, showing pregnenolone near top left
Biosynthesis 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. To assay conversion of cholesterol to pregnenolone, radiolabeled cholesterol has been used. Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns. This is in contrast to
pregnenolone sulfate, which does not cross the blood–brain barrier.
Metabolism Pregnenolone undergoes further steroid
metabolism in one of several ways: • Pregnenolone can be converted into
progesterone. The critical enzyme step is two-fold using a
3β-hydroxysteroid dehydrogenase and a
Δ5-4 isomerase. The latter transfers the
double bond from C5 to C4 on the A ring. Progesterone is the entry into the Δ4 pathway, resulting in production of
17α-hydroxyprogesterone and
androstenedione, precursor to
testosterone and
estrone.
Aldosterone and
corticosteroids are also derived from progesterone or its derivatives. • 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). • Pregnenolone can be converted to
pregnenolone sulfate by
steroid sulfotransferase, and this conversion can be reversed by
steroid sulfatase.
Levels Normal circulating levels of pregnenolone are as follows: 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. Conversely, medical castration has been found to partially suppress pregnenolone levels in premenopausal women. Similarly, an
adrenalectomized premenopausal woman showed incompletely diminished circulating pregnenolone levels. ==Chemistry==