:11β-Hydroxyprogesterone

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| ImageFile1 = {{wikidata|property|raw|P117}}

| ImageSize1 = 220px

| ImageAlt1 = {{wikidata|qualifier|raw|P117|P2096}}

| IUPACName = 11β-Hydroxypregn-4-ene-3,20-dione

| SystematicName = (1S,3aS,3bS,9aR,9bS,10S,11aS)-1-Acetyl-10-hydroxy-9a,11a-dimethyl-1,2,3,3a,3b,4,5,8,9,9a,9b,10,11,11a-tetradecahydro-7H-cyclopenta[a]phenanthren-7-one

| OtherNames = 11β-OHP; 21-Deoxycorticosterone; 21-Desoxycorticosterone

| Section1 = {{Chembox Identifiers

| CASNo = 600-57-7

| ChEBI = 28247

| ChEMBL = 2440888

| ChemSpiderID = 91968

| InChI = 1S/C21H30O3/c1-12(22)16-6-7-17-15-5-4-13-10-14(23)8-9-20(13,2)19(15)18(24)11-21(16,17)3/h10,15-19,24H,4-9,11H2,1-3H3/t15-,16+,17-,18-,19+,20-,21+/m0/s1

| InChIKey = BFZHCUBIASXHPK-ATWVFEABSA-N

| KEGG = C05498

| PubChem = 101788

| SMILES = CC(=O)[C@H]1CC[C@@H]2[C@@]1(C[C@@H]([C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)O)C

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| Section2 = {{Chembox Properties

| C=21 | H=30 | O=3

| MolarMass = 330.468 g/mol

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| Section3 = {{Chembox Hazards

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11β-Hydroxyprogesterone (11β-OHP), also known as 21-deoxycorticosterone, as well as 11β-hydroxypregn-4-ene-3,20-dione, is a naturally occurring, endogenous steroid and derivative of progesterone.{{cite web|url=http://www.hmdb.ca/metabolites/HMDB04031|publisher=hmdb.ca|title=Human Metabolome Database: Showing metabocard for 11b-Hydroxyprogesterone (HMDB04031)|access-date=16 December 2016|archive-date=21 December 2016|archive-url=https://web.archive.org/web/20161221001304/http://www.hmdb.ca/metabolites/HMDB04031|url-status=live}} It is a potent mineralocorticoid. Syntheses of 11β-OHP from progesterone is catalyzed by the steroid 11β-hydroxylase (CYP11B1) enzyme,{{cite journal | vauthors = Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW | title = Structural insights into aldosterone synthase substrate specificity and targeted inhibition | journal = Molecular Endocrinology | volume = 27 | issue = 2 | pages = 315–24 | date = February 2013 | pmid = 23322723 | pmc = 5417327 | doi = 10.1210/me.2012-1287 }}{{cite journal | vauthors = van Rooyen D, Gent R, Barnard L, Swart AC | title = The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 178 | pages = 203–212 | date = April 2018 | pmid = 29277707 | doi = 10.1016/j.jsbmb.2017.12.014 | s2cid = 3700135 }} and, to a lesser extent, by the aldosterone synthase enzyme (CYP11B2).

Function

Along with its epimer 11α-hydroxyprogesterone (11α-OHP), 11β-OHP has been identified as a very potent competitive inhibitor of both isoforms (1 and 2) of 11β-hydroxysteroid dehydrogenase (11β-HSD).{{cite journal | vauthors = Souness GW, Latif SA, Laurenzo JL, Morris DJ | title = 11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase (isoforms 1 and 2), confer marked mineralocorticoid activity on corticosterone in the ADX rat | journal = Endocrinology | volume = 136 | issue = 4 | pages = 1809–12 | date = April 1995 | pmid = 7895695 | doi = 10.1210/endo.136.4.7895695 }}{{cite journal | vauthors = Souness GW, Morris DJ | title = 11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat | journal = Hypertension | volume = 27 | issue = 3 Pt 1 | pages = 421–5 | date = March 1996 | pmid = 8698448 | doi = 10.1161/01.hyp.27.3.421 }}

Outcome of 21-hydroxylase deficiency

It has been known since 1987 that increased levels of 11β-OHP occur in 21-hydroxylase deficiency.{{cite journal | vauthors = Gueux B, Fiet J, Galons H, Boneté R, Villette JM, Vexiau P, Pham-Huu-Trung MT, Raux-Eurin MC, Gourmelen M, Brérault JL | display-authors = 6 | title = The measurement of 11 beta-hydroxy-4-pregnene-3,20-dione (21-deoxycorticosterone) by radioimmunoassay in human plasma | journal = Journal of Steroid Biochemistry | volume = 26 | issue = 1 | pages = 145–50 | date = January 1987 | pmid = 3546944 | doi = 10.1016/0022-4731(87)90043-4 | department = primary }}{{cite journal | vauthors = Fiet J, Gueux B, Raux-DeMay MC, Kuttenn F, Vexiau P, Brerault JL, Couillin P, Galons H, Villette JM, Julien R | display-authors = 6 | title = Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 68 | issue = 3 | pages = 542–7 | date = March 1989 | pmid = 2537337 | doi = 10.1210/jcem-68-3-542 | department = primary }} A study in 2017 has shown that in subjects with 21-hydroxylase deficiency, serum 11β-OHP concentrations range from 0.012 to 3.37 ng/mL, while in control group it was below detection limit of 0.012 ng/mL.{{cite journal | vauthors = Fiet J, Le Bouc Y, Guéchot J, Hélin N, Maubert MA, Farabos D, Lamazière A | title = A Liquid Chromatography/Tandem Mass Spectometry [sic] Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia | journal = Journal of the Endocrine Society | volume = 1 | issue = 3 | pages = 186–201 | date = March 2017 | pmid = 29264476 | pmc = 5686660 | doi = 10.1210/js.2016-1048 | department = primary }} 21-hydroxylase is an enzyme that is also involved in progesterone metabolism, producing 11-deoxycorticosterone. In normal conditions, 21-hydroxylase has higher activity on progesterone than steroid 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) that convert progesterone to 11β-OHP.{{verify source|date=November 2020}} That's why in 21-hydroxylase deficiency, given the normal function of the CYP11B enzymes, the progesterone is directed towards 11β-OHP pathway rather than towards 11-deoxycorticosterone pathway, that is also usually accompanied by an increase in progesterone levels.{{cite journal | vauthors = Nie M, Cui MX, Mao JF, Tong AL, Chen S, Wang X, Lu L, Wu XY | display-authors = 6 | title = [Possibility of progesterone as the diagnostic biomarker of 21-hydroxylase deficiency] | journal = Zhonghua Yi Xue Za Zhi | volume = 96 | issue = 48 | pages = 3866–3869 | date = December 2016 | pmid = 28057154 | doi = 10.3760/cma.j.issn.0376-2491.2016.48.003 }} In the normal route to aldosterone and cortisol, progesterone and 17α-hydroxyprogesterone are first hydroxylated at position 21 and then hydroxylated at other positions. In 21-hydroxylase deficiency, progesterone and 17α-hydroxyprogesterone accumulate and are the substrates of steroid 11β-hydroxylase, leading to 1β-OHP and 21-deoxycortisol, respectively.{{cite journal | vauthors = Turcu AF, Auchus RJ | title = Adrenal steroidogenesis and congenital adrenal hyperplasia | journal = Endocrinology and Metabolism Clinics of North America | volume = 44 | issue = 2 | pages = 275–96 | date = June 2015 | pmid = 26038201 | pmc = 4506691 | doi = 10.1016/j.ecl.2015.02.002 }} In the 2017 study mentioned above, serum progesterone concentrations in boys (10 days to 18 years old) with 21-hydroxylase deficiency reached levels similar to female luteal values (up to 10.14 ng/mL, depending on severity and treatment), while in the control group of boys progesterone was 0.07 ng/mL (0.22 nmol/L) on average, ranged from 0.05 to 0.40 ng/mL.

In a 2016 study, classical CAH patients receiving glucocorticoid therapy had C₁₉ 11-oxygenated steroid serum levels that were elevated 3-4 fold compared to healthy controls.{{cite journal|vauthors=Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano TJ, Shields JJ, Merke DP, Rainey WE, Auchus RJ |year=2016|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency|journal=Eur J Endocrinol|volume=174|issue=5|pages=601–9|doi=10.1530/EJE-15-1181|pmc=4874183|pmid=26865584}} In that same study, the levels of C₁₉ 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were four times higher than that of T in women with the condition. In adult women with CAH, the ratio of DHT produced in a backdoor pathway to that produced in a conventional pathway increases as control of androgen excess by glucocorticoid therapy deteriorates.{{cite journal |title=Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency |journal=J Clin Endocrinol Metab |volume=99 |issue=8 |pages=2763–70 |year=2014 |pmid=24780050 |pmc=4121028 |doi=10.1210/jc.2014-1258 |vauthors=Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK}} In CAH patients with poor disease control, 11-oxygenated androgens remain elevated for longer than 17OHP, thus serving as a better biomarker for the effectiveness of the disease control.{{cite journal|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free|vauthors=Turcu AF, Mallappa A, Nella AA, Chen X, Zhao L, Nanba AT, Byrd JB, Auchus RJ, Merke DP}}{{cite journal|title=11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=102|issue=8|pages=2701–2710|doi=10.1210/jc.2016-3989|pmc=5546849|pmid=28472487|vauthors=Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, Tsodikov A, Auchus RJ, Merke DP|date=2017 }} In males with CAH, 11-oxygenated androgen levels may indicate the presence testicular adrenal rest tumors.{{cite journal|vauthors=((Schröder MAM)), Turcu AF, O'Day P, van Herwaarden AE, Span PN, Auchus RJ, Sweep FC, Claahsen-van der Grinten HL|year=2022|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors|journal=J Clin Endocrinol Metab|volume=107|issue=1|pages=e272–e280|doi=10.1210/clinem/dgab598|pmc=8684463|pmid=34390337}}{{cite journal|doi=10.15347/WJM/2023.003 |doi-access=free|title=Alternative androgen pathways |year=2023 | vauthors = Masiutin M, Yadav M |journal=WikiJournal of Medicine |volume=10 |pages=29 |s2cid=257943362 |url=https://upload.wikimedia.org/wikiversity/en/a/a7/Alternative_androgens_pathways.pdf}}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}

While studies suggest that 11β-OHP, also known as 21-deoxycorticosterone, can be used as marker for adrenal 21-hydroxylase deficiency, another 21-carbon steroid — 21-deoxycortisol (produced from 17α-hydroxyprogesterone) gained acceptance for this purpose.{{cite journal |vauthors=Greaves RF, Kumar M, Mawad N, Francescon A, Le C, O'Connell M, Chi J, Pitt J |title=Best Practice for Identification of Classical 21-Hydroxylase Deficiency Should Include 21 Deoxycortisol Analysis with Appropriate Isomeric Steroid Separation |journal=Int J Neonatal Screen |volume=9 |issue=4 |date=October 2023 |page=58 |pmid=37873849 |pmc=10594498 |doi=10.3390/ijns9040058 |url= |doi-access=free }}{{cite journal | vauthors = Cristoni S, Cuccato D, Sciannamblo M, Bernardi LR, Biunno I, Gerthoux P, Russo G, Weber G, Mora S | display-authors = 6 | title = Analysis of 21-deoxycortisol, a marker of congenital adrenal hyperplasia, in blood by atmospheric pressure chemical ionization and electrospray ionization using multiple reaction monitoring | journal = Rapid Communications in Mass Spectrometry | volume = 18 | issue = 1 | pages = 77–82 | year = 2004 | pmid = 14689562 | doi = 10.1002/rcm.1284 | bibcode = 2004RCMS...18...77C | department = primary }}{{cite journal | vauthors = Sarathi V, Atluri S, Pradeep TV, Rallapalli SS, Rakesh CV, Sunanda T, Kumar KD | title = Utility of a Commercially Available Blood Steroid Profile in Endocrine Practice | journal = Indian Journal of Endocrinology and Metabolism | volume = 23 | issue = 1 | pages = 97–101 | year = 2019 | pmid = 31016162 | pmc = 6446682 | doi = 10.4103/ijem.IJEM_531_18 | department = primary | doi-access = free }}