Pregnenolone

Source: Wikipedia, the free encyclopedia.
Not to be confused with
Pregneninolone
.
This article is about pregnenolone as a hormone. For its use as a medication or supplement, see Pregnenolone (medication).
Pregnenolone
Names
IUPAC name
3β-Hydroxypregn-5-en-20-one
Systematic IUPAC name
1-[(1S,3aS,3bS,7S,9aR,9bS,11aS)-7-Hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[a]phenanthren-1-yl]ethan-1-one
Other names
P5; 5-Pregnenolone; δ5-Pregnene-3β-ol-20-one; Pregn-5-en-3β-ol-20-one; NSC-1616
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.005.135 Edit this at Wikidata
KEGG
UNII
  • 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
    Key: ORNBQBCIOKFOEO-QGVNFLHTSA-N
  • 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
Properties
C21H32O2
Molar mass 316.485 g/mol
Melting point 193 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an

precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids.[1] In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.[2]

In addition to its role as a natural hormone, pregnenolone has been used as a medication and supplement; for information on pregnenolone as a medication or supplement, see the pregnenolone (medication) article.

Biological function

Pregnenolone and its 3β-

neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester may improve cognitive and memory function.[3] In addition, they may have protective effects against schizophrenia.[2]

Biological activity

Neurosteroid activity

Pregnenolone is an allosteric

CB1 receptor.[4][5] Pregnenolone is involved in a natural negative feedback loop against CB1 receptor activation in animals. It prevents CB1 receptor agonists like tetrahydrocannabinol, the main active constituent in cannabis, from fully activating the CB1.[6] A related compound AEF0117
has been derived from pregnenolone and is more specific for this type of activity.

Pregnenolone has been found to bind with high,

aging.[7][8]

Although pregnenolone itself does not possess these activities, its

pancreatic islets causing calcium entry and subsequent insulin release.[12]

Nuclear receptor activity

Pregnenolone has been found to act as an agonist of the pregnane X receptor.[13]

Pregnenolone has no progestogenic, corticosteroid, estrogenic, androgenic, or antiandrogenic activity.[1]

Biochemistry

Steroidogenesis
, showing pregnenolone near top left

Biosynthesis

Pregnenolone is

20α,22R-dihydroxycholesterol, and all three steps in the transformation are catalyzed by P450scc.[14] Pregnenolone is produced mainly in the adrenal glands, the gonads, and the brain.[4] Although pregnenolone is also produced in the gonads and brain, most circulating pregnenolone is derived from the adrenal cortex.[15]

To assay conversion of cholesterol to pregnenolone, radiolabeled cholesterol has been used.[16] Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns.[16]

Distribution

Pregnenolone is

lipophilic and readily crosses the blood–brain barrier.[17] This is in contrast to pregnenolone sulfate, which does not cross the blood–brain barrier.[18][19]

Metabolism

Pregnenolone undergoes further steroid metabolism in one of several ways:

Levels

Normal circulating levels of pregnenolone are as follows:[15]

  • Men: 10 to 200 ng/dL
  • Women: 10 to 230 ng/dL
  • Children: 10 to 48 ng/dL
  • Adolescent boys: 10 to 50 ng/dL
  • Adolescent girls: 15 to 84 ng/dL

Mean levels of pregnenolone have been found not to significantly differ in postmenopausal women and elderly men (40 and 39 ng/dL, respectively).[20]

Studies have found that pregnenolone levels are not significantly changed after

medical castration in men, which is in accordance with the fact that pregnenolone is mainly derived from the adrenal glands.[21][22][23] Conversely, medical castration has been found to partially suppress pregnenolone levels in premenopausal women.[24][25] Similarly, an adrenalectomized premenopausal woman showed incompletely diminished circulating pregnenolone levels.[26]

Chemistry

See also: List of neurosteroids

Pregnenolone is also known chemically as pregn-5-en-3β-ol-20-one.

sulfated derivative, pregnenolone sulfate
, is water-soluble.

3β-Dihydroprogesterone (pregn-4-en-3β-ol-20-one) is an isomer of pregnenolone in which the C5 double bond has been replaced with a C4 double bond.[1]

History

Pregnenolone was first synthesized by Adolf Butenandt and colleagues in 1934.[29]

References

  1. ^
    PMID 15415436
    .
  2. ^
    S2CID 26396652
    .
  3. S2CID 22186709
    .
  4. ^
    S2CID 3468546
    .
  5. PMID 26408156
  6. ^ Vallée, M., Vitiello, S., Bellocchio, L., Hébert-Chatelain, E., Monlezun, S., Martin-Garcia, E., Kasanetz, F., Baillie, GL., Panin, F., Cathala, A., Roullot-Lacarrière, V., Fabre, S., Hurst, DP., Lynch, DL., Shore, DM., Deroche-Gamonet, V., Spampinato, U., Revest, JM., Maldonado, R., Reggio, PH., Ross, RA., Marsicano, G., Piazza, PV. [1], "Pregnenolone Can Protect the Brain from Cannabis Intoxication", Science, January 2014 Science 343(6166):94-8.
  7. ^
    PMID 17651807
    .
  8. ^
    PMID 16537405
    .
  9. S2CID 1101046
    .
  10. PMID 1654510
    .
  11. S2CID 36972583
    .
  12. S2CID 19925356
    .
  13. PMID 10548883
    .
  14. ^
    ISBN 978-0-7817-6879-5
    .
  15. ^ a b "The Quest Diagnostics Manual. Endocrinology. Test Selection and Interpretation. Fourth Edition". docplayer.net. p. 152. Retrieved 15 September 2023.
  16. ^
    doi:10.1016/S0021-9673(00)85545-4
    .
  17. PMID 23348009
    .
  18. ISBN 978-1-4200-8560-0
    .
  19. ISBN 978-0-470-51399-6
    .
  20. PMID 6274897
    .
  21. ISBN 978-94-009-5588-2
    . On the other hand there were no significant changes in serum levels of the steroid precursors pregnenolone and progesterone. [...] Unchanged levels of pregnenolone, in the presence of decreased 17α-OH-progesterone and testosterone concentrations, suggest that a block of 17-hydroxylase and 17,20-desmolase activity takes place in the human testis.
  22. PMID 6086697
    .
  23. PMID 6800852
    .
  24. PMID 2199228
    .
  25. PMID 3116031
    .
  26. PMID 4270264
    .
  27. ^
    ISBN 978-1-4757-2085-3
    .
  28. ^
    ISBN 978-3-88763-075-1
    .
  29. doi:10.1002/cber.19340670931
    .