Written by Lily Robinson - February 15, 2023
How is Testosterone Synthesized?
Testosterone is a vital hormone that regulates many biological processes in humans. It is produced primarily in the testes and plays an important role in growth, development, and sexual maturation. Testosterone synthesis begins with cholesterol and occurs through a series of biochemical steps known as the testosterone biosynthesis pathway.
The testosterone biosynthesis pathway can be broken down into two major stages: the initial cleavage of cholesterol and the subsequent conversion of intermediates into testosterone through various enzymatic reactions. The overall process involves several enzymes, including 3β-hydroxysteroid dehydrogenases (3β-HSDs), 17 β-hydroxysteroid dehydrogenases (17β-HSDs), and 5α-reductase. These enzymes catalyze the reaction steps which lead to the production of testosterone from cholesterol.
Cholesterol, a lipid found in all cells, is the first intermediate molecule in testosterone synthesis as it provides both carbon atoms necessary for testosterone formation. 3β-HSD utilizes NADPH as a cofactor to convert lanosterol to 4,4a-dihydrolanosterol. Lanosterol is then converted to progesterone by 17β hydroxylase before it is further oxidized by 3α hydroxysteroid oxidoreductase to form pregnenolone within mitochondria and endoplasmic reticulum. From pregnenolone onwards, several metabolic pathways are available that result in the synthesis of other steroid hormones such as corticosterone and progesterone depending on cell types.
For testosterone synthesis, 7 cytochrome P450s catalyze oxidation reactions that transform pregnenolone into 17α Hydroxyprogesterone (17 OHP) followed by 7α hydroxylation to produce 7α hydroxydeoxycorticosterone (7 α OHDC). This serves as an intermediate in transforming 7α Hydroxylated Deoxycortisol (7 α OHDF) via 17, 20 lyase into 11 Hydroxypregnelonate 18 Oxime or Androstenedione (Andro). Subsequently these intermediates are transformed into DHEA/DHEA sulfate before 5 alpha reductase catalyses reduction again forming dihydrotestosterone also known as DHT or androstanediol glucuronic acid (ADG). In some organs like prostate or scalp hair follicles expression of 5 Alpha Reductase increases leading to increased DHT levels resulting in adverse effects like Alopecia Areata or benign prostatic hypertrophy respectively.. Finally aromatization step results in formation of estrogens but it does not occur extensively outside reproductive organs where testes acts as source for circulating Estrogens if aromatization occurs at all
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