Lh Control Of Testosterone Synthesis

Testosterone, a C19 3-keto, 17P-hydroxy A4 steroid, is synthesized from cholesterol through a series of cytochrome P450- and dehydrogenase-dependent enzymatic reactions (40). The conversion of cholesterol to pregnenolone occurs within mitochondria and is catalyzed by P450scc, the cytochrome P450 side-chain cleavage enzyme. Preg-nenolone exits the mitochondria and can be converted to testosterone by two alternative routes that are referred to as the A4-pathway or the A5-pathway, based on whether the steroid intermediates are 3-keto, A4 steroids (A4) or 3-hydroxy, A5 steroids (A5). Classical experiments using human testicular microsomes incubated with radiolabeled steroids revealed that the A5-pathway predominates in the human testis. In that pathway, C17 hydroxylation of pregnenolone to form 17a-hydroxypregnenolone is followed by cleavage of the C17-C20 bond of 17a-hydroxypregnenolone to produce dehydroepiandrosterone (DHEA). Oxidation of the 3P-hydroxy group and isomeriza-tion of the C5-C6 double bond of DHEA by 3P-hydroxysteroid dehydrogenase/A5-A4 isomerase (3PHSD) forms androstenedione. The C17 keto group of androstenedione is oxidized to a hydroxyl group by 17P-hydroxysteroid dehydrogenase (17P HSD) producing testosterone (see Chapter 2).

In the A4-pathway that predominates in rodents, pregnenolone is metabolized to progesterone by 3PHSD. Progesterone is hydroxylated at C17 to produce 17a-hydrox-yprogesterone, followed by cleavage of the C17-C20 bond of 17a-hydroxyproges-terone to produce androstenedione. Cytochrome P450c17 catalyzes both reactions. Finally, the C17 keto group of androstenedione is oxidized to a hydroxy group by 17P HSD to produce testosterone.

LH stimulates testosterone biosynthesis in Leydig cells through a G protein-associated seven-transmembrane receptor (41). LH binding to the receptor initiates a signaling cascade by activating Gs that stimulate adenylate cyclase activity and increase intracellular cAMP levels to activate cAMP-dependent protein kinase A (PKA). cAMP-dependent PKA stimulates testosterone synthesis in at least two ways. An acute response, within minutes of hormonal stimulation, is characterized by an increase in cholesterol transport into the mitochondria and is mediated by the steroidogenic acute regulatory (StAR) protein (42). StAR functions at the mitochondrial outer membrane, but how it regulates cholesterol transport is not known. The chronic response to LH, which requires several hours, involves transcriptional activation of the genes encoding the steroidogenic enzymes of the testosterone biosynthetic pathway, P450scc, P450c17, 3pHSD, and 17pHSD.

Other factors that stimulate testosterone synthesis directly include PRL, GH, T3, PACAP, VIP, and inhibin, whereas glucocorticoids, estradiol, activin, AVP, CRF, and IL-1 reduce testosterone production by Leydig cells. Although controversial for many years, recent experiments with recombinant FSH suggest that FSH is not an important regulator of Leydig cell function (43,44). However, unidentified Sertoli cell proteins regulated by the FSH receptor may stimulate testosterone biosynthesis.

The blood production rate of testosterone in normal adult men has been estimated to range from 5000 to 7500 ^g/24 h (45), and levels of total testosterone in normal men range from 250 to 1000 ng/dL (10-40 nmol/L) in most assays. The testosterone level in adult men declines by more than 95% if the testes are removed. The remainder of the testosterone is derived from androstenedione and DHEA production by the adrenal cortex.

Vanish Man Boobs

Vanish Man Boobs

Say goodbye to embarrassing man boobs forever. Thats right. Im going to share all of the research I collected and the cures I found with you. It is entirely possible to cure your man boobs forever without the use of drugs or surgery. Im going to show you how.

Get My Free Ebook

Post a comment