11β-Hydroxyprogesterone explained

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.[1] It is a potent mineralocorticoid. Syntheses of 11β-OHP from progesterone is catalyzed by the steroid 11β-hydroxylase (CYP11B1) enzyme,[2] [3] and, to a lesser extent, by the aldosterone synthase enzyme (CYP11B2).[2]

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).[4] [5]

Outcome of 21-hydroxylase deficiency

It has been known since 1987 that increased levels of 11β-OHP occur in 21-hydroxylase deficiency.[6] [7] 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.[8] 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. 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.[9] 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.[10] 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.[8]

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.[11] 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.[12] 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.[13] [14] In males with CAH, 11-oxygenated androgen levels may indicate the presence testicular adrenal rest tumors.[15] [16]

While studies suggest that 11β-OHP, also known as 21-deoxycorticosterone, can be used as marker for adrenal 21-hydroxylase deficiency,[6] another 21-carbon steroid — 21-deoxycortisol (produced from 17α-hydroxyprogesterone) gained acceptance for this purpose.[17] [18] [19]

See also

External links

Notes and References

  1. Web site: Human Metabolome Database: Showing metabocard for 11b-Hydroxyprogesterone (HMDB04031). hmdb.ca. 16 December 2016. 21 December 2016. https://web.archive.org/web/20161221001304/http://www.hmdb.ca/metabolites/HMDB04031. live.
  2. Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW . Structural insights into aldosterone synthase substrate specificity and targeted inhibition . Molecular Endocrinology . 27 . 2 . 315–24 . February 2013 . 23322723 . 5417327 . 10.1210/me.2012-1287 .
  3. van Rooyen D, Gent R, Barnard L, Swart AC . The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway . The Journal of Steroid Biochemistry and Molecular Biology . 178 . 203–212 . April 2018 . 29277707 . 10.1016/j.jsbmb.2017.12.014 . 3700135 .
  4. Souness GW, Latif SA, Laurenzo JL, Morris DJ . 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 . Endocrinology . 136 . 4 . 1809–12 . April 1995 . 7895695 . 10.1210/endo.136.4.7895695 .
  5. Souness GW, Morris DJ . 11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat . Hypertension . 27 . 3 Pt 1 . 421–5 . March 1996 . 8698448 . 10.1161/01.hyp.27.3.421 .
  6. Gueux B, Fiet J, Galons H, Boneté R, Villette JM, Vexiau P, Pham-Huu-Trung MT, Raux-Eurin MC, Gourmelen M, Brérault JL . 6 . The measurement of 11 beta-hydroxy-4-pregnene-3,20-dione (21-deoxycorticosterone) by radioimmunoassay in human plasma . Journal of Steroid Biochemistry . 26 . 1 . 145–50 . January 1987 . 3546944 . 10.1016/0022-4731(87)90043-4 . primary .
  7. Fiet J, Gueux B, Raux-DeMay MC, Kuttenn F, Vexiau P, Brerault JL, Couillin P, Galons H, Villette JM, Julien R . 6 . Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway . The Journal of Clinical Endocrinology and Metabolism . 68 . 3 . 542–7 . March 1989 . 2537337 . 10.1210/jcem-68-3-542 . primary .
  8. Fiet J, Le Bouc Y, Guéchot J, Hélin N, Maubert MA, Farabos D, Lamazière A . 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 of the Endocrine Society . 1 . 3 . 186–201 . March 2017 . 29264476 . 5686660 . 10.1210/js.2016-1048 . primary .
  9. Nie M, Cui MX, Mao JF, Tong AL, Chen S, Wang X, Lu L, Wu XY . 6 . [Possibility of progesterone as the diagnostic biomarker of 21-hydroxylase deficiency] . Zhonghua Yi Xue Za Zhi . 96 . 48 . 3866–3869 . December 2016 . 28057154 . 10.3760/cma.j.issn.0376-2491.2016.48.003 .
  10. Turcu AF, Auchus RJ . Adrenal steroidogenesis and congenital adrenal hyperplasia . Endocrinology and Metabolism Clinics of North America . 44 . 2 . 275–96 . June 2015 . 26038201 . 4506691 . 10.1016/j.ecl.2015.02.002 .
  11. Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano TJ, Shields JJ, Merke DP, Rainey WE, Auchus RJ . 2016. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol. 174. 5. 601–9. 10.1530/EJE-15-1181. 4874183. 26865584.
  12. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency . J Clin Endocrinol Metab . 99 . 8 . 2763–70 . 2014 . 24780050 . 4121028 . 10.1210/jc.2014-1258 . Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK.
  13. 2021. 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne). 12. 751191. 10.3389/fendo.2021.751191. 8636728. 34867794. free. Turcu AF, Mallappa A, Nella AA, Chen X, Zhao L, Nanba AT, Byrd JB, Auchus RJ, Merke DP.
  14. 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency. The Journal of Clinical Endocrinology and Metabolism. 102. 8. 2701–2710. 10.1210/jc.2016-3989. 5546849. 28472487. Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, Tsodikov A, Auchus RJ, Merke DP. 2017 .
  15. ((Schröder MAM)), Turcu AF, O'Day P, van Herwaarden AE, Span PN, Auchus RJ, ((Sweep FCGJ)), Claahsen-van der Grinten HL. 2022. Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors. J Clin Endocrinol Metab. 107. 1. e272–e280. 10.1210/clinem/dgab598. 8684463. 34390337.
  16. 10.15347/WJM/2023.003 . free. Alternative androgen pathways . 2023 . Masiutin M, Yadav M . WikiJournal of Medicine . 10 . 29 . 257943362 .
  17. Greaves RF, Kumar M, Mawad N, Francescon A, Le C, O'Connell M, Chi J, Pitt J . Best Practice for Identification of Classical 21-Hydroxylase Deficiency Should Include 21 Deoxycortisol Analysis with Appropriate Isomeric Steroid Separation . Int J Neonatal Screen . 9 . 4 . October 2023 . 58 . 37873849 . 10594498 . 10.3390/ijns9040058 . free .
  18. Cristoni S, Cuccato D, Sciannamblo M, Bernardi LR, Biunno I, Gerthoux P, Russo G, Weber G, Mora S . 6 . Analysis of 21-deoxycortisol, a marker of congenital adrenal hyperplasia, in blood by atmospheric pressure chemical ionization and electrospray ionization using multiple reaction monitoring . Rapid Communications in Mass Spectrometry . 18 . 1 . 77–82 . 2004 . 14689562 . 10.1002/rcm.1284 . 2004RCMS...18...77C . primary .
  19. Sarathi V, Atluri S, Pradeep TV, Rallapalli SS, Rakesh CV, Sunanda T, Kumar KD . Utility of a Commercially Available Blood Steroid Profile in Endocrine Practice . Indian Journal of Endocrinology and Metabolism . 23 . 1 . 97–101 . 2019 . 31016162 . 6446682 . 10.4103/ijem.IJEM_531_18 . primary . free .

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