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-
sulfate, pregnenolone sulfate, like DHEA,
DHEA sulfate, and progesterone, belong to the group of
neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are
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
endocannabinoid, as it is a
negative allosteric modulator of the
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.
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]
Pregnenolone can be converted to
17α-hydroxypregnenolone by the enzyme 17α-hydroxylase (
CYP17A1). Using this pathway, termed Δ5 pathway, the next step is conversion to
dehydroepiandrosterone (DHEA) via 17,20-lyase (CYP17A1). DHEA is the precursor of androstenedione.
Pregnenolone can be converted to
androstadienol by 16-ene synthase (CYP17A1).
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
surgical or
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]
^
abMarx CE, Bradford DW, Hamer RM, et al. (September 2011). "Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence". Neuroscience. 191: 78–90.
doi:
10.1016/j.neuroscience.2011.06.076.
PMID21756978.
S2CID26396652.
^Vallée M, Mayo W, Le Moal M (November 2001). "Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging". Brain Research. Brain Research Reviews. 37 (1–3): 301–12.
doi:
10.1016/S0165-0173(01)00135-7.
PMID11744095.
S2CID22186709.
^Pertwee, Roger G. (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,
ISBN9783319208244,
PMID26408156
^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.
^Vermeulen A, Deslypere JP, Schelfhout W, Verdonck L, Rubens R (January 1982). "Adrenocortical function in old age: response to acute adrenocorticotropin stimulation". J. Clin. Endocrinol. Metab. 54 (1): 187–91.
doi:
10.1210/jcem-54-1-187.
PMID6274897.
^B.H. Vickery; J.J. Nestor; E.S. Hafez (6 December 2012).
LHRH and Its Analogs: Contraceptive and Therapeutic Applications. Springer Science & Business Media. pp. 341–.
ISBN978-94-009-5588-2. 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.
^Bélanger A, Dupont A, Labrie F (September 1984). "Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer". J. Clin. Endocrinol. Metab. 59 (3): 422–6.
doi:
10.1210/jcem-59-3-422.
PMID6086697.
^Butenandt, Adolf; Westphal, Ulrich; Cobler, Heinz (12 September 1934). "Über einen Abbau des Stigmasterins zu corpus-luteum-wirksamen Stoffen; ein Beitrag zur Konstitution des Corpusluteum-Hormons (Vorläuf. Mitteil.)". Berichte der Deutschen Chemischen Gesellschaft (A and B Series). 67 (9): 1611–1616.
doi:
10.1002/cber.19340670931.