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

In the paper

“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]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“This results in significant DHEAS output and accounts for DHEAS being the most abundant steroid in circulation (Table 2) [39,41].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Other Δ5 steroids, e.g. pregnenolone, 17α-hydroxypregnenolone and androstenediol, can also be released in their respective sulfated form [[42], [43], [44]].”

What the sources say

• Not checked yetcites [42] Strott C.A. Sulfonation and molecular action Endocr. Rev. 23 2002 703 732 12372849 source
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“During that time, the development of a distinct zona reticularis is accompanied by an extreme increase in the adrenal androgen precursor production due to the decreased expression of HSD3B2 in conjunction with increased CYB5A expression [[34], [35], [36], [37], [38]].”

What the sources say

• Not checked yetcites [34] Kohara T. Matsui Y. Fujii T.K. Tanaka N. Cefpirome in obstetrics and gynecology Chemotherapy 39 1991 452 457
• Not checked yetcites [35] Nakamura Y. Gang H.X. Suzuki T. Sasano H. Rainey W.E. Adrenal changes associated with adrenarche Rev. Endocr. Metab. Disord. 10 2009 19 26 18821019 PMC3712864 source
• Not checked yetcites [36] Auchus R.J. Rainey W.E. Adrenarche – physiology, biochemistry and human disease Clin. Endocrinol. (Oxf.) 60 2004 288 296 15008992 source

In the paper

“Androsterone, considered an inactive metabolite of DHT under normal circumstances, can then be reactivated by the sequential 17β-reduction and 3α-oxidase reactions [[63], [64], [65]].”

What the sources say

• Not checked yetcites [63] Kamrath C. Hochberg Z. Hartmann M.F. Remer T. Wudy S.A. Increased activation of the alternative “backdoor” pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis J. Clin. Endocrinol. Metab. 97 2012 E367 E375 22170725 source
• Not checked yetcites [64] Fukami M. Homma K. Hasegawa T. Ogata T. Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development Dev. Dyn. 242 2013 320 329 23073980 source
• Not checked yetcites [65] Bauman D.R. Steckelbroeck S. Williams M.V. Peehl D.M. Penning T.M. Identification of the major oxidative 3alpha-hydroxysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha,17beta-diol to 5alpha-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease Mol. Endocrinol. 20 2006 444 458 16179381 source

In the paper

“It should be highlighted that with the exception of testosterone produced by the testes, the vast majority of C19 steroids produced by the adrenal and ovaries are inactive androgen precursors.”

What the sources say

• Not checked yetcites [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

In the paper

“In selected circumstances, such as CYP21A2 deficiency and during fetal development (Section 2.6), accumulation of progesterone and 17OHP in circulation can lead to the activation of an alternative pathway of DHT biosynthesis (Fig. 3). This is sometimes referred to as the “backdoor pathway” to DHT [62].”

What the sources say

• Not checked yetcites [62] Auchus R.J. The backdoor pathway to dihydrotestosterone Trends Endocrinol. Metab. 15 2004 432 438 15519890 source

In the paper

“In addition to de novo steroidogenesis, it is important to note that the ovary also utilizes circulating DHEA and A4 of adrenal origin for the biosynthesis of androgens and estrogens [80].”

What the sources say

• Not checked yetcites [80] Haning R.V. Austin C.W. Carlson I.H. Kuzma D.L. Zweibel W.J. Role of dehydroepiandrosterone sulfate as a prehormone for ovarian steroidogenesis Obstet. Gynecol. 65 1985 199 205 http://www.ncbi.nlm.nih.gov/pubmed/3155830 3155830

In the paper

“A4 can also be 5α-reduced to 5α-androstanedione prior to conversion to DHT by AKR1C3, thereby bypassing testosterone (Fig. 3) [45,55].”

What the sources say

• Not checked yetcites [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 yetcites [55] Sharifi N. The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer J. Invest. Med. 60 2012 504 507 PMC3262939 22064602 source

In the paper

“Indeed, the enzyme steroid 5α-reductase 1 (SRD5A1) catalyzes the 5α-reduction of A4 more efficiently than that of testosterone [56,57].”

What the sources say

• Not checked yetcites [56] Thigpen A.E. Cala K.M. Russell D.W. Characterization of Chinese hamster ovary cell lines expressing human steroid 5α-reductase isozymes J. Biol. Chem. 268 1993 17404 17412 8394341 source
• Not checked yetcites [57] Andersson S. Russell D.W. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases Proc. Natl. Acad. Sci. U. S. A. 87 1990 3640 3644 2339109 PMC53958 source

In the paper

“However, differences in the concentration of 11KA4 measured in the adrenal vein and inferior vena cava suggest that 11KA4 is predominantly produced from conversion of 11OHA4 in peripheral tissue expressing HSD11B2 such as the kidney [39,69].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“while HSD11B2 only oxidizes the 7α-hydroxy-stereoisomer [110,111].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“These reactions are catalyzed by members of the aldo-keto reductase family, namely AKR1C1, AKR1C2, AKR1C3 and AKR1C4.”

In the paper

“Enzymes from the SDR and AKR superfamilies regulate the activity of androgens and estrogens by catalyzing the interconversion of bioactive 17β-hydroxy- and inactive keto- containing forms”

In the paper

“with the result that 5α- and 5β-reduced metabolites are produced with different ratios for different structural classes of steroids.”

In the paper

“5β-reduced steroids are predominantly converted to the 3α-hydroxy epimer as the 5β-reduced bent confirmation of the A/B-ring sterically does not allow binding in the AKR1C active site for 3β-reduction [102,103].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Additionally, conjugation with a charged group limits transport over membranes to active transport, thereby allowing for the concentration of the metabolite on one side [87,88].”

What the sources say

• Not checked yetcites [87] Hachey D.L. Dawling S. Roodi N. Parl F.F. Sequential action of phase I and II enzymes cytochrome p450 1B1 and glutathione S-transferase P1 in mammary estrogen metabolism Cancer Res. 63 2003 8492 8499 14679015
• Not checked yetcites [88] Hevir N. Sinkovec J. Rizner T.L. Disturbed expression of phase I and phase II estrogen-metabolizing enzymes in endometrial cancer: lower levels of CYP1B1 and increased expression of S-COMT Mol. Cell. Endocrinol. 331 2011 158 167 20887769 source

In the paper

“Excreted metabolites are therefore predominantly in the keto-form [112].”

What the sources say

• Not checked yetcites [112] Shackleton C.H.L. Marcos P. GC/MS steroid profiling: diagnosis of disorders affecting steroid synthesis and metabolism Encycl. Mass Spectrom. 8 2011 789 813

In the paper

“SRD5As and AKR1D1 exhibit different catalytic efficiencies towards structurally different steroids [57,100]”

What the sources say

• Not checked yetcites [57] Andersson S. Russell D.W. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases Proc. Natl. Acad. Sci. U. S. A. 87 1990 3640 3644 2339109 PMC53958 source
• Not checked yetcites [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

In the paper

“AKR1C2 is the major isoform for 3-reduction to the 3α-hydroxyepimer in peripheral tissue”

What the sources say

• Not checked yetcites [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

In the paper

“and hepatic failure [101]”

What the sources say

• Not checked yetcites [101] Palermo M. Marazzi M.G. Hughes B.A. Stewart P.M. Clayton P.T. Shackleton C.H. Human delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency and steroid metabolism Steroids 73 2008 417 423 18243262 source

In the paper

“Additionally, some steroids can directly undergo phase 2 metabolism without being subjected to a phase 1 reaction, e.g. testosterone can be directly conjugated at its 17β-hydroxy group and corticosteroids through 21-sulfation [90].”

What the sources say

• Not checked yetcites [90] Kornel L. Patel S.K. Ezzeraimi E. Shackleton C.H. Corticosteroids in human blood: IX. Evidence for adrenal secretion of sulfate-conjugated cortisol, 11 beta,17 alpha-dihydroxy-4-pregnene-3,20-dione-21-yl-sulfate Steroids 60 1995 817 823 8650705 source

In the paper

“AKR1D1 deficiency leads to severely reduced or abolished urinary 5β-reduced steroid excretion”

What the sources say

• Not checked yetcites [101] Palermo M. Marazzi M.G. Hughes B.A. Stewart P.M. Clayton P.T. Shackleton C.H. Human delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency and steroid metabolism Steroids 73 2008 417 423 18243262 source

In the paper

“Glucuronidation makes a substantial contribution to the phase 2 metabolism of Δ4 steroids.”

In the paper

“is predominantly catalyzed by AKR1C1 [104,115].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“A-ring reduced steroid metabolites are predominantly excreted as 3-glucuronides.”

In the paper

“Hepatic xenobiotic-metabolizing members of the CYP superfamily are able to modify steroid hormones and generate a plethora of minor steroid metabolites [116].”

What the sources say

• Not checked yetcites [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

In the paper

“CYP2C19 and CYP3A4 can 21-hydroxylate progesterone and pregnenolone”

What the sources say

• Not checked yetcites [140] Gomes L.G. Huang N. Agrawal V. Mendonca B.B. Bachega T.A. Miller W.L. Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency J Clin Endocrinol Metab. 94 2009 89 95 18957504 PMC2630875 source

In the paper

“the two enzymes are not capable of catalyzing the 21-hydroxylation of 17OHP to 11-deoxycortisol [140].”

What the sources say

• Not checked yetcites [140] Gomes L.G. Huang N. Agrawal V. Mendonca B.B. Bachega T.A. Miller W.L. Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency J Clin Endocrinol Metab. 94 2009 89 95 18957504 PMC2630875 source

In the paper

“Five cytoplasmic SULTs are involved in the sulfation of steroids in humans: SULT1A1, SULT2E1, SULT2A1 and two isoforms of SULT2B1 (SULT2B1a and SULT2B1b) [40,165].”

What the sources say

• Not checked yetcites [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 yetcites [165] Coughtrie M.W.H. Function and organization of the human cytosolic sulfotransferase (SULT) family Chem Biol Interact. 259 2016 2 7 27174136 source

In the paper

“Unconjugated steroids passively diffuse over the membranes of the acinar cells in the salivary glands independent of salivary flow rate [209].”

What the sources say

• Not checked yetcites [209] Vining R.F. McGinley R.A. Symons R.G. Hormones in saliva: mode of entry and consequent implications for clinical interpretation Clin Chem. 29 1983 1752 1756 6225566 source

In the paper

“17-deoxysteroids (mineralocorticoids and precursors) have high biliary excretion as opposed to 17-hydroxy C21 steroids like cortisol [147].”

What the sources say

• Not checked yetcites [147] Laatikainen T. Identification of C21-O3 and C21-O4 steroids in human bile Eur J Biochem. 14 1970 372 378 5506175 source

In the paper

“makes the major contribution to steroid metabolism.”

What the sources say

• Not checked yetcites [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
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In the paper

“but its role in drug and steroid metabolism is limited due to its generally low activity and expression in a relatively small percentage of individuals [[123], [124], [125]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Hepatic CYPs are promiscuous enzymes accepting a wide range of substrates with low stereo- and regioselectivity compared to their steroidogenic counterparts.”

In the paper

“Sulfation is of particular relevance for Δ5 steroids which are almost exclusively excreted as their sulfates.”

In the paper

“glucuronidation is irreversible in humans, with the exception of the activity of some gut bacteria”

In the paper

“Biliary excretion is increased during pregnancy [201,203,204]”

What the sources say

• Not checked yetcites [201] Laatikainen T. Karjalainen O. Excretion of conjugates of neutral steroids in human bile during late pregnancy Acta Endocrinol. 69 1972 775 788 4259560
• Not checked yetcites [203] Eriksson H. Gustafsson J.A. Excretion of steroid hormones in adults. Steroids in faeces from adults Eur J Biochem. 18 1971 146 150 5540510 source
• Not checked yetcites [204] Gustafsson J.A. Shackleton C.H. Sjovall J. Steroids in newborns and infants. A semiquantitative analysis of steroids in faeces from infants Acta Endocrinol. 65 1970 18 28 5468971

In the paper

“Metabolism by the gut microbiome is relevant for C17-deoxy corticosteroids, e.g. mineralocorticoids and their precursors, which have a high biliary excretion [147].”

What the sources say

• Not checked yetcites [147] Laatikainen T. Identification of C21-O3 and C21-O4 steroids in human bile Eur J Biochem. 14 1970 372 378 5506175 source

In the paper

“Urinary excretion of unconjugated steroids is low, accounting for only 5–10% of the total urine steroid pool.”

In the paper

“Their levels in saliva therefore provide a measure of their free concentrations in serum [210].”

What the sources say

• Not checked yetcites [210] Vining R.F. McGinley R.A. Maksvytis J.J. Ho K.Y. Salivary cortisol: a better measure of adrenal cortical function than serum cortisol Ann Clin Biochem. 20 Pt 6 1983 329 335 6316831 source

In the paper

“Reactions catalyzed by different strains of gut bacteria include (1) A-ring reduction, (2) reduction of the Δ5-double bond, (3) reduction of 17-keto estrogens and 17-keto androstenes, (4) 17,20-cleavage of 17α-hydroxysteroids, and (5) 16α- and 21-dehydroxylation”

What the sources say

• Not checked yetcites [148] Winter J. Bokkenheuser V.D. Bacterial metabolism of natural and synthetic sex hormones undergoing enterohepatic circulation J Steroid Biochem. 27 1987 1145 1149 3320550 source
• Not checked yetcites [149] Bokkenheuser V.D. Winter J. Honour J.W. Shackleton C.H. Reduction of aldosterone by anaerobic bacteria: origin of urinary 21-deoxy metabolites in man J Steroid Biochem. 11 1979 1145 1149 502556 source
• Not checked yetcites [150] Winter J. Shackleton C.H.L. O’rourke S. Bokkenheuser V.D. Bacterial formation of aldosterone metabolites J. Steroid Biochem. 21 1984 563 569 6513554 source

In the paper

“The classic phase 2 conjugation reactions – sulfation and glucuronidation – increase the polarity and water solubility of the steroids and thereby facilitate their excretion and concentration in the urine.”

In the paper

“Cortisone is in-turn reactivated to cortisol by the action of HSD11B1 expressed predominantly in the liver, as well as some peripheral tissues such as adipose tissue, muscle, skin and bone [74,[232], [233], [234], [235]].”

What the sources say

• Not checked yetcites [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 yetcites [232] Hardy R.S. Doig C.L. Hussain Z. O’Leary M. Morgan S.A. Pearson M.J. Naylor A. Jones S.W. Filer A. Stewart P.M. Buckley C.D. Lavery G.G. Cooper M.S. Raza K. 11β-hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation J. Pathol. 240 2016 472 483 27578244 PMC5111591 source
• Not checked yetcites [233] Cooper M.S. Rabbitt E.H. Goddard P.E. Bartlett W.A. Hewison M. Stewart P.M. Osteoblastic 11β-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure J. Bone Miner. Res. 17 2002 979 986 12054173 source

In the paper

“subsequently occurs in peripheral mineralocorticoid target tissue, such as the kidney, the colon and the salivary glands all of which express HSD11B2 [74].”

What the sources say

• Not checked yetcites [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

In the paper

“both corticosterone and 11-dehydrocorticosterone can either be 5α- or 5β-reduced, prior to 3α-reduction leading to a tetrahydro and a 5α-tetrahydro metabolite for each.”

In the paper

“the presence of HSD11B2 in the parotid gland makes salivary cortisone a useful marker for serum free cortisol and adrenal stimulation [[211], [212], [213]].”

What the sources say

• Not checked yetcites [211] Perogamvros I. Keevil B.G. Ray D.W. Trainer P.J. Salivary cortisone is a potential biomarker for serum free cortisol J Clin Endocrinol Metab. 95 2010 4951 4958 20685855 source
• Not checked yetcites [212] Debono M. Harrison R.F. Whitaker M.J. Eckland D. Arlt W. Keevil B.G. Ross R.J. Salivary cortisone reflects cortisol exposure under physiological conditions and after hydrocortisone J. Clin. Endocrinol. Metab. 101 2016 1469 1477 26812690 source
• Not checked yetcites [213] Harrison R.F. Debono M. Whitaker M.J. Keevil B.G. Newell-Price J. Ross R.J. Salivary cortisone to estimate cortisol exposure and sampling frequency required based on serum cortisol measurements J. Clin. Endocrinol. Metab. 104 3 2018 765 772 PMC6349003 30285244 source

In the paper

“AKR1C1 is the predominant 20-ketosteroid reductase in human [104].”

What the sources say

• Not checked yetcites [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

In the paper

“women who have increased estrogenlevels due to oral or transdermal contraceptives or pregnancy, have increased total serum cortisol due to an increase in CBG”

What the sources say

• Not checked yetcites [248] Jung C. Ho J.T. Torpy D.J. Rogers A. Doogue M. Lewis J.G. Czajko R.J. Inder W.J. A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum J. Clin. Endocrinol. Metab. 96 2011 1533 1540 21367926 source
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In the paper

“Aldosterone is preferentially 18-glucuronidated in the liver by UGT2B7 and UGT1A10 [223].”

What the sources say

• Not checked yetcites [223] Knights K.M. Winner L.K. Elliot D.J. Bowalgaha K. Miners J.O. Aldosterone glucuronidation by human liver and kidney microsomes and recombinant UDP-glucuronosyltransferases: inhibition by NSAIDs Br. J. Clin. Pharmacol. 68 2009 402 412 19740398 PMC2766480 source

In the paper

“THAldo-glucuronides are consistently five-fold more prevalent than aldosterone-18β-glucuronide irrespective of sodium intake [221].”

What the sources say

• Not checked yetcites [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

In the paper

“during neonatal life, THA, 5α-THA and the polar metabolite 6α-hydroxy-THA are the more relevant corticosterone metabolites (Fig. 4(g)) [130].”

What the sources say

• Not checked yetcites [130] Shackleton C.H.L. Honour J.W. Taylor N.F. Metabolism of fetal and neonatal adrenal steroids J. Steroid Biochem. 11 1979 523 529 573819 source

In the paper

“18-hydroxycorticosterone is converted to the tetrahydro metabolite, 18-hydroxy-tetrahydro-11-dehydrocorticosterone (18OHTHA), but this requires the additional conversion of the 11β-hydroxy group to an 11-keto group, a reaction catalyzed by HSD11B2 [[216], [217], [218]].”

What the sources say

• Not checked yetcites [216] Ulick S. Kusch K. August J.T. Correction of the structure of a urinary metabolite of aldosterone J. Amer. Chem. Soc. 8 1961 4482 source
• Not checked yetcites [217] Ulick S. Vetter K. Identification of two C18 oxygenated corticosteroids isolated from human urine J Biol Chem. 237 1962 3364 3374 http://www.jbc.org/content/237/11/3364.short 13995287 source
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In the paper

“This follows a distinct pattern with nadir concentrations around midnight and the highest levels observed between 3 and 5 a.m., although the exact timings can show inter-individual variability [[240], [241], [242]].”

What the sources say

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In the paper

“A vital aspect to consider when measuring cortisol and cortisone is their diurnal secretion rhythm [239].”

What the sources say

• Not checked yetcites [239] Weitzman E.D. Czeisler C.A. Zimmerman J.C. Moore-Ede M.C. Biological rhythms in man: relationship of sleep-wake, cortisol, growth hormone, and temperature during temporal isolation Adv. Biochem. Psychopharmacol. 28 1981 475 499 http://www.ncbi.nlm.nih.gov/pubmed/7010946 7010946

In the paper

“cortisone and the resulting 11-keto-metabolites (e.g. tetrahydrocortisone) are substantially increased during the neonatal period [74].”

What the sources say

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In the paper

“HSD11B2 converts cortisol to cortisone to protect the MR from activation by cortisol, thus allowing the dedicated MR agonist aldosterone to bind [[228], [229], [230], [231]].”

What the sources say

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In the paper

“the human enzyme(s) responsible for the formation of the 20β-hydroxy isomers of the cortols and cortolones has not yet been identified.”

What the sources say

• Not checked yetcites [254] Tokarz J. Mindnich R. Norton W. Möller G. Hrabé de Angelis M. Adamski J. Discovery of a novel enzyme mediating glucocorticoid catabolism in fish: 20beta-hydroxysteroid dehydrogenase type 2 Mol. Cell. Endocrinol. 349 2012 202 213 22061621 source
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In the paper

“Any healthy individual’s serum cortisol concentration will be significantly higher in the morning than at midnight.”

In the paper

“While the levels of 11-oxygenated androgens and their precursors have been shown to be significantly elevated in patients with polycystic ovary syndrome (PCOS) and 21-hydroxylase deficiency [41,69], one study reported that the circulating levels of 11KT were also higher than that of testosterone in a healthy female control group (BMI 21.2–26.1 kg/m2) [41].”

What the sources say

• Not checked yetcites [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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In the paper

“UGT2B7 has been shown to efficiently catalyze the conjugation of glucocorticoids [224].”

What the sources say

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In the paper

“While the levels of 11-oxygenated androgens and their precursors have been shown to be significantly elevated in patients with polycystic ovary syndrome (PCOS) and 21-hydroxylase deficiency [41,69], one study reported that the circulating levels of 11KT were also higher than that of testosterone in a healthy female control group (BMI 21.2–26.1 kg/m2) [41].”

What the sources say

• Not checked yetcites [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

In the paper

“11KA4 is the next most abundant 11-oxygenated androgen precursor in circulation (Table 2) [39,41,68,69,289].”

What the sources say

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• Not checked yetcites [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
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In the paper

“Even 5β-DHT, the product of the 5β-reduction of testosterone, is an inactive androgen metabolite [54].”

What the sources say

• Not checked yetcites [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

In the paper

“Cortisol can also be 6β-hydroxylated by CYP3A4 expressed in the liver, resulting in 6β-hydroxycortisol (6β-OHF) [259,260].”

What the sources say

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In the paper

“The remaining 50% originates from the peripheral conversion of androgen precursors such as A4 to testosterone [[276], [277], [278]].”

What the sources say

• Not checked yetcites [276] Labrie F. Luu-The V. Labrie C. Bélanger A. Simard J. Lin S.-X.X. Pelletier G. Bélanger A. Simard J. Lin S.-X.X. Pelletier G. Bélanger A. Simard J. Lin S.-X.X. Pelletier G. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone Endocr. Rev. 24 2003 152 182 12700178 source
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In the paper

“They are particularly important in patients in glucocorticoid remediable aldosteronism or with aldosterone-producing adenomas associated with KCNJ5 mutations [261,[264], [265], [266], [267], [268], [269], [270], [271], [272]].”

What the sources say

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• Not checked yetcites [264] Lifton R.P. Dluhy R.G. Powers M. Rich G.M. Cook S. Ulick S. Lalouel J.-M. A chimaeric llβ-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension Nature 355 1992 262 265 1731223 source
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In the paper

“Nonetheless, it is clear that 11OHA4, the major 11-oxygenated androgen precursor produced by the adrenal, circulates at higher levels than A4.”

In the paper

“Undoubtedly, the most important step in androgen activation and inactivation is the 5α-/5β-reduction of the Δ4 steroid moiety common to all androgen precursors as well as the potent androgen testosterone (Fig. 8).”

In the paper

“Hydroxylation of the tetra- and hexahydro-metabolites of cortisol (e.g., THE and the cortolones) at 1β- and 6α-carbon position is quantitatively important in the neonatal period. [130].”

What the sources say

• Not checked yetcites [130] Shackleton C.H.L. Honour J.W. Taylor N.F. Metabolism of fetal and neonatal adrenal steroids J. Steroid Biochem. 11 1979 523 529 573819 source

In the paper

“Those androgens and precursors that escape the tissue specific activation via 5α-reduction are metabolized within the liver, which expresses both 5α- and 5β-reductases [54,94,100].”

What the sources say

• Not checked yetcites [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 yetcites [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
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In the paper

“Circulating DHEA is readily 16α-hydroxylated by CYP3A4/7 within the liver [136,299].”

What the sources say

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In the paper

“SULT1E1 is the major SULT for estrogen sulfation [328,329], while SULT1A1 and SULT1A3 also sulfate estrogens, but with a lower affinity [327].”

What the sources say

• Not checked yetcites [327] Wang L.-Q. James M.O. Sulfotransferase 2A1 forms estradiol-17-sulfate and celecoxib switches the dominant product from estradiol-3-sulfate to estradiol-17-sulfate J. Steroid Biochem. Mol. Biol. 96 2005 367 374 16011896 source

In the paper

“As a result, androgen metabolites are excreted with a 17-keto/17β-hydroxy ratio of approximately 10:1 [112].”

What the sources say

• Not checked yetcites [112] Shackleton C.H.L. Marcos P. GC/MS steroid profiling: diagnosis of disorders affecting steroid synthesis and metabolism Encycl. Mass Spectrom. 8 2011 789 813

In the paper

“Therefore, the primary urine androgen metabolites are androsterone (An; 5α-androstan-3α-ol-17-one) and etiocholanolone (Et; 5β-androstan-3α-ol-17-one) (Table 3).”

In the paper

“It should be noted that this peripheral estrogen production often functions in a paracrine and intracrine manner and as such circulating concentrations are not reflective of the concentrations achieved locally [304,305].”

What the sources say

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• Not checked yetcites [305] Labrie F. All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause J. Steroid Biochem. Mol. Biol. 145 2015 133 138 24923731 source

In the paper

“This peripheral production of estrogens is especially important in postmenopausal women and men [61].”

What the sources say

• Not checked yetcites [61] Labrie F. Intracrinology in action: importance of extragonadal sex steroid biosynthesis and inactivation in peripheral tissues in both women and men J. Steroid Biochem. Mol. Biol. 145 2015 131 132 25240498 source

In the paper

“Following 5α/5β-reduction, androgen metabolites are subject to reduction of the 3-keto group with predominant 3α-stereoselectivity [54].”

What the sources say

• Not checked yetcites [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

In the paper

“The majority of 5α/β-3α-metabolites of testosterone and DHT, which contain a 17β-hydroxy, are converted to 17-keto steroids by the action of the oxidative 17β-HSDs, HSD17B2 and HSD17B4 [106].”

What the sources say

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In the paper

“11OHA4 undergoes sequential 5α- and 3α- reduction yielding 11β-OHAn, which is readily quantifiable in urine (Table 3).”

In the paper

“Estrogens and catecholestrogens are efficiently sulfated at several positions [[325], [326], [327]].”

What the sources say

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• Not checked yetcites [327] Wang L.-Q. James M.O. Sulfotransferase 2A1 forms estradiol-17-sulfate and celecoxib switches the dominant product from estradiol-3-sulfate to estradiol-17-sulfate J. Steroid Biochem. Mol. Biol. 96 2005 367 374 16011896 source

In the paper

“UGT2B7 is the most efficient UGT for androstanediol conjugation [176].”

What the sources say

• Not checked yetcites [176] Turgeon D. Carrier J.-S. Lévesque É. Hum D.W. Bélanger A. Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members Endocrinology 142 2001 778 787 11159850 source

In the paper

“SULT1E1 is the major SULT for estrogen sulfation [328,329], while SULT1A1 and SULT1A3 also sulfate estrogens, but with a lower affinity [327].”

What the sources say

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In the paper

“The glucuronidation of C19 steroids is catalyzed by three members of the UGT2B subfamily, namely: UGT2B7, UGT2B15 and UGT2B17 [175].”

What the sources say

• Not checked yetcites [175] Bélanger A. Pelletier G. Labrie F. Barbier O. Chouinard S. Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans Trends Endocrinol. Metab. 14 2003 473 479 14643063 source

In the paper

“Progesterone metabolites reduced at 5α position are subject to extrahepatic 6α-hydroxylation, which is distinct from the hepatic 6α-hydroxylation active on Δ4 steroids [338].”

What the sources say

• Not checked yetcites [338] Chantilis S. Dombroski R. Shackleton C.H. Casey M.L. MacDonald P.C. Metabolism of 5 alpha-dihydroprogesterone in women and men: 3 beta- and 3 alpha-,6 alpha-dihydroxy-5 alpha-pregnan-20-ones are major urinary metabolites J. Clin. Endocrinol. Metab. 81 1996 3644 3649 8855816

In the paper

“Levels change substantially during the course of the menstrual cycle, peaking during the luteal phase (Table 3).”

In the paper

“As an example, this approach has been used for automating differentiation of adrenocortical carcinoma (ACC) from benign adrenocortical tumors based on the detection of a “malignant steroid fingerprint”, a distinct set of urine steroid metabolites characteristically increased in ACC [348].”

What the sources say

• Not checked yetcites [348] Arlt W. Biehl M. Taylor A.E. Hahner S. Libe R. Hughes B.A. Schneider P. Smith D.J. Stiekema H. Krone N. Libé R. Hughes B.A. Schneider P. Smith D.J. Stiekema H. Krone N. Porfiri E. Opocher G. Bertherat J. Mantero F. Allolio B. Terzolo M. Nightingale P. Shackleton C.H.L. Bertagna X. Fassnacht M. Stewart P.M. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors J. Clin. Endocrinol. Metab. 96 2011 3775 3784 21917861 PMC3232629 source

In the paper

“During the second and third trimesters of pregnancy placental trophoblasts produce large amounts of progesterone, which displaces glucocorticoids from CBG [287,335].”

What the sources say

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In the paper

“Progestogens are primarily metabolized by the liver largely to form pregnanediols and pregnanolones [336,337].”

What the sources say

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