Pregnenolone

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. 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. 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. 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. In addition, they may have protective effects against schizophrenia. Pregnenolone is an allosteric endocannabinoid, as it is a negative allosteric modulator of the CB1 receptor. 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. Pregnenolone has been found to bind with high, nanomolar affinity to microtubule-associated protein 2 (MAP2) in the brain. In contrast to pregnenolone, pregnenolone sulfate did not bind to microtubules. However, progesterone did and with similar affinity to pregnenolone, although unlike pregnenolone, it did not increase binding of MAP2 to tubulin. Pregnenolone was found to induce tubule polymerization in neuronal cultures and to increase neurite growth in PC12 cells treated with nerve growth factor. As such, pregnenolone may control formation and stabilization of microtubules in neurons and may affect both neural development during prenatal development and neural plasticity during aging. Although pregnenolone itself does not possess these activities, its metabolite pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor as well as a positive allosteric modulator of the NMDA receptor. In addition, pregnenolone sulfate has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets causing calcium entry and subsequent insulin release. Pregnenolone has been found to act as an agonist of the pregnane X receptor. Pregnenolone has no progestogenic, corticosteroid, estrogenic, androgenic, or antiandrogenic activity. Pregnenolone is synthesized from cholesterol. This conversion involves hydroxylation of the side chain at the C20 and C22 positions, with cleavage of the side chain. The enzyme performing this task is cytochrome P450scc, located in the mitochondria, and controlled by anterior pituitary trophic hormones, such as adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone, in the adrenal glands and gonads. There are two intermediates in the transformation of cholesterol into pregnenolone, 22R-hydroxycholesterol and 20α,22R-dihydroxycholesterol, and all three steps in the transformation are catalyzed by P450scc. Pregnenolone is produced mainly in the adrenal glands, the gonads, and the brain. Although pregnenolone is also produced in the gonads and brain, most circulating pregnenolone is derived from the adrenal cortex.