Pregnenolone

Pregnenolone is the main steroid synthesized from cholesterol in mammals and invertebrates and is often known as the precursor to the other steroids rather than as an active steroid in its own right. ^[1] In steroidogenic tissues cholesterol is the common precursor of all steroid hormones, and its conversion to pregnenolone is the initial and rate-limiting step in hormone biosynthesis. ^[2] Pregnenolone has three main sources of synthesis, the gonads, the adrenal glands, and the brain. ^[1]

The quantitative regulation of steroidogenesis occurs at the first step, the conversion of cholesterol to pregnenolone, which is catalyzed by the cytochrome P450 side-chain-cleavage enzyme (P450scc) that resides on the inner mitochondrial membrane. ^[3] Acute regulation of this step is mediated by steroidogenic acute regulatory protein (StAR), which facilitates the rapid influx of cholesterol into the mitochondria where P450scc converts it to pregnenolone. ^[3] When synthesized de novo in neural tissue, pregnenolone acts as a neurosteroid, and one described mechanism is its binding to microtubule-associated protein type 2 (MAP2) to increase tubulin polymerization and microtubule assembly. ^{[4] [5]}