11β-Hydroxyprogesterone

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11β-Hydroxyprogesterone
11b-Hydroxyprogesterone.svg
Names
IUPAC name
11β-Hydroxypregn-4-ene-3,20-dione
Systematic IUPAC name
(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
Other names
11β-OHP; 21-Deoxycorticosterone; 21-Desoxycorticosterone
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.009.088 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
  • 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
    Key: BFZHCUBIASXHPK-ATWVFEABSA-N
  • 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
Properties
C21H30O3
Molar mass 330.468 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. [1] 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.[ verification needed ] 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. [14] [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

Related Research Articles

<span class="mw-page-title-main">Progestogen</span> Steroid hormone that activates the progesterone receptor

Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. The progestogens are named for their function in maintaining pregnancy, although they are also present at other phases of the estrous and menstrual cycles.

<span class="mw-page-title-main">Adrenal cortex</span> Cortex of the adrenal gland

The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is also a secondary site of androgen synthesis.

<span class="mw-page-title-main">Congenital adrenal hyperplasia</span> Medical condition

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. It is one of the most common autosomal recessive disorders in humans.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene CYP17A1, which produces the enzyme 17α-hydroxylase. It causes decreased synthesis of cortisol and sex hormones, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild cortisol deficiency, ambiguous genitalia in men or amenorrhea at puberty in women, and hypokalemic hypertension. However, partial (incomplete) deficiency often has inconsistent symptoms between patients, and affected women may be asymptomatic except for infertility.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 21-hydroxylase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.

<span class="mw-page-title-main">17α-Hydroxyprogesterone</span> Chemical compound

17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many other endogenous steroids, including androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as neurosteroids.

<span class="mw-page-title-main">Aldosterone synthase</span> Protein-coding gene in the species Homo sapiens

Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone and other steroids. The enzyme catalyzes sequential hydroxylations of the steroid angular methyl group at C18 after initial 11β-hydroxylation. It is encoded by the CYP11B2 gene in humans.

<span class="mw-page-title-main">21-Hydroxylase</span> Human enzyme that hydroxylates steroids

Steroid 21-hydroxylase is a protein that in humans is encoded by the CYP21A2 gene. The protein is an enzyme that hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on the substrate acted upon and the chemical process performed. Biochemically, this enzyme is involved in the biosynthesis of the adrenal gland hormones aldosterone and cortisol, which are important in blood pressure regulation, sodium homeostasis and blood sugar control. The enzyme converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively, within metabolic pathways which in humans ultimately lead to aldosterone and cortisol creation—deficiency in the enzyme may cause congenital adrenal hyperplasia.

<span class="mw-page-title-main">Steroid 11β-hydroxylase</span> Protein found in mammals

Steroid 11β-hydroxylase, also known as steroid 11β-monooxygenase, is a steroid hydroxylase found in the zona glomerulosa and zona fasciculata of the adrenal cortex. Named officially the cytochrome P450 11B1, mitochondrial, it is a protein that in humans is encoded by the CYP11B1 gene. The enzyme is involved in the biosynthesis of adrenal corticosteroids by catalyzing the addition of hydroxyl groups during oxidation reactions.

<span class="mw-page-title-main">11-Deoxycortisol</span> Chemical compound

11-Deoxycortisol, also known as cortodoxone (INN), cortexolone as well as 17α,21-dihydroxyprogesterone or 17α,21-dihydroxypregn-4-ene-3,20-dione, is an endogenous glucocorticoid steroid hormone, and a metabolic intermediate toward cortisol. It was first described by Tadeusz Reichstein in 1938 as Substance S, thus has also been referred to as Reichstein's Substance S or Compound S.

<span class="mw-page-title-main">Isolated 17,20-lyase deficiency</span> Medical condition

Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare endocrine and autosomal recessive genetic disorder which is characterized by a complete or partial loss of 17,20-lyase activity and, in turn, impaired production of the androgen and estrogen sex steroids. The condition manifests itself as pseudohermaphroditism in males, in whom it is considered to be a form of intersex, and, in both sexes, as a reduced or absent puberty/lack of development of secondary sexual characteristics, resulting in a somewhat childlike appearance in adulthood.

<span class="mw-page-title-main">Inborn errors of steroid metabolism</span> Medical condition

An inborn error of steroid metabolism is an inborn error of metabolism due to defects in steroid metabolism.

<span class="mw-page-title-main">21-Deoxycortisol</span> Chemical compound

21-Deoxycortisol, also known as 11β,17α-dihydroxyprogesterone or as 11β,17α-dihydroxypregn-4-ene-3,20-dione, is a naturally occurring, endogenous steroid related to cortisol (11β,17α,21-trihydroxyprogesterone) which is formed as a metabolite from 17α-hydroxyprogesterone via 11β-hydroxylase.

<span class="mw-page-title-main">21-Deoxycortisone</span> Chemical compound

21-Deoxycortisone, also known as 21-desoxycortisone, 11-keto-17α-hydroxyprogesterone, or 17α-hydroxypregn-4-ene-3,11,20-trione, is a naturally occurring, endogenous steroid and minor intermediate and metabolite in corticosteroid metabolism. It is related to 21-deoxycortisol (11β,17α-dihydroxyprogesterone) and is reversibly formed from it by 11β-hydroxysteroid dehydrogenase, analogously to the reversible formation of cortisone from cortisol. 21-Deoxycortisone can be transformed into cortisone by 21-hydroxylase.

Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia, is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.

<span class="mw-page-title-main">Androgen backdoor pathway</span> Series of interconnected biochemical reactions

The androgen backdoor pathway synthesizes physiologically relevant androgens from 21-carbon steroids (pregnanes) via 5α-reduction, bypassing testosterone. This differs from the conventional, canonical androgenic pathway, which involves testosterone.

<span class="mw-page-title-main">5α-Pregnan-17α-ol-3,20-dione</span> Chemical compound

5α-Pregnan-17α-ol-3,20-dione, also known as 17α-hydroxy-dihydroprogesterone (17‐OH-DHP) is an endogenous steroid, a metabolite of 17α-hydroxyprogesterone.

<span class="mw-page-title-main">5α-Pregnane-3α,17α-diol-20-one</span> Chemical compound

5α-Pregnane-3α,17α-diol-20-one, also known as 17α-hydroxyallopregnanolone (17-OH-allo) is an endogenous steroid.

<span class="mw-page-title-main">11-Ketoandrosterone</span> Chemical compound

11-Ketoandrosterone is an endogenous steroid.

<span class="mw-page-title-main">5α-Pregnane-3α,11β-diol-20-one</span> Chemical compound

5α-Pregnane-3α,11β-diol-20-one, abbreviated as 3,11diOH-DHP4, also known as 3α,11β-dihydroxy-5α-pregnan-20-one, is an endogenous steroid.

References

  1. 1 2 "Human Metabolome Database: Showing metabocard for 11b-Hydroxyprogesterone (HMDB04031)". hmdb.ca. Archived from the original on 21 December 2016. Retrieved 16 December 2016.
  2. 1 2 Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW (February 2013). "Structural insights into aldosterone synthase substrate specificity and targeted inhibition". Molecular Endocrinology. 27 (2): 315–24. doi:10.1210/me.2012-1287. PMC   5417327 . PMID   23322723.
  3. ↑ van Rooyen D, Gent R, Barnard L, Swart AC (April 2018). "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. doi:10.1016/j.jsbmb.2017.12.014. PMID   29277707. S2CID   3700135.
  4. ↑ Souness GW, Latif SA, Laurenzo JL, Morris DJ (April 1995). "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. doi:10.1210/endo.136.4.7895695. PMID   7895695.
  5. ↑ Souness GW, Morris DJ (March 1996). "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. doi:10.1161/01.hyp.27.3.421. PMID   8698448.
  6. 1 2 Gueux B, Fiet J, Galons H, Boneté R, Villette JM, Vexiau P, et al. (January 1987). "The measurement of 11 beta-hydroxy-4-pregnene-3,20-dione (21-deoxycorticosterone) by radioimmunoassay in human plasma". primary. Journal of Steroid Biochemistry. 26 (1): 145–50. doi:10.1016/0022-4731(87)90043-4. PMID   3546944.
  7. ↑ Fiet J, Gueux B, Raux-DeMay MC, Kuttenn F, Vexiau P, Brerault JL, et al. (March 1989). "Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway". primary. The Journal of Clinical Endocrinology and Metabolism. 68 (3): 542–7. doi:10.1210/jcem-68-3-542. PMID   2537337.
  8. 1 2 Fiet J, Le Bouc Y, Guéchot J, Hélin N, Maubert MA, Farabos D, Lamazière A (March 2017). "A Liquid Chromatography/Tandem Mass Spectometry [sic] Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia". primary. Journal of the Endocrine Society. 1 (3): 186–201. doi:10.1210/js.2016-1048. PMC   5686660 . PMID   29264476.
  9. ↑ Nie M, Cui MX, Mao JF, Tong AL, Chen S, Wang X, et al. (December 2016). "[Possibility of progesterone as the diagnostic biomarker of 21-hydroxylase deficiency]". Zhonghua Yi Xue Za Zhi. 96 (48): 3866–3869. doi:10.3760/cma.j.issn.0376-2491.2016.48.003. PMID   28057154.
  10. ↑ Turcu AF, Auchus RJ (June 2015). "Adrenal steroidogenesis and congenital adrenal hyperplasia". Endocrinology and Metabolism Clinics of North America. 44 (2): 275–96. doi:10.1016/j.ecl.2015.02.002. PMC   4506691 . PMID   26038201.
  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. doi:10.1530/EJE-15-1181. PMC   4874183 . PMID   26865584.
  12. ↑ Auchus RJ, Buschur EO, Chang AY, Hammer GD, Ramm C, Madrigal D, Wang G, Gonzalez M, Xu XS, Smit JW, Jiao J, Yu MK (2014). "Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency". J Clin Endocrinol Metab. 99 (8): 2763–70. doi:10.1210/jc.2014-1258. PMC   4121028 . PMID   24780050.
  13. ↑ Turcu AF, Mallappa A, Nella AA, Chen X, Zhao L, Nanba AT, Byrd JB, Auchus RJ, Merke DP (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. doi: 10.3389/fendo.2021.751191 . PMC   8636728 . PMID   34867794.
  14. 1 2 Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, Tsodikov A, Auchus RJ, Merke DP (2017). "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. doi:10.1210/jc.2016-3989. PMC   5546849 . PMID   28472487.
  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. doi:10.1210/clinem/dgab598. PMC   8684463 . PMID   34390337.
  16. ↑ Masiutin M, Yadav M (2023). "Alternative androgen pathways" (PDF). WikiJournal of Medicine. 10: 29. doi: 10.15347/WJM/2023.003 . S2CID   257943362. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  17. ↑ Greaves RF, Kumar M, Mawad N, Francescon A, Le C, O'Connell M, Chi J, Pitt J (October 2023). "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): 58. doi: 10.3390/ijns9040058 . PMC   10594498 . PMID   37873849.
  18. ↑ Cristoni S, Cuccato D, Sciannamblo M, Bernardi LR, Biunno I, Gerthoux P, et al. (2004). "Analysis of 21-deoxycortisol, a marker of congenital adrenal hyperplasia, in blood by atmospheric pressure chemical ionization and electrospray ionization using multiple reaction monitoring". primary. Rapid Communications in Mass Spectrometry. 18 (1): 77–82. Bibcode:2004RCMS...18...77C. doi:10.1002/rcm.1284. PMID   14689562.
  19. ↑ Sarathi V, Atluri S, Pradeep TV, Rallapalli SS, Rakesh CV, Sunanda T, Kumar KD (2019). "Utility of a Commercially Available Blood Steroid Profile in Endocrine Practice". primary. Indian Journal of Endocrinology and Metabolism. 23 (1): 97–101. doi: 10.4103/ijem.IJEM_531_18 . PMC   6446682 . PMID   31016162.
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