Chemistry:Pregnenolone (medication)

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Short description: Medication and supplement
Pregnenolone
Pregnenolone.svg
Pregnenolona3D.png
Clinical data
Trade namesArthenolone, Bina-Skin, Enelone, Natolone, Pregneton, Prenolone, Regnosone, Sharmone, Skinostelon[1][2]
Other namesP5; 5-Pregnenolone; δ5-Pregnene-3β-ol-20-one; Pregn-5-en-3β-ol-20-one; NSC-1616
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth, transdermal
Drug classNeurosteroid; Anti-inflammatory
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H32O2
Molar mass316.485 g·mol−1
3D model (JSmol)
  (verify)

Pregnenolone, sold under the brand name Enelone among others, is a medication and supplement as well as a naturally occurring and endogenous steroid.[3][1][4][5][6] It is described as a neurosteroid and anti-inflammatory drug and was used in the treatment of rheumatoid arthritis and soft-tissue rheumatism in the 1950s but is no longer used today.[3][2][4] Pregnenolone can be taken by mouth, as a topical medication, or by injection into muscle.[3][2]

Pregnenolone is promoted online with false claims that it can treat a variety of health conditions including cancer, arthritis and multiple sclerosis.[7]

Medical uses

Pregnenolone was approved for use as a pharmaceutical medication in the treatment of rheumatoid arthritis and soft-tissue rheumatism in the 1950s.[2] It is no longer used today.[4]

Available forms

Pregnenolone acetate was available as Enelone in the form of 100 mg oral tablets and as a 100 mg/mL crystalline aqueous suspension in 10 mL vials.[2]

Pharmacology

Pregnenolone is a neurosteroid.[5][6] It is a negative allosteric modulator of the CB1 receptor,[5][8] a ligand of the microtubule-associated protein 2 (MAP2),[9][10] and an agonist of the pregnane X receptor.[11] Pregnenolone has no progestogenic, corticosteroid, estrogenic, androgenic, or antiandrogenic activity.[3] In addition to its own activities, pregnenolone is a precursor for other neurosteroids such as pregnenolone sulfate, allopregnanolone, and pregnanolone and for steroid hormones.[12][13][14][15]

Pregnenolone has low bioavailability and is subject to high metabolism.[5] Oral administration of 50 or 100 mg pregnenolone has been found to have minimal or negligible effect on urinary levels of testosterone and testosterone metabolites, including of androsterone, etiocholanolone, 5β-androstanediol, androstadienol, and androstenol (and/or their conjugates), and this suggests that only a small amount of pregnenolone is converted into testosterone.[13][14] This is in accordance with findings on the conversion of DHEA into testosterone, in which only 1.5% of an oral dose of DHEA was found to be converted into testosterone.[13] In contrast to the androstanes, 50 or 100 mg oral pregnenolone has been found to significantly and in fact "strongly" increase urinary levels of the progesterone metabolites pregnanediol and pregnanolone (and/or their conjugates), whereas pregnanetriol was unaffected.[13][14] Unlike the case of oral administration, transdermal administration of 30 mg/day pregnenolone cream has not been found to affect urinary levels of metabolites of any other steroids, including of progesterone.[14] Intranasal administration of pregnenolone was found to have low bioavailability of around 23%.[5]

Sripada et al. reported that oral pregnenolone is preferentially metabolized into the neurosteroid allopregnanolone rather than into other steroids such as DHEA or cortisol.[15] In further research by their group, a single 400 mg dose of oral pregnenolone at 3 hours post-administration was found to result in a 3-fold elevation in serum levels of pregnenolone and a 7-fold increase in allopregnanolone levels.[15] Pregnanolone levels increased by approximately 60% while DHEA levels decreased non-significantly by approximately 5% and cortisol levels were not affected.[15] Another study found that allopregnanolone levels were increased by 3-fold at 2 hours post-administration following a single 400 mg oral dose of pregnenolone.[15]

In addition to allopregnanolone, pregnenolone acts as a prodrug of pregnenolone sulfate.[12] However, pregnenolone sulfate does not cross the blood–brain barrier.[16][17]

Chemistry

Pregnenolone, also known as 5-pregnenolone or as pregn-5-en-3β-ol-20-one, is a naturally occurring pregnane steroid and a derivative of cholesterol.[3][1][4] Related steroids include pregnenolone sulfate, 3β-dihydroprogesterone (4-pregnenolone), progesterone, allopregnanolone, and pregnanolone.[3][1][4]

Derivatives

A few synthetic ester derivatives of pregnenolone exist.[1] These include pregnenolone acetate (Antofin, Previsone, Pregno-Pan) and pregnenolone succinate (Panzalone, Formula 405).[1] Prebediolone acetate (Acetoxanon, Acetoxy-Prenolon, Artisone, Artivis, Pregnartrone, Sterosone), the 21-acetate ester of 21-hydroxypregnenolone, also exists.[1] These esters are all described as glucocorticoids similarly to pregnenolone.[1]

The 3β-methyl ether of pregnenolone, 3β-methoxypregnenolone (MAP-4343), retains similar activity to pregnenolone in regard to interaction with MAP2,[9][10] and is under development for potential clinical use for indications such as the treatment of brain and spinal cord injury and depressive disorders.[18][19][20][21]

History

Pregnenolone was first synthesized by Adolf Butenandt and colleagues in 1934.[3] It was first used in medicine, as an anti-inflammatory medication, in the 1940s.[5]

Society and culture

Generic names

Pregnenolone is the generic name of the drug and its INN, BAN, DCF, and JAN.[1][4][22]

Brand names

Pregnenolone has been marketed in the past under a variety of brand names including Arthenolone, Bina-Skin, Enelone, Natolone, Pregnetan, Pregneton, Pregnolon, Prenolon, Prenolone, Regnosone, Sharmone, and Skinostelon.[1][4]

Availability

Pregnenolone is no longer marketed as a medication, but remains available as a supplement.[4][23]

Alternative medicine

Pregnenolone has been promoted online with claims it can treat a variety of diseases including multiple sclerosis, arthritis, and cancer, but such claims are not backed by evidence.[7]

Research

(As of 2016) pregnenolone is being researched for possible therapeutic applications, but its poor bioavailability makes its prospects for usefulness low.[5] Pregnenolone is available as an over-the-counter supplement, for instance in the United States .[23]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 665–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA665. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Modern Drug Encyclopedia and Therapeutic Index. Yorke Medical Group. 1955. pp. 382–. https://books.google.com/books?id=IrXGAAAAIAAJ&pg=PA382. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Pregnenolone". The Journal of Clinical Endocrinology and Metabolism 10 (4): 455–474. April 1950. doi:10.1210/jcem-10-4-455. PMID 15415436. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 872–873. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA872. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Neurosteroids and potential therapeutics: Focus on pregnenolone". The Journal of Steroid Biochemistry and Molecular Biology 160: 78–87. June 2016. doi:10.1016/j.jsbmb.2015.09.030. PMID 26433186. 
  6. ↑ 6.0 6.1 "Nongenomic actions of neurosteroid pregnenolone and its metabolites". Steroids 111: 54–59. July 2016. doi:10.1016/j.steroids.2016.01.017. PMID 26844377. 
  7. ↑ 7.0 7.1 "Pregnenolone". American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies (2nd ed.). American Cancer Society. 2009. pp. 807-810. ISBN 9780944235713. https://archive.org/details/americancancerso0000unse/page/807. 
  8. ↑ "Endocannabinoids and Their Pharmacological Actions" (in en). Endocannabinoids. Handbook of Experimental Pharmacology. 231. Springer International Publishing. 2015. pp. 1–37. doi:10.1007/978-3-319-20825-1_1. ISBN 9783319208244. 
  9. ↑ 9.0 9.1 "Neurosteroid regulation of central nervous system development". Pharmacology & Therapeutics 116 (1): 107–124. October 2007. doi:10.1016/j.pharmthera.2007.04.011. PMID 17651807. 
  10. ↑ 10.0 10.1 "Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor". Proceedings of the National Academy of Sciences of the United States of America 103 (12): 4711–4716. March 2006. doi:10.1073/pnas.0600113103. PMID 16537405. Bibcode: 2006PNAS..103.4711F. 
  11. ↑ "The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways". Recent Progress in Hormone Research 54: 345–67; discussion 367–8. 1999. PMID 10548883. 
  12. ↑ 12.0 12.1 "Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration". European Journal of Pharmacology 641 (2-3): 128–134. September 2010. doi:10.1016/j.ejphar.2010.05.033. PMID 20570588. 
  13. ↑ 13.0 13.1 13.2 13.3 "Urinary marker of oral pregnenolone administration". Steroids 70 (3): 179–183. March 2005. doi:10.1016/j.steroids.2004.12.007. PMID 15763596. 
  14. ↑ 14.0 14.1 14.2 14.3 "Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration". Drug Testing and Analysis 3 (5): 283–290. May 2011. doi:10.1002/dta.281. PMID 21538944. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits". Biological Psychiatry 73 (11): 1045–1053. June 2013. doi:10.1016/j.biopsych.2012.12.008. PMID 23348009. 
  16. ↑ "Impact of Neuroendocrine Factors on Seizure Genesis and Treatment". Epilepsy: Mechanisms, Models, and Translational Perspectives. CRC Press. 18 June 2010. pp. 479–. ISBN 978-1-4200-8560-0. https://books.google.com/books?id=8prMBQAAQBAJ&pg=PA479. 
  17. ↑ CIBA Foundation Symposium (30 April 2008). Steroids and Neuronal Activity. John Wiley & Sons. pp. 101–. ISBN 978-0-470-51399-6. https://books.google.com/books?id=KeZlL3XbmQsC&pg=PA101. 
  18. ↑ "Pregnenolone methyl ether". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800034216. 
  19. ↑ "Treatment of experimental spinal cord injury with 3β-methoxy-pregnenolone". Brain Research 1403: 57–66. July 2011. doi:10.1016/j.brainres.2011.05.065. PMID 21704982. 
  20. ↑ "3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders". Proceedings of the National Academy of Sciences of the United States of America 109 (5): 1713–1718. January 2012. doi:10.1073/pnas.1121485109. PMID 22307636. Bibcode: 2012PNAS..109.1713B. 
  21. ↑ "From steroid hormones to depressive states and senile dementias: New mechanistic, therapeutical and predictive approaches". Comptes Rendus Biologies 338 (8-9): 613–616. 2015. doi:10.1016/j.crvi.2015.06.003. PMID 26251072. 
  22. ↑ "145-13-1 - ORNBQBCIOKFOEO-QGVNFLHTSA-N - Pregnenolone [INN:BAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information". ChemIDplus. U.S. National Library of Medicine. https://chem.nlm.nih.gov/chemidplus/rn/145-13-1. 
  23. ↑ 23.0 23.1 "Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation". Psychoneuroendocrinology 29 (4): 486–500. May 2004. doi:10.1016/S0306-4530(03)00056-8. PMID 14749094. 



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