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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“However, the majority of DHEA is efficiently sulfated by the major DHEA sulfotransferase (SULT2A1), which is abundantly expressed in the zona reticularis [40].”

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

In the paper

“Gonadal steroidogenesis is also active during ‘minipuberty’, a short period of hypothalamic-pituitary-gonadal axis activation during the neonatal period [24].”

What the sources say

• Not checked yetcites [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

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

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Some of the resulting DHEA is converted to androstenediol by AKR1C3, which exhibits minor expression in the zona reticularis [39].”

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

In the paper

“Androgens and estrogens provide negative feedback at the hypothalamus and pituitary level to suppress LH in men and women, respectively [23].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Progesterone is subsequently converted to 11-deoxycorticosterone (DOC) by CYP21A2, which is abundantly expressed in the ER of the zona glomerulosa [26,27].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

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

“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].”

What the sources say

• Not checked yetcites [14] Penning T.M. Molecular endocrinology of hydroxysteroid dehydrogenases Endocr. Rev. 18 1997 281 305 9183566

In the paper

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

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“A4 can serve as an additional substrate for AKR1C3, yielding testosterone [45].”

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

“CYP11A1 converts cholesterol to pregnenolone, followed by the HSD3B2-catalyzed conversion of pregnenolone to the Δ4 steroid, progesterone.”

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
• Not checked yetcites [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

In the paper

“HSD3B2 is present in both the mitochondria and ER of zona glomerulosa cells [25,26].”

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
• Not checked yetcites [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

In the paper

“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]].”

What the sources say

• Not checked yetcites [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 yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• 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
• Not checked yetcites [58] Chang K.H. Li R. Papari-zareei M. Watumull L. Zhao Y.D. Auchus R.J. Sharifi N. Daniel Y. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer Proc. Natl. Acad. Sci. U. S. A. 108 2011 13728 13733 /-/DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1107898108 21795608 PMC3158152 source

In the paper

“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].”

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 [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 yetcites [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

In the paper

“Indeed, androgen secretion by the theca cells surpasses the secretion of estrogens, while progesterone is the primary progestogen produced [85].”

What the sources say

• Not checked yetcites [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

In the paper

“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]].”

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 [59] Labrie F. Intracrinology Mol. Cell. Endocrinol. 78 1991 13 18 1838082 source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

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

“This reaches a minimum by the age of 70, with only about 5–10% of the peak levels observed in young adulthood [46].”

What the sources say

• Not checked yetcites [46] Papierska L. Adrenopause – does it really exist? Menopausal Rev. 2 2017 57 60 PMC5509973 28721131 source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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]].”

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 [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 yetcites [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

In the paper

“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].”

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

In the paper

“However, 11OHA4 is by far the predominant product due to the significantly higher levels of A4 produced in the zona reticularis [39].”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Testicular steroid output is predominantly testosterone, with lower levels of A4 and DHEA also being released into circulation [[51], [52], [53]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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]].”

What the sources say

• Not checked yetcites [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 yetcites [78] Mikhail G. Hormone secretion by the human ovaries Gynecol. Obstet. Invest. 1 1970 5 20 5481651 source
• Not checked yetcites [79] Baird D.T. The endocrinology of ovarian steroid secretion Eur. J. Obstet. Gynecol. Reprod. Biol. 1974 31 39 4607188 source

In the paper

“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].”

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

“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]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“AKR1C3 expression has been reported in Leydig cells and may also contribute to testosterone production [49,50].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“with its disruption leading to disordered sex development in 46,XY individuals [95]”

What the sources say

• Not checked yetcites [95] Wilson J.D. Griffin J.E. Russell D.W. Steroid 5 alpha-reductase 2 deficiency Endocr. Rev. 14 1993 577 593 8262007

In the paper

“only two of these, SRD5A1 and SRD5A2, function as genuine steroid 5α-reductases.”

In the paper

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

“SRD5A3 appears to have only minor steroid 5α-reductase activity”

In the paper

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

In the paper

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

In the paper

“the direct 20α-reduction of progesterone terminates its progestogenic activity”

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

“SRD5A2 is expressed mainly in male reproductive and genital tissues”

What the sources say

• Not checked yetcites [95] Wilson J.D. Griffin J.E. Russell D.W. Steroid 5 alpha-reductase 2 deficiency Endocr. Rev. 14 1993 577 593 8262007

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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)).”

What the sources say

• Not checked yetcites [92] Penning T.M. New frontiers in androgen biosynthesis and metabolism Curr. Opin. Endocrinol. Diab. Obes. 17 2010 233 239 PMC3206266 20186052 source

In the paper

“It is the only human enzyme catalyzing the 5β-reduction of 3-keto-Δ4 steroids and bile acids [100].”

What the sources say

• 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

“has been shown to play an important role in N-linked protein glycosylation [[96], [97], [98]]”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [97] Stiles A.R. Russell D.W. SRD5A3: a surprising role in glycosylation Cell 142 2010 196 198 20655462 PMC3104503 source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [114] Moeller G. Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases Mol. Cell. Endocrinol. 301 2009 7 19 19027824 source

In the paper

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

In the paper

“To date, 14 human enzymes with 17β-HSD/oxoreductase activities have been identified [105,106,113].”

What the sources say

• Not checked yetcites [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 yetcites [106] Moeller G. Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases Mol. Cell. Endocrinol. 301 2009 7 19 19027824 source
• Not checked yetcites [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

In the paper

“SRD5A1 is mainly expressed in the liver and peripheral tissues [94]”

What the sources say

• 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

In the paper

“mainly activating cortisone to cortisol [109]”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“This metabolism is traditionally divided into two sequential stages, namely phase 1 and phase 2 reactions [86].”

What the sources say

• Not checked yetcites [86] Williams R.T. Detoxication Mechanisms; the Metabolism and Detoxication of Drugs, Toxic Substances, and Other Organic Compounds 1959 Wiley New York

In the paper

“AKR1C1 is the most important isoform for the formation of the 3β-hydroxyepimer [102].”

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

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

In the paper

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

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

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

In the paper

“HSD11B2 functions exclusively as an oxidative enzyme, inactivating cortisol to cortisone [108].”

What the sources say

• Not checked yetcites [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

In the paper

“as colocalized hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH required for its cortisone reductase activity”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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]”

What the sources say

• Not checked yetcites [179] Axelrod J. Tomchick R. Enzymatic O-methylation of epinephrine and other catechols J Biol Chem. 233 1958 702 705 13575440 source

In the paper

“The hydroxylation by hepatic CYPs inactivates the steroids and increases their polarity and water solubility.”

In the paper

“with at least 17 hepatic CYPs potentially participating in the metabolism of steroids [[116], [117], [118]].”

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
• Not checked yetcites [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 yetcites [118] You L. Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes Chem. Biol. Interact. 147 2004 233 246 15135080 source

In the paper

“and differs from CYP3A4 in terms of expression and function.”

In the paper

“estrogens seem to undergo higher biliary excretion than other steroids, but also higher reabsorption leading to low fecal excretion [194,206].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“In terms of Δ5 steroids, e.g. DHEA, 16α-hydroxylation is the most frequent hydroxylation detected in adults followed by 7α-hydroxylation”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“CYP3A5 catalyzes a comparable range of reactions as CYP3A4”

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

“sulfation is reversible and unconjugated bioactive steroids can be regenerated from their sulfates by STS, which is ubiquitously expressed in all tissues [40].”

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

In the paper

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

In the paper

“steroid metabolism by gut bacteria has been shown to be influenced by the administration of antibiotics [157].”

What the sources say

• Not checked yetcites [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

In the paper

“CYP3A4 is the most abundant CYP expressed in the adult liver [121,122]”

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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“COMT methylates 2- and 4-hydroxyestrogens, thereby producing the so-called methoxyestrogens [180].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“The remaining cortisol is either bound to albumin (5–10%) or circulates in its free (active) form (<10%) [[245], [246], [247]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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)”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“though corticosterone’s MR-activating potency is considerably lower than that of aldosterone [219].”

What the sources say

• Not checked yetcites [219] Gomez-Sanchez E. Gomez-Sanchez C.E. The multifaceted mineralocorticoid receptor Compr. Physiol. 4 2014 965 994 24944027 PMC4521600 source

In the paper

“while 17OHP and cortisol can be either 5α- or 5β-reduced, 11-deoxycortisol and cortisone are predominantly 5β-reduced [108].”

What the sources say

• Not checked yetcites [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

In the paper

“aldosterone-18β-glucuronide and THAldo-glucuronides contribute 5–15% and 15–40% towards the daily urinary excretion of aldosterone [221,226].”

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
• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“The primary mineralocorticoid in circulation is aldosterone.”

In the paper

“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”

What the sources say

• Not checked yetcites [219] Gomez-Sanchez E. Gomez-Sanchez C.E. The multifaceted mineralocorticoid receptor Compr. Physiol. 4 2014 965 994 24944027 PMC4521600 source

In the paper

“The majority of cortisol circulates bound to proteins, with 80–90% bound to CBG.”

In the paper

“HSD11B1 expression is low/undetectable at birth, but thereafter increases rapidly, with adult levels reached after 6–12 months [237].”

What the sources say

• Not checked yetcites [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

In the paper

“which cannot activate the glucocorticoid receptor or the MR”

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

“While 5α-THF is also a substrate for this side-chain cleavage reaction, this reaction is catalyzed less efficiently [257].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

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

“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].”

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 [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 [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

In the paper

“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.”

In the paper

“SHBG binds sex steroids (including active androgens and estrogens) with high affinity (nanomolar ranges) and specificity [[285], [286], [287]].”

What the sources say

• Not checked yetcites [285] Anderson D.C. Sex‐hormone binding-globulin Clin. Endocrinol. (Oxf). 3 1974 69 96 4134992 source
• Not checked yetcites [286] Mendel C.M. The Free hormone hypothesis: a physiologically based mathematical model Endocr. Rev. 10 1989 232 274 2673754 source
• Not checked yetcites [287] Hammond G.L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action J. Endocrinol. 230 2016 R13 R25 27113851 PMC5064763 source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

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

In the paper

“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]].”

What the sources say

• Not checked yetcites [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 yetcites [280] Miller W.L. Steroidogenesis: unanswered questions Trends Endocrinol. Metab. 28 2017 771 793 29031608 source
• Not checked yetcites [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

In the paper

“These metabolites are often referred to as “hybrid steroids” as they require enzymatic machinery from both the glucocorticoid and mineralocorticoid pathways [[261], [262], [263]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

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
• Not checked yetcites [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 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
• Not checked yetcites [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

In the paper

“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).”

In the paper

“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.”

In the paper

“The primary estrogens in circulation are estrone, estrone sulfate and 17β-estradiol, with 17β-estradiol considered the biologically active form [82,[301], [302], [303]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [302] Simpson E.R. Sources of estrogen and their importance J. Steroid Biochem. Mol. Biol. 86 2003 225 230 14623515 source

In the paper

“Estrone undergoes 16α-hydroxylation and HSD17B1 catalyzed reduction, while 17β-estradiol only requires 16α-hydroxylation [[311], [312], [313], [314]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Estriol and 16α-hydroxyestrone are conjugated at the 3-hydroxygroup by UGT1A10 and at the 16α-hydroxy group by UGT2B7 [330,331].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“Circulating levels of estrogens vary greatly during the course of the menstrual cycle and decrease significantly in postmenopausal women (Table 3) [[306], [307], [308]].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Estriol is rapidly excreted in urine and, as a result, serum levels are low to undetectable [318].”

What the sources say

• Not checked yetcites [318] Henderson B.E. Ponder B.A.J. Ross R.K. Hormones, Genes, and Cancer 2003 Oxford University Press USA

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“SULT2A2 can target 3α- and 17β-hydroxyl groups and has been shown to sulfate An, testosterone and DHT [294,295].”

What the sources say

• Not checked yetcites [294] Strott C.A. Steroid sulfotransferases Endocr. Rev. 17 1996 670 697 8969973 source
• Not checked yetcites [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

In the paper

“In the liver approximately 80% of 17β-estradiol is hydroxylated to the 2 position and 20% at the 4 position [322].”

What the sources say

• Not checked yetcites [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

In the paper

“Conversely, CYP1A2 is the dominant enzyme catalyzing the 16α-hydroxylation of 17β-estradiol, with CYP3A4, CYP1A1 and CYP1B1 also demonstrating this activity [317].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

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 [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 yetcites [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

In the paper

“Like with androgens, the majority of unconjugated estrogen circulates bound to SHBG with high affinity and albumin with low affinity [[285], [286], [287]].”

What the sources say

• Not checked yetcites [285] Anderson D.C. Sex‐hormone binding-globulin Clin. Endocrinol. (Oxf). 3 1974 69 96 4134992 source
• Not checked yetcites [286] Mendel C.M. The Free hormone hypothesis: a physiologically based mathematical model Endocr. Rev. 10 1989 232 274 2673754 source
• Not checked yetcites [287] Hammond G.L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action J. Endocrinol. 230 2016 R13 R25 27113851 PMC5064763 source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• 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

“Low levels of circulating progesterone are also detectable in men [334].”

What the sources say

• Not checked yetcites [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

In the paper

“Catcholestrogens can additionally be glucuronidated in positions 2 and 4 [332].”

What the sources say

• Not checked yetcites [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

In the paper

“Indeed, there is a drive within the endocrine community to phase out immunoassays where possible [343].”

What the sources say

• Not checked yetcites [343] Auchus R.J. Steroid assays and endocrinology: Best practices for basic scientists Endocrinology 155 2014 2049 2051 24837046 PMC4020931 source

In the paper

“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].”

What the sources say

• Not checked yetcites [339] Shackleton C.H.L. Profiling steroid hormones and urinary steroids J Chromatogr. 379 1986 91 156 3525596 source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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