the clearance of steroid sulfates [195], presumably due to the irreversible nature of glucuronidation in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Hellman L. Rosenfeld R.S. Metabolism of testosterone-1,2-3H in man. Distribution of the major 17-ketosteroid metabolites in plasma: relation to thyroid states J Clin Endocrinol Metab. 38 1974 424 435 4592659 source

      Not checked in the free run.

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

    Premisenone given

    CYP3A7 is the major CYP3A isoform in prenatal and early postnatal life.

    “CYP3A7 is the major CYP3A isoform in prenatal and early postnatal life”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    COMT methylates 2- and 4-hydroxyestrogens, producing methoxyestrogens.

    “COMT methylates 2- and 4-hydroxyestrogens, thereby producing the so-called methoxyestrogens [180].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Ball P. Knuppen R. Haupt M. Breuer H. Interactions between estrogens and catechol amines. 3. Studies on the methylation of catechol estrogens, catechol amines and other catechols by the ctechol-O-methyltransferases of human liver J Clin Endocrinol Metab. 34 1972 736 746 5012775 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Steroids are excreted predominantly as their conjugates in urine and bile, with urine excretion accounting for approximately 80% of excretion following exogenous administration.

    “Steroids are excreted predominantly as their conjugates in the urine and bile, with urine excretion accounting for approximately 80% of excretion following exogenous administration [194].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] van Kammen E. Thijssen J.H. Donker G.H. Schwarz F. The excretion of metabolites of testosterone and of estradiol in male patients with chronic renal failure Steroids 26 1975 508 515 1202665 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Steroid sulfation is reversible and sulfated steroids can be hydrolyzed to free steroids by steroid sulfatase (STS).

    “steroid sulfation is reversible and sulfated steroids can be hydrolyzed to free steroids by steroid sulfatase (STS)”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The remaining cortisol is either bound to albumin (5-10%) or circulates in its free active form (<10%).

    “The remaining cortisol is either bound to albumin (5–10%) or circulates in its free (active) form (<10%) [[245], [246], [247]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [245] Daughaday W.H. Binding of corticosteroids by plasma proteins. IV. The electrophoretic demonstration of corticosteroid binding globulin J. Clin. Invest. 37 1958 519 523 13539190 PMC293116 source

      Not checked in the free run.

    • cites [246] Siiteri P.K. Murai J.T. Raymoure W.J. Kuhn R.W. Hammond G.L. Nisker J.A. The serum transport of steroid hormones Proc. 1981 Laurentian Horm. Conf. 1982 457 510 6750727 source

      Not checked in the free run.

    • cites [247] Meulenberg P. Hofman J. Differences between concentrations of salivary cortisol and cortisone and of free cortisol and cortisone in plasma during pregnancy and postpartum Clin. Chem. 36 1990 70 75 http://clinchem.aaccjnls.org/content/36/1/70.short 2297937 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Serum levels of the glucocorticoid precursors progesterone, 17OHP and 11-deoxycortisol are all ≤10nM in the healthy population and are significantly lower than cortisol (100-600 nM) and cortisone (30-100 nM).

    “The serum levels of the glucocorticoid precursors, progesterone, 17OHP and 11-deoxycortisol are all ≤10nM in the healthy population and therefore significantly lower than that of cortisol (ranging from 100 to 600 nM) and cortisone (ranging from 30 to 100 nM)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    20α/β-reduction of tetrahydrocortisol (THF) yields cortols (α- and β-cortol), and that of tetrahydrocortisone (THE) yields cortolones (α- and β-cortolone).

    “Of quantitative importance is the 20α/β-reduction of tetrahydrocortisol (THF), yielding the so called cortols (α- and β-cortol), and that of tetrahydrocortisone (THE), which yields the equivalent cortolones (α- and β-cortolone) [253].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Shackleton C.H.L.H. Roitman E. Monder C. Bradlow H.L.L. Gas chromatographic and mass spectrometric analysis of urinary acidic metabolites of cortisol Steroids 36 1980 289 298 7434401 source

      Not checked in the free run.

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

    Premisecitation

    Corticosterone's MR-activating potency is considerably lower than that of aldosterone.

    “though corticosterone’s MR-activating potency is considerably lower than that of aldosterone [219].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Gomez-Sanchez E. Gomez-Sanchez C.E. The multifaceted mineralocorticoid receptor Compr. Physiol. 4 2014 965 994 24944027 PMC4521600 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While 17OHP and cortisol can be either 5α- or 5β-reduced, 11-deoxycortisol and cortisone are predominantly 5β-reduced.

    “while 17OHP and cortisol can be either 5α- or 5β-reduced, 11-deoxycortisol and cortisone are predominantly 5β-reduced [108].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Tomlinson J.W. Walker E.A. Bujalska I.J. Draper N. Lavery G.G. Cooper M.S. Hewison M. Stewart P.M. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response Endocr. Rev. 25 2004 831 866 15466942 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aldosterone-18β-glucuronide and THAldo-glucuronides contribute 5-15% and 15-40% towards the daily urinary excretion of aldosterone.

    “aldosterone-18β-glucuronide and THAldo-glucuronides contribute 5–15% and 15–40% towards the daily urinary excretion of aldosterone [221,226].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [221] Gomez-Sanchez C.E. Holland O.B. Urinary tetrahydroaldosterone and aldosterone-18-glucuronide excretion in white and black normal subjects and hypertensive patients J Clin Endocrinol Metab. 52 1981 214 219 https://academic.oup.com/jcem/article-abstract/52/2/214/2677463 7462387 source

      Not checked in the free run.

    • cites [226] Luetscher J.A. Camargo C.A. Cohn A.P. Dowdy A.J. Callaghan A.M. Observations on metabolism of aldosterone in man Ann. Intern. Med. 59 1963 1 7 http://annals.org/data/journals/aim/19349/aime196307010-00001.pdf 14042607 source

      Not checked in the free run.

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

    Premisenone given

    The primary active glucocorticoid in circulation is cortisol, which is produced by the adrenal cortex.

    “The primary active glucocorticoid in circulation is cortisol, which is produced by the adrenal cortex”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The diurnal rhythm of cortisol can be lost in severe illness or stress, with significant increases in circulating cortisol throughout the entire 24-h period observed in patients with sepsis and during surgical procedures.

    “This rhythm can be lost in times of severe illness or stress, with significant increases in circulating cortisol throughout the entire 24-h period observed in patients with sepsis and during surgical procedures [243,244].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [243] Whitaker M.J. Debono M. Huatan H. Merke D.P. Arlt W. Ross R.J. An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure Clin. Endocrinol. (Oxf). 80 2014 554 561 23980724 PMC3937303 source

      Not checked in the free run.

    • cites [244] Prete A. Yan Q. Al-Tarrah K. Akturk H.K. Prokop L.J. Alahdab F. Foster M.A. Lord J.M. Karavitaki N. Wass J.A. Murad M.H. Arlt W. Bancos I. The cortisol stress response induced by surgery: a systematic review and meta-analysis Clin. Endocrinol. (Oxf). 89 2018 554 567 30047158 source

      Not checked in the free run.

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

    Premisecitation

    Approximately one third of aldosterone circulates in the free form, with the remainder bound to corticosteroid binding globulin (CBG) and serum albumin.

    “It is estimated that approximately one third of aldosterone circulates in the free form, with the remainder bound to corticosteroid binding globulin (CBG) and serum albumin [214].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Becker K.L. Bilezikian J.P. Bremner W.J. Hung W. Kahn R. Loriaux L. Nylén E.S. Rebar R.W. Robertson G.L. Snider R.H. Principles and Practice of Endocrinology and Metabolism 2001 Lippincott Williams & Wilkins

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glucocorticoid contribution to urine 11β-OHAn is very low in healthy individuals, with the majority originating from the metabolism of the androgen 11OHA4.

    “As a result, the glucocorticoid contribution to urine 11β-OHAn is very low in healthy individuals, with the majority originating from the metabolism of the androgen 11OHA4 (Section 4.3.2) [258].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Shackleton C.H.L. Neres M.S. Hughes B.A. Stewart P.M. Kater C.E. 17-Hydroxylase/C17, 20-lyase (CYP17) is not the enzyme responsible for side-chain cleavage of cortisol and its metabolites Steroids 73 2008 652 656 18355883 source

      Not checked in the free run.

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

    Premisenone given

    The primary mineralocorticoid in circulation is aldosterone.

    “The primary mineralocorticoid in circulation is aldosterone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Corticosterone can be converted to 11-dehydrocorticosterone by HSD11B2 in the kidney, preventing activation of the mineralocorticoid receptor (MR) by corticosterone.

    “Corticosterone can be converted to 11-dehydrocorticosterone by the action of HSD11B2 in the kidney, which prevents the activation of the mineralocorticoid receptor (MR) by corticosterone”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Gomez-Sanchez E. Gomez-Sanchez C.E. The multifaceted mineralocorticoid receptor Compr. Physiol. 4 2014 965 994 24944027 PMC4521600 source

      Not checked in the free run.

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

    Premisecitation

    The majority of cortisol circulates bound to proteins, with 80-90% bound to CBG.

    “The majority of cortisol circulates bound to proteins, with 80–90% bound to CBG.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HSD11B1 expression is low or undetectable at birth, but thereafter increases rapidly, with adult levels reached after 6-12 months.

    “HSD11B1 expression is low/undetectable at birth, but thereafter increases rapidly, with adult levels reached after 6–12 months [237].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Rogers S.L. Hughes B.A. Jones C.A. Freedman L. Smart K. Taylor N. Stewart P.M. Shackleton C.H.L. Krone N.P. Blissett J. Tomlinson J.W. Diminished 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased weight and weight gain across the first year of life J Clin Endocrinol Metab. 99 2014 E821 E831 24517145 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortisone cannot activate the glucocorticoid receptor or the MR.

    “which cannot activate the glucocorticoid receptor or the MR”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Gathercole L.L. Lavery G.G. Morgan S.A. Cooper M.S. Sinclair A.J. Tomlinson J.W. Stewart P.M. 11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects Endocr. Rev. 34 2013 525 555 23612224 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5α-THF is a substrate for the side-chain cleavage reaction that produces C19 metabolites of glucocorticoid origin, but this reaction is catalyzed less efficiently than for THF/THE.

    “While 5α-THF is also a substrate for this side-chain cleavage reaction, this reaction is catalyzed less efficiently [257].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [257] Burstein S. Savard K. Dorfman R.I. The in vivo metabolism of hydrocortisone Endocrinology 52 1953 88 97 https://academic.oup.com/endo/article-abstract/53/1/88/2759520 13068334 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DOC and aldosterone are both preferentially 5β-reduced by AKR1D1 followed by 3α-reduction, yielding THDOC and THAldo, respectively.

    “DOC and aldosterone are both preferentially 5β-reduced by AKR1D1 followed by 3α-reduction yielding the tetrahydro metabolites, tetrahydrodeoxycorticosterone (THDOC) and tetrahydroaldosterone (THAldo), respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Two studies report unconjugated excretion of cortisol (30%), cortisone, 20αDHE, 20βDHE, 20βDHF (40-60%); and 20αDHF, 6β-OH-cortisol, 6β-OH-E and 18-OH-cortisol (80-100%).

    “Two studies report unconjugated excretion of the following individual steroids: cortisol (30%), cortisone, 20αDHE, 20βDHE, 20βDHF (40–60%); 20αDHF, 6β-OH-cortisol, 6β-OH-E and 18-OH-cortisol (80–100%) [273,274].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [273] Palermo M. Gomez-Sanchez C. Roitman E. Shackleton C.H.L. Quantitation of cortisol and related 3-oxo-4-ene steroids in urine using gas chromatography/mass spectrometry with stable isotope-labeled internal standards Steroids 61 1996 583 589 8910971 source

      Not checked in the free run.

    • cites [274] Marcos J. Renau N. Casals G. Segura J. Ventura R. Pozo O.J. Investigation of endogenous corticosteroids profiles in human urine based on liquid chromatography tandem mass spectrometry Anal. Chim. Acta. 812 2014 92 104 24491769 source

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  • May combine two claims.

    Premisecitation

    The circulating androgen metabolome consists of both active androgens and androgen precursors, with both contributing to androgen action in target tissues.

    “It is important to note the that circulating androgen metabolome consist of both active androgens and androgen precursors, with both of these contributing to androgen action in target tissues [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Schiffer L. Arlt W. Storbeck K.H. Intracrine androgen biosynthesis, metabolism and action revisited Mol. Cell. Endocrinol. 465 2018 4 26 28865807 PMC6565845 source

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

    Premisecitation

    DHEAS is primarily thought to serve as an inactive waste product of adrenal steroidogenesis, produced to prevent an excessive androgen load.

    “However, it is primarily thought to serve as an inactive waste product of adrenal steroidogenesis, produced to prevent an excessive androgen load [39,40,279].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Rege J. Nakamura Y. Satoh F. Morimoto R. Kennedy M.R. Layman L.C. Honma S. Sasano H. Rainey W.E. Liquid chromatography – tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation J. Clin. Endocrinol. Metab. 98 2013 1182 1188 23386646 PMC3590473 source

      Not checked in the free run.

    • cites [40] Mueller J.W. Gilligan L.C. Idkowiak J. Arlt W. Foster P.A. The regulation of steroid action by sulfation and desulfation Endocr. Rev. 36 2015 526 563 26213785 PMC4591525 source

      Not checked in the free run.

    • cites [279] Hammer F. Subtil S. Lux P. Maser-Gluth C. Stewart P.M. Allolio B. Arlt W. No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies J. Clin. Endocrinol. Metab. 90 2005 3600 3605 15755854 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Female androgens are equally derived from the adrenal glands and the ovaries, which are each estimated to contribute 25% towards the circulating levels of testosterone in both pre- and postmenopausal women.

    “Conversely, female androgens are equally derived from the adrenal glands and the ovaries (Section 2.5.3.1), which are each estimated to contribute 25% towards the circulating levels of testosterone in both pre- and postmenopausal women.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    SHBG binds sex steroids (including active androgens and estrogens) with high affinity (nanomolar ranges) and specificity.

    “SHBG binds sex steroids (including active androgens and estrogens) with high affinity (nanomolar ranges) and specificity [[285], [286], [287]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [285] Anderson D.C. Sex‐hormone binding-globulin Clin. Endocrinol. (Oxf). 3 1974 69 96 4134992 source

      Not checked in the free run.

    • cites [286] Mendel C.M. The Free hormone hypothesis: a physiologically based mathematical model Endocr. Rev. 10 1989 232 274 2673754 source

      Not checked in the free run.

    • cites [287] Hammond G.L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action J. Endocrinol. 230 2016 R13 R25 27113851 PMC5064763 source

      Not checked in the free run.

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

    Premisecitation

    In women, testosterone and A4 demonstrate cyclic changes in concentration during the course of the menstrual cycle due to the ovarian contribution, with levels peaking mid-cycle.

    “In women, testosterone and A4 demonstrate cyclic changes in concentration during the course of the menstrual cycle due to the ovarian contribution, with levels peaking mid-cycle [283,284].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [283] Massafra C. De Felice C. Agnusdei D.P. Gioia D. Bagnoli F. Androgens and osteocalcin during the menstrual cycle J. Clin. Endocrinol. Metab. 84 1999 971 974 10084581

      Not checked in the free run.

    • cites [284] Abraham G.E. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle J. Clin. Endocrinol. Metab. 39 1974 340 346 4278727 source

      Not checked in the free run.

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

    Premisecitation

    Unlike the classical androgens, the circulating levels of 11-oxygenated androgens do not decrease with age in women, suggested to be due to the involution of the zona reticularis with age and the appearance of areas co-expressing HSD3B2 and CYB5A.

    “Significantly, a recent study has revealed that unlike the classical androgens, the circulating levels of 11-oxygenated androgens do not decrease with age in women, suggested to be due to the involution of the zona reticularis with age and the appearance of areas co-expressing HSD3B2 and CYB5A [289].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [289] Nanba A.T. Rege J. Ren J. Auchus R.J. Rainey W.E. Turcu A.F. 11-oxygenated C19 steroids Do not decline with age in women J. Clin. Endocrinol. Metab. 104 7 2019 2615 2622 30753518 PMC6525564 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The production of adrenal androgen precursors increases at adrenarche at 6-9 years of age, peaks between 20 to 30 years of age, and subsequently declines gradually with age.

    “The production of adrenal androgen precursors increases at adrenarche at 6–9 years of age, peak between 20 to 30 years of age, and subsequently decline gradually with age (Section 2.5.3.1).”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The circulating levels of DHEAS dwarf those of any other steroid in circulation and DHEAS is the only human steroid that circulates in micromolar concentrations.

    “In fact, the circulating levels of DHEAS dwarf those of any other steroid in circulation (Table 2) and DHEAS is the only human steroid that circulates in micromolar concentrations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Urine free cortisol is commonly measured in clinical chemistry laboratories for the diagnosis of Cushing's syndrome.

    “Urine free cortisol, i.e. the free fraction of total, non-metabolized urine cortisol, is commonly measured in clinical chemistry laboratories for the diagnosis of Cushing’s syndrome [275] whereas gas chromatography-mass spectrometry (GC-MS) measures total urine cortisol following deconjugation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Raff H. Auchus R.J. Findling J.W. Nieman L.K. Urine Free cortisol in the diagnosis of cushing’s syndrome: Is It worth doing and, If so, how? J. Clin. Endocrinol. Metab. 100 2015 395 397 25423573 PMC4318888 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “Although albumin binds all unconjugated steroids with low affinities (micromolar ranges), it makes a significant contribution to steroid binding due to its high abundance [45,287].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Schiffer L. Arlt W. Storbeck K.H. Intracrine androgen biosynthesis, metabolism and action revisited Mol. Cell. Endocrinol. 465 2018 4 26 28865807 PMC6565845 source

      Not checked in the free run.

    • cites [287] Hammond G.L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action J. Endocrinol. 230 2016 R13 R25 27113851 PMC5064763 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following full initiation at puberty, gonadal androgen production decreases significantly after menopause in women, while in men the testicular output of testosterone gradually decreases with age, resulting in significantly lower combined androgen levels in men aged 60 and over.

    “Following full initiation at puberty gonadal androgen production decreases significantly after menopause in women, while in men the testicular output of testosterone gradually decreases with age, resulting in significantly lower combined androgen levels in men aged 60 and over [24,[280], [281], [282]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Lanciotti L. Cofini M. Leonardi A. Penta L. Esposito S. Up-to-date review about minipuberty and overview on hypothalamic-pituitary-gonadal axis activation in fetal and neonatal life Front. Endocrinol. (Lausanne) 9 2018 410 30093882 PMC6070773 source

      Not checked in the free run.

    • cites [280] Miller W.L. Steroidogenesis: unanswered questions Trends Endocrinol. Metab. 28 2017 771 793 29031608 source

      Not checked in the free run.

    • cites [281] Labrie F. Bélanger A. Pelletier G. Martel C. Archer D.F. Utian W.H. Science of intracrinology in postmenopausal women Menopause 24 2017 702 712 28098598 source

      Not checked in the free run.

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

    Premisecitation

    18-Hydroxycortisol and 18-oxocortisol are often referred to as 'hybrid steroids' because they require enzymatic machinery from both the glucocorticoid and mineralocorticoid pathways.

    “These metabolites are often referred to as “hybrid steroids” as they require enzymatic machinery from both the glucocorticoid and mineralocorticoid pathways [[261], [262], [263]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [261] Lenders J.W.M. Williams T.A. Reincke M. Gomez-Sanchez C.E. 18-oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? Eur. J. Endocrinol. 178 2018 R1 R9 28904009 PMC5705277 source

      Not checked in the free run.

    • cites [262] Gomez-Sanchez C.E. Gomez-Sanchez E.P. Smith J.S. Ferris M.W. Foecking M.F. Receptor binding and biological activity of 18 oxocortisol Endocrinology 116 1985 6 10 2856875 source

      Not checked in the free run.

    • cites [263] Geller D.S. Zhang J. Wisgerhof M.V. Shackleton C. Kashgarian M. Lifton R.P. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism J. Clin. Endocrinol. Metab. 93 2008 3117 3123 18505761 PMC2515083 source

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  • May combine two claims.

    Premisecitation

    Although multiple studies have measured circulating concentrations of 11-oxygenated androgens in healthy control groups, there are significant variations in the levels reported and no reference ranges have been established to date.

    “However, although multiple studies have measured the circulating concentrations of 11-oxygenated androgens in healthy control groups, there are significant variations in the levels reported and as such, no reference ranges have been established to date [39,41,68,69,289].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [39] Rege J. Nakamura Y. Satoh F. Morimoto R. Kennedy M.R. Layman L.C. Honma S. Sasano H. Rainey W.E. Liquid chromatography – tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation J. Clin. Endocrinol. Metab. 98 2013 1182 1188 23386646 PMC3590473 source

      Not checked in the free run.

    • cites [41] O’Reilly M.W. Kempegowda P. Jenkinson C. Taylor A.E. Quanson J.L. Storbeck K.-H.H. Arlt W. O’Reilly M.W. Kempegowda P. Jenkinson C. Taylor A.E. Quanson J.L. Storbeck K.-H.H. Arlt W. 11-Oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome J. Clin. Endocrinol. Metab. 102 2017 840 848 27901631 PMC5460696 source

      Not checked in the free run.

    • cites [68] Davis S.R. Turcu A.F. Robinson P.J. Bell R.J. Exogenous testosterone does not influence 11-oxygenated C19 steroid concentrations in healthy postmenopausal women J. Endocr. Soc. 3 2019 670 677 30842991 PMC6397421 source

      Not checked in the free run.

    • cites [69] Turcu A.F. Nanba A.T. Chomic R. Upadhyay S.K. Giordano T.J. Shields J.J. Merke D.P. Rainey W.E. Auchus R.J. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency Eur. J. Endocrinol. 174 2016 601 609 26865584 PMC4874183 source

      Not checked in the free run.

    • cites [289] Nanba A.T. Rege J. Ren J. Auchus R.J. Rainey W.E. Turcu A.F. 11-oxygenated C19 steroids Do not decline with age in women J. Clin. Endocrinol. Metab. 104 7 2019 2615 2622 30753518 PMC6525564 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Circulating testosterone concentrations in men are approximately 10-fold higher than those of women, due to dedicated biosynthesis in the testes together with a very minor contribution from the adrenals.

    “Circulating testosterone concentrations in men are approximately 10-fold higher than those of women, due to the dedicated biosynthesis in the testes, together with a very minor contribution from the adrenals (Section 2.5.3.1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In premenopausal women, estrogens are predominantly produced by the ovaries, but estrogens are also synthesized in peripheral tissues expressing aromatase, such as adipose tissue, using adrenal-derived androgen precursors.

    “In premenopausal women, these estrogens are predominantly produced by the ovaries (Section 2.5.4), but estrogens are also synthesized in peripheral tissues expressing aromatase, such as adipose tissue, using adrenal-derived androgen precursors.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The primary estrogens in circulation are estrone, estrone sulfate and 17β-estradiol, with 17β-estradiol considered the biologically active form.

    “The primary estrogens in circulation are estrone, estrone sulfate and 17β-estradiol, with 17β-estradiol considered the biologically active form [82,[301], [302], [303]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [82] Noel T. Noel C.T. Reed M.J. Jacobs H.S. James V.H.T. The plasma concentration of oestrone sulphate in postmenopausal women: lack of diurnal variation, effect of ovariectomy, age and weight J. Steroid Biochem. 14 1981 1101 1105 7198170 source

      Not checked in the free run.

    • cites [301] Towobola O.A. Crilly R.C. Oakey R.E. Oestrone sulphate in plasma from postmenopausal women and the effects of oestrogen and androgen therapy Clin. Endocrinol. (Oxf) 13 1980 461 471 http://www.ncbi.nlm.nih.gov/pubmed/6261992 6261992 source

      Not checked in the free run.

    • cites [302] Simpson E.R. Sources of estrogen and their importance J. Steroid Biochem. Mol. Biol. 86 2003 225 230 14623515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrone undergoes 16α-hydroxylation and HSD17B1 catalyzed reduction, while 17β-estradiol only requires 16α-hydroxylation to yield estriol.

    “Estrone undergoes 16α-hydroxylation and HSD17B1 catalyzed reduction, while 17β-estradiol only requires 16α-hydroxylation [[311], [312], [313], [314]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [311] Peltoketo H. Luu-The V. Simard J. Adamski J. 17beta-hydroxysteroid dehydrogenase (HSD)/17-ketosteroid reductase (KSR) family; Nomenclature and main characteristics of the 17HSD/KSR enzymes J. Mol. Endocrinol. 23 1999 1 11 10431140 source

      Not checked in the free run.

    • cites [312] Miettinen M.M. Mustonen M.V. Poutanen M.H. Isomaa V.V. Vihko R.K. Human 17 beta-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic cell- and tissue-specific expression Biochem. J. 314 1996 839 845 8615778 PMC1217133 source

      Not checked in the free run.

    • cites [313] Labrie F. Luu-The V. Lin S.-X. Claude L. Simard J. Breton R. Bélanger A. The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology Steroids 62 1997 148 158 9029730 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While 11-oxygenated steroids do appear to be glucuronidated, the limited data at hand suggests that glucuronidation of these steroids is less efficient than what is observed for the classic androgens.

    “While these steroids do appear to be glucuronidated, the limited data at hand suggests that glucuronidation of these steroids is less efficient than what is observed for the classic androgens [300].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [300] du Toit T. Swart A.C. Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer Mol. Cell. Endocrinol. 461 2018 265 276 28939401 source

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  • May combine two claims.

    Premisecitation

    Estriol and 16α-hydroxyestrone are conjugated at the 3-hydroxygroup by UGT1A10 and at the 16α-hydroxy group by UGT2B7.

    “Estriol and 16α-hydroxyestrone are conjugated at the 3-hydroxygroup by UGT1A10 and at the 16α-hydroxy group by UGT2B7 [330,331].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [330] Kallionpää R.A. Järvinen E. Finel M. Glucuronidation of estrone and 16α-hydroxyestrone by human UGT enzymes: the key roles of UGT1A10 and UGT2B7 J. Steroid Biochem. Mol. Biol. 154 2015 104 111 26220143 source

      Not checked in the free run.

    • cites [331] Sneitz N. Vahermo M. Mosorin J. Laakkonen L. Poirier D. Finel M. Regiospecificity and stereospecificity of human UDP-glucuronosyltransferases in the glucuronidation of estriol, 16-epiestriol, 17-epiestriol, and 13-epiestradiol Drug Metab. Dispos. 41 2013 582 591 23288867 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    While A4 and testosterone can be metabolized to either androsterone or etiocholanolone, DHT is 5α-reduced and thus only reflected in the androsterone fraction.

    “While, A4 and testosterone can be metabolized to either androsterone or etiocholanolone, DHT is 5α-reduced and thus only reflected in the androsterone fraction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Circulating levels of estrogens vary greatly during the course of the menstrual cycle and decrease significantly in postmenopausal women.

    “Circulating levels of estrogens vary greatly during the course of the menstrual cycle and decrease significantly in postmenopausal women (Table 3) [[306], [307], [308]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [306] Stricker R. Eberhart R. Chevailler M.-C. Quinn F.A. Bischof P. Stricker R. Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the abbott ARCHITECT analyzer Clin. Chem. Lab. Med. 44 2006 883 887 16776638 source

      Not checked in the free run.

    • cites [307] Rothman M.S. Carlson N.E. Xu M. Wang C. Swerdloff R. Lee P. Goh V.H.H. Ridgway E.C. Wierman M.E. Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography–tandem mass spectrometry Steroids 76 2011 177 182 21070796 PMC3005029 source

      Not checked in the free run.

    • cites [308] Fuhrman B.J. Xu X. Falk R.T. Dallal C.M. Veenstra T.D. Keefer L.K. Graubard B.I. Brinton L.A. Ziegler R.G. Gierach G.L. Assay reproducibility and interindividual variation for 15 serum estrogens and estrogen metabolites measured by liquid Chromatography–Tandem mass spectrometry Cancer Epidemiol. Prev. Biomarkers 23 2014 2649 2657 PMC4289148 25472673 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estriol is rapidly excreted in urine and, as a result, serum levels are low to undetectable.

    “Estriol is rapidly excreted in urine and, as a result, serum levels are low to undetectable [318].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [318] Henderson B.E. Ponder B.A.J. Ross R.K. Hormones, Genes, and Cancer 2003 Oxford University Press USA

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP3A4 is the major enzyme responsible for the 16α-hydroxylation of estrone in adults, though CYP1A1, CYP2C19 and CYP3A5 can also catalyze the reaction.

    “CYP3A4 is the major enzyme responsible for the 16α-hydroxylation of estrone in adults, though CYP1A1, CYP2C19 and CYP3A5 can also catalyze the reaction [315,316].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [315] Huang Z. Guengerich F.P. Kaminsky L.S. 16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5 Carcinogenesis 19 1998 867 872 9635876 source

      Not checked in the free run.

    • cites [316] Cribb A.E. Knight M.J. Dryer D. Guernsey J. Hender K. Tesch M. Saleh T.M. Role of polymorphic human cytochrome P450 enzymes in estrone oxidation Cancer Epidemiol. Biomarkers Prev. 15 2006 551 558 16537715 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SULT2A2 can target 3α- and 17β-hydroxyl groups and has been shown to sulfate An, testosterone and DHT.

    “SULT2A2 can target 3α- and 17β-hydroxyl groups and has been shown to sulfate An, testosterone and DHT [294,295].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [294] Strott C.A. Steroid sulfotransferases Endocr. Rev. 17 1996 670 697 8969973 source

      Not checked in the free run.

    • cites [295] Chang H.-J. Shi R. Rehse P. Lin S.-X. Identifying androsterone (ADT) as a cognate substrate for human dehydroepiandrosterone sulfotransferase (DHEA-ST) important for steroid homeostasis J. Biol. Chem. 279 2004 2689 2696 14573603 source

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

    Premisecitation

    In the liver approximately 80% of 17β-estradiol is hydroxylated to the 2 position and 20% at the 4 position.

    “In the liver approximately 80% of 17β-estradiol is hydroxylated to the 2 position and 20% at the 4 position [322].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [322] Tsuchiya Y. Nakajima M. Yokoi T. Cytochrome P450-mediated metabolism of estrogens and its regulation in human Cancer Lett. 227 2005 115 124 16112414 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP1A2 is the dominant enzyme catalyzing the 16α-hydroxylation of 17β-estradiol, with CYP3A4, CYP1A1 and CYP1B1 also demonstrating this activity.

    “Conversely, CYP1A2 is the dominant enzyme catalyzing the 16α-hydroxylation of 17β-estradiol, with CYP3A4, CYP1A1 and CYP1B1 also demonstrating this activity [317].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [317] Badawi A.F. Cavalieri E.L. Rogan E.G. Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol Metabolism 50 2001 1001 1003 11555828 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrone sulfate is the predominant estrogen in circulation for both men and premenopausal women and serves as a biologically inactive reservoir for the generation of active estrogens in target tissues.

    “Notably, estrone sulfate is the predominant estrogen in circulation for both men and premenopausal women and serves as a biologically inactive reservoir for the generation of active estrogens in target tissues [40,309,310].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Mueller J.W. Gilligan L.C. Idkowiak J. Arlt W. Foster P.A. The regulation of steroid action by sulfation and desulfation Endocr. Rev. 36 2015 526 563 26213785 PMC4591525 source

      Not checked in the free run.

    • cites [309] Muir M. Romalo G. Wolf L. Elger W. Schweikert H.-U. Estrone sulfate Is a Major source of local estrogen formation in human bone J. Clin. Endocrinol. Metab. 89 2004 4685 4692 15356081 source

      Not checked in the free run.

    • cites [310] Reed M.J. Purohit A. Woo L.W.L. Newman S.P. Potter B.V.L. Steroid sulfatase: molecular biology, regulation, and inhibition Endocr. Rev. 26 2005 171 202 15561802 source

      Not checked in the free run.

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

    Premisecitation

    Like with androgens, the majority of unconjugated estrogen circulates bound to SHBG with high affinity and albumin with low affinity.

    “Like with androgens, the majority of unconjugated estrogen circulates bound to SHBG with high affinity and albumin with low affinity [[285], [286], [287]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [285] Anderson D.C. Sex‐hormone binding-globulin Clin. Endocrinol. (Oxf). 3 1974 69 96 4134992 source

      Not checked in the free run.

    • cites [286] Mendel C.M. The Free hormone hypothesis: a physiologically based mathematical model Endocr. Rev. 10 1989 232 274 2673754 source

      Not checked in the free run.

    • cites [287] Hammond G.L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action J. Endocrinol. 230 2016 R13 R25 27113851 PMC5064763 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UGT2B15 expressed in adipose tissue has been shown to demonstrate a higher activity in obese individuals, which may contribute to the increased levels of 3α-androstanediol glucuronide observed in obesity.

    “Interestingly, UGT2B15 which is expressed in adipose tissue has been shown to demonstrate a higher activity in obese individuals, which may contribute to the increased levels of 3α-androstanediol glucuronide observed in obesity [292,293].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [292] Tchernof A. Labrie F. Bélanger A. Prud’homme D. Bouchard C. Tremblay A. Nadeau A. Després J.-P. Androstane-3α,17β-diol glucuronide as a steroid correlate of visceral obesity in men J. Clin. Endocrinol. Metab. 82 1997 1528 1534 9141545

      Not checked in the free run.

    • cites [293] Tchernof A. Lévesque E. Beaulieu M. Couture P. Després J.P. Hum D.W. Bélanger A. Expression of the androgen metabolizing enzyme UGT2B15 in adipose tissue and relative expression measurement using a competitive RT-PCR method Clin. Endocrinol. (Oxf) 50 1999 637 642 http://www.ncbi.nlm.nih.gov/pubmed/10468930 10468930 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although 11β-OHAn can also derive from cortisol metabolism, this only contributes to approximately 5-10% of the measured levels, with at least 90% originating from 11OHA4.

    “It should be noted that although 11β-OHAn can also derive from cortisol metabolism (Section 4.2.2), this only contributes to approximately 5–10% of the measured levels, with at least 90% originating from 11OHA4 [258].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Shackleton C.H.L. Neres M.S. Hughes B.A. Stewart P.M. Kater C.E. 17-Hydroxylase/C17, 20-lyase (CYP17) is not the enzyme responsible for side-chain cleavage of cortisol and its metabolites Steroids 73 2008 652 656 18355883 source

      Not checked in the free run.

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

    Premisecitation

    The use of high-resolution accurate mass (HRAM) mass spectrometry coupled to liquid chromatography systems is being explored as an alternative to traditional MS/MS systems as accurate mass quantification offers the potential to resolve all steroid metabolites with the exception of steroid isomers, unless they are separated chromatographically.

    “Moreover, the use of high-resolution accurate mass (HRAM) mass spectrometry coupled to liquid chromatography systems is being explored as an alternative to traditional MS/MS systems as accurate mass quantification offers the potential to resolve all steroid metabolites with the exception of steroid isomers, unless they are separated chromatographically [344].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [344] Hines J.M. Bancos I. Bancos C. Singh R.D. Avula A.V. Young W.F. Grebe S.K. Singh R.J. High-Resolution, accurate-mass (HRAM) mass spectrometry urine steroid profiling in the diagnosis of adrenal disorders Clin. Chem. 63 2017 1824 1835 28814383 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alternatively, progesterone can first be reduced to 20α-hydroxyprogesterone, which can then be further 5β-reduced by AKR1D1 and 3α-reduced by AKR1C1-4.

    “Alternatively, progesterone can first be reduced to 20α-hydroxyprogesterone, which can then be further 5β-reduced by AKR1D1 and 3α-reduced by AKR1C1–4 [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Jin Y. Mesaros A.C. Blair I.A. Penning T.M. Stereospecific reduction of 5beta-reduced steroids by human ketosteroid reductases of the AKR (aldo-keto reductase) superfamily: role of AKR1C1-AKR1C4 in the metabolism of testosterone and progesterone via the 5beta-reductase pathway Biochem. J. 437 2011 53 61 21521174 PMC3825703 source

      Not checked in the free run.

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

    Premisecitation

    Low levels of circulating progesterone are also detectable in men.

    “Low levels of circulating progesterone are also detectable in men [334].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [334] Strott C.A. Yoshimi T. Lipsett M.B. Plasma progesterone and 17-hydroxyprogesterone in normal men and children with congenital adrenal hyperplasia J. Clin. Invest. 48 1969 930 939 4305376 PMC322302 source

      Not checked in the free run.

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

    Premisecitation

    Catecholestrogens can additionally be glucuronidated in positions 2 and 4.

    “Catcholestrogens can additionally be glucuronidated in positions 2 and 4 [332].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [332] Lépine J. Bernard O. Plante M. Têtu B. Pelletier G. Labrie F. Bélanger A. Guillemette C. Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium J. Clin. Endocrinol. Metab. 89 2004 5222 5232 15472229 source

      Not checked in the free run.

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

    Premisecitation

    There is a drive within the endocrine community to phase out immunoassays where possible.

    “Indeed, there is a drive within the endocrine community to phase out immunoassays where possible [343].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [343] Auchus R.J. Steroid assays and endocrinology: Best practices for basic scientists Endocrinology 155 2014 2049 2051 24837046 PMC4020931 source

      Not checked in the free run.

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

    Premisecitation

    Currently, gas chromatography-mass spectrometry (GC-MS) is the preferred method for the analysis of urine steroids in research laboratories due to the unparalleled resolution offered by this technique.

    “Currently, gas chromatography-mass spectrometry (GC-MS) is the preferred method for the analysis of urine steroids in research laboratories due to the unparalleled resolution offered by this technique [339,340].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [339] Shackleton C.H.L. Profiling steroid hormones and urinary steroids J Chromatogr. 379 1986 91 156 3525596 source

      Not checked in the free run.

    • cites [340] Shackleton C.H. Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research J. Steroid Biochem. Mol. Biol. 45 1993 127 140 http://www.ncbi.nlm.nih.gov/pubmed/8481337 8481337 source

      Not checked in the free run.

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

    Premisecitation

    There are increasing efforts to develop both ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UPHSFC-MS/MS) methods for the screening of multiple urine steroids.

    “However, of late, there are increasing efforts to develop both ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UPHSFC-MS/MS) methods for the screening of multiple urine steroids [341,342].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [341] Shackleton C. Pozo O.J. Marcos J. GC/MS in recent years has defined the Normal and clinically disordered steroidome: will It Soon Be surpassed by LC/Tandem MS in this role? J. Endocr. Soc. 2 2018 974 996 30094411 PMC6080058 source

      Not checked in the free run.

    • cites [342] Storbeck K.-H. Gilligan L. Jenkinson C. Baranowski E.S. Quanson J.L. Arlt W. Taylor A.E. The utility of ultra-high performance supercritical fluid chromatography–tandem mass spectrometry (UHPSFC-MS/MS) for clinically relevant steroid analysis J. Chromatogr. B 1085 2018 36 41 29627638 source

      Not checked in the free run.

136 of 136

  • The paper relies on this without support.

    A gulf exists between knowledge of steroid biosynthetic and metabolic pathways and application of this knowledge to interpretation of measured multi-steroid profiles in serum and urine.

    “While the biochemical pathways for the biosynthesis and metabolism of steroid hormones are now mostly well defined, a gulf still exists with regard to the application of this knowledge to the interpretation of the measured multi-steroid profiles in serum and urine.”

  • The paper relies on this without support.

    Researchers and clinicians are increasingly dependent on results obtained by steroid metabolome analysis but are often unfamiliar with the metabolic pathways resulting in observed steroid profiles and the distinct pathways explaining differences between serum and urine steroid metabolomes.

    “Researchers and clinicians are increasingly dependent on results obtained by steroid metabolome analysis, but are often unfamiliar with the metabolic pathways resulting in the observed steroid profile and the distinct metabolic pathways explaining the differences between serum and urine steroid metabolomes.”

  • The paper relies on this without support.

    Steroid hormones are produced through de novo steroidogenesis in the adrenal cortex, the gonads and the placenta.

    “Steroid hormones are produced through de novo steroidogenesis in the adrenal cortex, the gonads and the placenta.”

  • The paper relies on this without support.

    Steroidogenic tissues are unique in their ability to utilize cholesterol as starting material for mitochondrial biosynthesis of pregnenolone, the precursor steroid in biosynthesis of all steroid hormones.

    “Steroidogenic tissues are unique in their ability to utilize cholesterol as starting material for the mitochondrial biosynthesis of pregnenolone, the precursor steroid in the biosynthesis of all steroid hormones.”

  • The paper relies on this without support.

    The liver makes the major contribution to steroid metabolism.

    “Although the liver undoubtedly makes the major contribution to steroid metabolism, most peripheral tissues also possess enzymatic machinery for aspects of both steroid activation and subsequent inactivation by phase 1 and 2 metabolism.”

  • The paper relies on this without support.

    The majority (>90%) of the glucocorticoid metabolites described are glucuronidated in the liver prior to urinary excretion as mono-glucuronides with glycosidic bonds added at positions 3 or 21.

    “The majority (>90%) of the glucocorticoid metabolites described above are glucuronidated in the liver prior to urinary excretion as mono-glucuronides with glycosidic bonds added at positions 3 or 21.”

  • The paper relies on this without support.

    Within circulation, most active sex steroids are bound to SHBG or albumin and only a small fraction (1–2%) circulates unbound, which is the only form in which testosterone is accessible to target tissues.

    “Within circulation, most active sex steroids are bound to the plasma proteins sex hormone binding globulin (SHBG) or albumin and only a small fraction (1–2%) circulates unbound, which is the only form in which testosterone is accessible to the target tissues.”

  • The paper relies on this without support.

    The conjugated precursor DHEAS circulates only in its free form.

    “Moreover, the conjugated precursor, DHEAS, circulates only in its free form.”

  • The paper relies on this without support.

    Progesterone primarily circulates bound to CBG.

    “Progesterone primarily circulates bound to CBG.”

  • The paper relies on this without support.

    PD is efficiently glucuronidated at position 3, resulting in pregnanediol-3-glucuronide being the major progesterone metabolite identified in urine.

    “PD is efficiently glucuronidated at position 3, resulting in pregnanediol-3-glucuronide being the major progesterone metabolite identified in urine.”
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?

  • Alternative pathway steroid metabolites can be detected in patients of all ages with 21OHD, most prominently in the neonate.

    “Alternative pathway steroid metabolites can be detected in patients of all ages with 21OHD, most prominently in the neonate (120).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [120]

    The “alternative DHT biosynthesis pathway” section says CYP21A2 deficiency can activate the alternative pathway and identifies its steroid products. It does not say those metabolites are detectable in patients with 21-hydroxylase deficiency at all ages or that they are most prominent in neonates; its fetal discussion does not establish that comparison. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • High concentrations of 17OHP in individuals with 21OHD drive dihydrotestosterone production by the alternative pathway.

    “These studies indicate that the high concentrations of 17OHP in individuals with 21OHD drive dihydrotestosterone production by the alternative pathway.”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [120]

  • C19 11-oxygenated steroids are a class of active adrenal androgens recognized more than 60 years ago, which have been restudied recently.

    “C19 11-oxygenated steroids are a class of active adrenal androgens recognized 60+ years ago, which have been restudied recently.”

    From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [26]

  • C19 11-oxygenated steroids are likely better markers of adrenal androgen excess in congenital adrenal hyperplasia than DHEA, androstenedione and testosterone, classically employed to monitor therapeutic control.

    “Currently, the C19 11-oxygenated steroids are likely better markers of adrenal androgen excess in CAH than DHEA, androstenedione and testosterone, classically employed to monitor therapeutic control.”

    From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [26]

  • C19 11-oxygenated steroids are also increased in polycystic ovary syndrome, being correlated with markers of metabolic risk such as BMI and HOMA-IR index.

    “C19 11-oxygenated steroids are also increased in polycystic ovary syndrome (PCOS), being correlated with markers of metabolic risk, such BMI and HOMA-IR index ( 24 - 27 ).”

    From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [26]

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.

  • Estrogen sulfotransferase is absent from the exhaustive enzyme list

    Minor

    The stated list of five steroid-sulfating SULTs includes SULT2E1 but not SULT1E1, which the paper later identifies as the major enzyme for estrogen sulfation.

  • Testosterone and DHT are called 3α,17β-diols

    Minor

    The passage presents testosterone and DHT as examples of androstane-3α,17β-diols, whereas Table 1 names both as 3-keto steroids.

2 of 2

Cites

Flagged first, then by citations

17 of the 380 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Shackleton, 2011, GC/MS steroid profiling: diagnosis of disorders affecting steroid synthesis and metabolism, Encycl. Mass Spectrom., 8, 789
  2. Moeller, 2009, Integrated view on 17beta-hydroxysteroid dehydrogenases, Mol. Cell. Endocrinol., 301, 7, 10.1016/j.mce.2008.10.040 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H.
Affiliations
  • University of Birmingham (GB)
  • Stellenbosch University (ZA)
  • Birmingham Women’s and Children’s NHS Foundation Trust (GB)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
  • UCSF Benioff Children's Hospital (US)
Corresponding author
Storbeck, Karl-Heinz
ORCID
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
2019-11
Volume
194
Pages
105439
ISSN
0960-0760 (ISSN-L)
DOI
10.1016/j.jsbmb.2019.105439
PMC
PMC6857441
OpenAlex
W2966363656
Semantic Scholar
e4fd1a0dc4645d32b1f91b9d3051f87e38387633
Cited by
450
References
380
Citations by year
2026: 62 · 2025: 73 · 2024: 95 · 2023: 69 · 2022: 64 · 2021: 61 · 2020: 24 · 2018: 1
FWCI
3.29
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
  • SUNScholar (Stellenbosch University) (submittedVersion)
Funders
  • Medical Research Council
  • Academy of Medical Sciences
  • Wellcome Trust
  • University of Birmingham
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
Keywords
steroidogenesis, steroid metabolism, steroid excretion, steroid profiling, steroid precursors, steroid metabolites
MeSH terms
Humans, Mass Spectrometry, Steroids, Metabolomics, Metabolome

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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