5α-Pregnan-17α-ol-3,20-dione

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5α-Pregnan-17α-ol-3,20-dione
5-alpha-Pregnan-17-alpha-ol-3 20-dione.svg
Names
IUPAC name
17α-Hydroxy-5α-pregnane-3,20-dione [1] [2]
Systematic IUPAC name
(1R,3aS,3bR,5aS,9aS,9bS,11aS)-1-Acetyl-1-hydroxy-9a,11a-dimethylhexadecahydro-7H-cyclopenta[a]phenanthren-7-one
Other names
5α-17-Hydroxypregnane-3,20-dione, [3] 17‐OH-DHP, [4] 5α-Pregnane-17α-ol-3,20-dione, [4] 17-Hydroxydihydroprogesterone, [5] 17α-hydroxy-dihydroprogesterone [6]
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
  • Key: UUOHXXXJRQGPLC-JJFNZWTKSA-N
  • InChI=1S/C21H32O3/c1-13(22)21(24)11-8-18-16-5-4-14-12-15(23)6-9-19(14,2)17(16)7-10-20(18,21)3/h14,16-18,24H,4-12H2,1-3H3/t14-,16+,17-,18-,19-,20-,21-/m0/s1
  • CC(=O)[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CCC(=O)C4)C)C)O
Properties
C21H32O3
Molar mass 332.484 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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.

Function

The androgen backdoor pathway (red arrows) roundabout testosterone embedded in within conventional androgen synthesis that lead to 5a-dihydrotestosterone through testosterone. Androgen backdoor pathway.svg
The androgen backdoor pathway (red arrows) roundabout testosterone embedded in within conventional androgen synthesis that lead to 5α-dihydrotestosterone through testosterone.

5α-Pregnan-17α-ol-3,20-dione (17‐OH-DHP) is a progestogen, i.e., it binds to the progesterone receptors. However, 17‐OH-DHP is better studied as a metabolic intermediate than a progestogen per se.

17‐OH-DHP is the first intermediate product within the androgen backdoor pathway [7] in which 17α-hydroxyprogesterone (17‐OHP) is 5α-reduced and finally converted to 5α-dihydrotestosterone (DHT) without testosterone intermediate. The subsequent intermediate products in the pathway are 5α-pregnane-3α,17α-diol-20-one, androsterone and 5α-androstane-3α,17β-diol. [9] [10] The primary feature of the androgen backdoor pathway is that 17α-hydroxyprogesterone (17-OHP) can be 5α-reduced and finally converted to 5α-dihydrotestosterone (DHT) via an alternative route that bypasses the conventional [11] intermediates androstenedione and testosterone. [12] [13]

Biosynthesis

5α-Pregnan-17α-ol-3,20-dione is produced by 5α-reduction of 17-OHP. The reaction is catalyzed by SRD5A1 [14] and possibly, SRD5A2 enzymes. [7] While the role of the SRD5A1 enzyme in this reaction is well established, it is unclear whether SRD5A2 is also involved. [13] Some authors [4] [14] claim that the reduction of 17-OHP to 17OHDHP by SRD5A1 is not "sufficient" or "efficient", as supported by measurements of rat SRD5A2 activity in a 1971 study. [15] In a later study, conducted in 2017, however, it has been shown that recombinant human SRD5A1 and SRD5A2 can catalyze the reduction of 17-OHP at comparable rates to the reduction of progesterone. [16] Given both isozymes may be expressed in fetal tissues of both sexes, [17] [18] the action of SRD5A2 in this reaction in humans is yet to be established. [7]

See also

Related Research Articles

<span class="mw-page-title-main">Steroid</span> Polycyclic organic compound having sterane as a core structure

A steroid is an organic compound with four fused rings arranged in a specific molecular configuration.

<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">Dihydrotestosterone</span> Human hormone

Dihydrotestosterone is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production of sebum and body hair composition.

5α-Reductase Enzyme family

5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of 5α-reductase encoded by the genes SRD5A1, SRD5A2, and SRD5A3.

<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">Allopregnanolone</span> Endogenous inhibitory neurosteroid

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.

<span class="mw-page-title-main">SRD5A2</span> Protein-coding gene in the species Homo sapiens

The human gene SRD5A2 encodes the 3-oxo-5α-steroid 4-dehydrogenase 2 enzyme, also known as 5α-reductase type 2 (5αR2), one of three isozymes of 5α-reductase.

<span class="mw-page-title-main">SRD5A1</span> Protein-coding gene in the species Homo sapiens

3-Oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene. It is one of three forms of steroid 5α-reductase.

<span class="mw-page-title-main">3α-Androstanediol</span> Chemical compound

3α-Androstanediol also known as 5α-androstane-3α,17β-diol and sometimes shortened in the literature to 3α-diol, is an endogenous steroid hormone and neurosteroid and a metabolite of androgens like dihydrotestosterone (DHT).

<span class="mw-page-title-main">3β-Androstanediol</span> Chemical compound

3β-Androstanediol, also known as 5α-androstane-3β,17β-diol, and sometimes shortened in the literature to 3β-diol, is an endogenous steroid hormone and a metabolite of androgens like dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT).

<span class="mw-page-title-main">20α-Dihydroprogesterone</span> Chemical compound

20α-Dihydroprogesterone (20α-DHP), also known as 20α-hydroxyprogesterone (20α-OHP), is a naturally occurring, endogenous progestogen. It is a metabolite of progesterone, formed by the 20α-hydroxysteroid dehydrogenases (20α-HSDs) AKR1C1, AKR1C2, and AKR1C3 and the 17β-hydroxysteroid dehydrogenase (17β-HSD) HSD17B1. 20α-DHP can be transformed back into progesterone by 20α-HSDs and by the 17β-HSD HSD17B2. HSD17B2 is expressed in the human endometrium and cervix among other tissues. In animal studies, 20α-DHP has been found to be selectively taken up into and retained in target tissues such as the uterus, brain, and skeletal muscle.

<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">11β-Hydroxyprogesterone</span> Chemical compound

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

<span class="mw-page-title-main">16α-Hydroxyprogesterone</span> Chemical compound

16α-Hydroxyprogesterone (16α-OHP), also known as 16α-hydroxypregn-4-ene-3,20-dione, is a minor endogenous progestogen steroid hormone and a metabolite of progesterone that is formed in lower amounts than 17α-hydroxyprogesterone (17α-OHP). It occurs in micromolar concentrations and its physiological relevance hence is questionable. However, it may accumulate in target tissues and could have a physiological role in the reproductive system and mammary gland development as well as the cardiovascular and central nervous systems.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease and inborn error of metabolism caused by deficiency of cytochrome P450 oxidoreductase (POR). POR is a 2-flavin protein that is responsible for the transfer of electrons from NADPH to all 50 microsomal cytochrome P450 (CYP450) enzymes. This includes the steroidogenic enzymes CYP17A1 (17α-hydroxylase/17,20-lyase), CYP19A1 (aromatase), and CYP21A2 (21-hydroxylase); CYP26B1 ; and the hepatic drug-metabolizing CYP450 enzymes, among many other CYP450 enzymes. Virilization of female infants in PORD may also be caused by alternative biosynthesis of 5α-dihydrotestosterone via the so-called "androgen backdoor pathway". The ABS component of severe forms of PORD is probably caused by CYP26B1 deficiency, which results in retinoic acid excess and defects during skeletal embryogenesis. All forms of PORD in humans are likely partial, as POR knockout in mice results in death during prenatal development.

<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-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. ↑ Asahina K, Suzuki K, Aida K, Hibiya T, Tamaoki B (February 1985). "Relationship between the structures and steroidogenic functions of the testes of the urohaze-goby (Glossogobius olivaceus)". General and Comparative Endocrinology. 57 (2): 281–292. doi:10.1016/0016-6480(85)90273-4. PMID   3156787.
  2. ↑ Gal M, Orly J (2014). "Selective inhibition of steroidogenic enzymes by ketoconazole in rat ovary cells". Clinical Medicine Insights. Reproductive Health. 8: 15–22. doi:10.4137/CMRH.S14036. PMC   4007567 . PMID   24812532.
  3. ↑ "(5alpha)-17-Hydroxypregnane-3,20-dione - PubChem Compound Summary". Archived from the original on 23 October 2020. Retrieved 21 October 2020.
  4. 1 2 3 Fukami M, Homma K, Hasegawa T, Ogata T (April 2013). "Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development". Developmental Dynamics. 242 (4): 320–329. doi: 10.1002/dvdy.23892 . PMID   23073980. S2CID   44702659.
  5. ↑ Miller WL (January 2012). "The syndrome of 17,20 lyase deficiency". The Journal of Clinical Endocrinology and Metabolism. 97 (1): 59–67. doi:10.1210/jc.2011-2161. PMC   3251937 . PMID   22072737.
  6. ↑ Hastings C, Hansson V (August 1981). "Kinetic properties of the soluble 3 alpha-hydroxysteroid dehydrogenase from rat testis and epididymis". Journal of Steroid Biochemistry. 14 (8): 705–711. doi:10.1016/0022-4731(81)90005-4. PMID   6946263.
  7. 1 2 3 4 Masiutin MM, Yadav MK (3 April 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.
  8. ↑ O'Shaughnessy PJ, Antignac JP, Le Bizec B, Morvan ML, Svechnikov K, Söder O, et al. (February 2019). Rawlins E (ed.). "Alternative (backdoor) androgen production and masculinization in the human fetus". PLOS Biology. 17 (2): e3000002. doi: 10.1371/journal.pbio.3000002 . PMC   6375548 . PMID   30763313.
  9. 1 2 Miller WL, Auchus RJ (April 2019). "The "backdoor pathway" of androgen synthesis in human male sexual development". PLOS Biology. 17 (4): e3000198. doi: 10.1371/journal.pbio.3000198 . PMC   6464227 . PMID   30943210.
  10. ↑ Wilson JD, Auchus RJ, Leihy MW, Guryev OL, Estabrook RW, Osborn SM, et al. (February 2003). "5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate". Endocrinology. 144 (2): 575–580. doi: 10.1210/en.2002-220721 . PMID   12538619.
  11. ↑ Kinter KJ, Anekar AA (2021). Biochemistry, Dihydrotestosterone. StatPearls. PMID   32491566. Archived from the original on 21 April 2023. Retrieved 16 July 2023.
  12. ↑ Auchus RJ (November 2004). "The backdoor pathway to dihydrotestosterone". Trends in Endocrinology and Metabolism. 15 (9): 432–438. doi:10.1016/j.tem.2004.09.004. PMID   15519890. S2CID   10631647.
  13. 1 2 Kamrath C, Hochberg Z, Hartmann MF, Remer T, Wudy SA (March 2012). "Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis". The Journal of Clinical Endocrinology and Metabolism. 97 (3): E367–E375. doi: 10.1210/jc.2011-1997 . PMID   22170725. S2CID   3162065.
  14. 1 2 Reisch N, Taylor AE, Nogueira EF, Asby DJ, Dhir V, Berry A, et al. (October 2019). "Alternative pathway androgen biosynthesis and human fetal female virilization". Proceedings of the National Academy of Sciences of the United States of America. 116 (44): 22294–22299. Bibcode:2019PNAS..11622294R. doi: 10.1073/pnas.1906623116 . PMC   6825302 . PMID   31611378.
  15. ↑ Frederiksen DW, Wilson JD (April 1971). "Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate". The Journal of Biological Chemistry. 246 (8): 2584–2593. doi: 10.1016/S0021-9258(18)62328-2 . PMID   4396507.
  16. ↑ Barnard L, Gent R, van Rooyen D, Swart AC (November 2017). "Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone". The Journal of Steroid Biochemistry and Molecular Biology. 174: 86–95. doi:10.1016/j.jsbmb.2017.07.034. PMID   28774496. S2CID   24071400.
  17. ↑ Ellsworth K, Harris G (October 1995). "Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues". Biochemical and Biophysical Research Communications. 215 (2): 774–780. doi:10.1006/bbrc.1995.2530. PMID   7488021.
  18. ↑ Lunacek A, Schwentner C, Oswald J, Fritsch H, Sergi C, Thomas LN, et al. (August 2007). "Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development". The Journal of Urology. 178 (2): 716–721. doi:10.1016/j.juro.2007.03.089. PMID   17574609.


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