Pregnenolone (medication)

Last updated
Pregnenolone
Pregnenolone.svg
Pregnenolona3D.png
Clinical data
Trade names Arthenolone, 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.com International Drug Names
Routes of
administration 		By mouth, transdermal
Drug class Neurosteroid; Anti-inflammatory
ATC code
  • None
Legal status
Legal status
Identifiers
  • 1-[(3S,8S,9S,10R,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C21H32O2
Molar mass 316.485 g·mol−1
3D model (JSmol)
  • CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC=C4[C@@]3(CC[C@@H](C4)O)C)C
  • InChI=1S/C21H32O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h4,15-19,23H,5-12H2,1-3H3/t15-,16-,17+,18-,19-,20-,21+/m0/s1 Yes check.svgY
  • Key:ORNBQBCIOKFOEO-QGVNFLHTSA-N Yes check.svgY
   (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 and is no longer prescribed today, but remains available as a supplement. [3] [2] [4] Pregnenolone can be taken by mouth, as a topical medication, or by injection into muscle. [3] [2]

Contents

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 Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, and JAN Tooltip Japanese Accepted Name. [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

Related Research Articles

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

Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functions as a metabolic intermediate in the biosynthesis of the androgen and estrogen sex steroids both in the gonads and in various other tissues. However, DHEA also has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface receptors, and acting as a neurosteroid and modulator of neurotrophic factor receptors.

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

Progestogens, also sometimes written progestins, 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">Androstenedione</span> Endogenous weak androgen

Androstenedione, or 4-androstenedione, also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA). It is closely related to androstenediol (androst-5-ene-3β,17β-diol).

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

Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.

<span class="mw-page-title-main">Neurosteroid</span> Compounds that affect neuronal excitability through modulation of specific ionotropic receptors

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Dehydroepiandrosterone sulfate</span> Chemical compound

Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepiandrosterone (DHEA) and circulates in far greater relative concentrations than DHEA. The steroid is hormonally inert and is instead an important neurosteroid and neurotrophin.

3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase (3β-HSD) is an enzyme that catalyzes the biosynthesis of the steroid progesterone from pregnenolone, 17α-hydroxyprogesterone from 17α-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone (DHEA) in the adrenal gland. It is the only enzyme in the adrenal pathway of corticosteroid synthesis that is not a member of the cytochrome P450 family. It is also present in other steroid-producing tissues, including the ovary, testis and placenta. In humans, there are two 3β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes.

<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">Pregnanolone</span> Chemical compound

Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. It is closely related to allopregnanolone, which has similar properties.

<span class="mw-page-title-main">Pregnenolone sulfate</span> Chemical compound

Pregnenolone sulfate is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.

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

Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone, and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of allopregnanolone. It has been reported to act as a subunit-selective negative allosteric modulator of the GABAA receptor, and antagonizes in animals and humans some but not all of the GABAA receptor-mediated effects of allopregnanolone, such as anesthesia, sedation, and reduced saccadic eye movements, but not learning impairment. Isopregnanolone has no hormonal effects and appears to have no effect on the GABAA receptor by itself; it selectively antagonizes allopregnanolone and does not affect the effects of other types of GABAA receptor positive allosteric modulators such as benzodiazepines or barbiturates.

A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others. By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.

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

3β-Dihydroprogesterone (3β-DHP), also known as 3β-hydroxyprogesterone, or pregn-4-en-3β-ol-20-one, is an endogenous steroid. It is biosynthesized by 3β-hydroxysteroid dehydrogenase from progesterone. Unlike 3α-dihydroprogesterone (3α-DHP), 3β-DHP does not act as a positive allosteric modulator of the GABAA receptor, which is in accordance with the fact that other 3β-hydroxylated progesterone metabolites such as isopregnanolone and epipregnanolone similarly do not act as potentiators of this receptor and instead inhibit it as well as reverse the effects of potentiators like allopregnanolone. 3β-DHP has been reported to possess about the same potency as progesterone in a bioassay of progestogenic activity, whereas 3α-DHP was not assessed.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

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

3β-Methoxypregnenolone, or pregnenolone 3β-methyl ether, also known as 3β-methoxypregn-5-en-20-one, is a synthetic neuroactive steroid and derivative of pregnenolone. It interacts with microtubule-associated protein 2 (MAP2) in a similar manner to pregnenolone and is under development for potential clinical use for indications such as the treatment of brain and spinal cord injury and depressive disorders.

<span class="mw-page-title-main">Pregnenolone succinate</span> Chemical compound

Pregnenolone succinate is a synthetic pregnane steroid and an ester of pregnenolone which is described as a glucocorticoid and anti-inflammatory drug and has been patented and marketed as a topical medication in the form of a cream for the treatment of allergic, pruritic, and inflammatory dermatitis. It has also been described as a non-hormonal sterol, having neurosteroid activity, and forming a progesterone analogue via dehydrogenation.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Pharmacokinetics of progesterone</span>

The pharmacokinetics of progesterone, concerns the pharmacodynamics, pharmacokinetics, and various routes of administration of progesterone.

References

  1. 1 2 3 4 5 6 7 8 9 10 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 665–. ISBN   978-1-4757-2085-3.
  2. 1 2 3 4 5 Gutman J (1955). Modern Drug Encyclopedia and Therapeutic Index. Yorke Medical Group. pp. 382–.
  3. 1 2 3 4 5 6 7 Henderson E, Weinberg M, Wright WA (April 1950). "Pregnenolone". The Journal of Clinical Endocrinology and Metabolism. 10 (4): 455–474. doi:10.1210/jcem-10-4-455. PMID   15415436.
  4. 1 2 3 4 5 6 7 8 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 872–873. ISBN   978-3-88763-075-1.
  5. 1 2 3 4 5 6 7 Vallée M (June 2016). "Neurosteroids and potential therapeutics: Focus on pregnenolone". The Journal of Steroid Biochemistry and Molecular Biology. 160: 78–87. doi:10.1016/j.jsbmb.2015.09.030. PMID   26433186. S2CID   3468546.
  6. 1 2 Weng JH, Chung BC (July 2016). "Nongenomic actions of neurosteroid pregnenolone and its metabolites". Steroids. 111: 54–59. doi:10.1016/j.steroids.2016.01.017. PMID   26844377. S2CID   21839652.
  7. 1 2 Russell J, Rovere A, eds. (2009). "Pregnenolone" . American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies (2nd ed.). American Cancer Society. pp.  807-810. ISBN   9780944235713.
  8. ↑ Pertwee RG (2015). "Endocannabinoids and Their Pharmacological Actions". Endocannabinoids. Handbook of Experimental Pharmacology. Vol. 231. Springer International Publishing. pp. 1–37. doi:10.1007/978-3-319-20825-1_1. ISBN   9783319208244. PMID   26408156.
  9. 1 2 Mellon SH (October 2007). "Neurosteroid regulation of central nervous system development". Pharmacology & Therapeutics. 116 (1): 107–124. doi:10.1016/j.pharmthera.2007.04.011. PMC   2386997 . PMID   17651807.
  10. 1 2 Fontaine-Lenoir V, Chambraud B, Fellous A, David S, Duchossoy Y, Baulieu EE, Robel P (March 2006). "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. Bibcode:2006PNAS..103.4711F. doi: 10.1073/pnas.0600113103 . PMC   1450236 . PMID   16537405.
  11. ↑ Kliewer SA, Lehmann JM, Milburn MV, Willson TM (1999). "The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways". Recent Progress in Hormone Research. 54: 345–67, discussion 367–8. PMID   10548883.
  12. 1 2 Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA (September 2010). "Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration". European Journal of Pharmacology. 641 (2–3): 128–134. doi:10.1016/j.ejphar.2010.05.033. PMC   3008321 . PMID   20570588.
  13. 1 2 3 4 Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M (March 2005). "Urinary marker of oral pregnenolone administration". Steroids. 70 (3): 179–183. doi:10.1016/j.steroids.2004.12.007. PMID   15763596. S2CID   25490229.
  14. 1 2 3 4 Piper T, Schlug C, Mareck U, Schänzer W (May 2011). "Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration". Drug Testing and Analysis. 3 (5): 283–290. doi:10.1002/dta.281. PMID   21538944.
  15. 1 2 3 4 5 Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I (June 2013). "Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits". Biological Psychiatry. 73 (11): 1045–1053. doi:10.1016/j.biopsych.2012.12.008. PMC   3648625 . PMID   23348009.
  16. ↑ Klein P, Janousek J (18 June 2010). "Impact of Neuroendocrine Factors on Seizure Genesis and Treatment". In Rho J, Sankar R, Stafstrom CE (eds.). Epilepsy: Mechanisms, Models, and Translational Perspectives. CRC Press. pp. 479–. ISBN   978-1-4200-8560-0.
  17. ↑ CIBA Foundation Symposium (30 April 2008). Steroids and Neuronal Activity. John Wiley & Sons. pp. 101–. ISBN   978-0-470-51399-6.
  18. ↑ "Pregnenolone methyl ether". AdisInsight. Springer Nature Switzerland AG.
  19. ↑ Duchossoy Y, David S, Baulieu EE, Robel P (July 2011). "Treatment of experimental spinal cord injury with 3β-methoxy-pregnenolone". Brain Research. 1403: 57–66. doi:10.1016/j.brainres.2011.05.065. PMID   21704982. S2CID   42657539.
  20. ↑ Bianchi M, Baulieu EE (January 2012). "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. Bibcode:2012PNAS..109.1713B. doi: 10.1073/pnas.1121485109 . PMC   3277154 . PMID   22307636.
  21. ↑ Baulieu ÉÉ (2015). "From steroid hormones to depressive states and senile dementias: New mechanistic, therapeutical and predictive approaches". Comptes Rendus Biologies. 338 (8–9): 613–616. 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.
  23. 1 2 Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM (May 2004). "Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation". Psychoneuroendocrinology. 29 (4): 486–500. doi:10.1016/S0306-4530(03)00056-8. PMID   14749094. S2CID   36847870.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.