Testosterone as steroid hormone —

Synthesized by liver

Steroidogenic tissues like testes — cholesterol transported to mitochondria

Testes of men, in ovaries of women — and adrenal glands:

Testosterone, like all steroid hormones, is synthesized from cholesterol. The process of converting cholesterol into testosterone involves several steps and takes place primarily in the testes in men and in the ovaries and adrenal glands in both men and women. Here’s a detailed overview of how testosterone is synthesized from cholesterol:

1. Cholesterol Uptake

Cholesterol is the precursor for all steroid hormones, including testosterone. It can be sourced from dietary intake or synthesized by the liver. In steroidogenic tissues (like the testes), cholesterol is transported to the mitochondria, where steroid hormone synthesis begins.

2. Conversion to Pregnenolone

Inside the mitochondria, cholesterol undergoes the first enzymatic reaction, which is the conversion to pregnenolone. This reaction is catalyzed by the enzyme cholesterol side-chain cleavage enzyme (CYP11A1), also known as desmolase. This step is the rate-limiting step in the synthesis of all steroid hormones.

3. Conversion to 17α-Hydroxypregnenolone

Pregnenolone is then converted to 17α-hydroxypregnenolone by the enzyme 17α-hydroxylase (CYP17A1). This enzyme is crucial for the production of androgens, including testosterone.

4. Formation of Dehydroepiandrosterone (DHEA)

17α-hydroxypregnenolone is then converted into dehydroepiandrosterone (DHEA) by the same enzyme, CYP17A1, through a lyase reaction. DHEA is a weak androgen and an important intermediate in the synthesis of more potent androgens.

5. Conversion to Androstenedione

DHEA is further converted into androstenedione by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). Androstenedione is a direct precursor to testosterone and is itself a weak androgen.

6. Conversion to Testosterone

Finally, androstenedione is converted into testosterone by the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD). This enzyme reduces the ketone group on the androstenedione molecule to a hydroxyl group, producing testosterone.

7. Regulation of Testosterone Synthesis

The synthesis of testosterone is tightly regulated by the hypothalamus and pituitary gland through the hypothalamic-pituitary-gonadal (HPG) axis:

• The hypothalamus secretes gonadotropin-releasing hormone (GnRH).
• GnRH stimulates the pituitary gland to release luteinizing hormone (LH).
• LH acts on the Leydig cells in the testes, promoting the production of testosterone by increasing the conversion of cholesterol to pregnenolone.

8. Transport and Function

Once synthesized, testosterone is released into the bloodstream. In circulation, testosterone is largely bound to proteins such as sex hormone-binding globulin (SHBG) and albumin, with only a small fraction being free and biologically active. Testosterone exerts its effects by binding to androgen receptors in various tissues, influencing everything from muscle mass and bone density to mood and libido.

9. Conversion to Other Hormones

Testosterone can also be converted into other hormones:

• Dihydrotestosterone (DHT): In some tissues, testosterone is converted to the more potent androgen DHT by the enzyme 5α-reductase.
• Estradiol: Testosterone can be aromatized to estradiol (an estrogen) by the enzyme aromatase, particularly in adipose tissue. This conversion is crucial for maintaining bone density and other functions, especially in men.

Summary

Testosterone synthesis from cholesterol is a complex, multi-step process involving various enzymes. It begins with the conversion of cholesterol into pregnenolone in the mitochondria and ends with the production of testosterone in the testes, ovaries, or adrenal glands. This synthesis is under tight regulatory control, ensuring that testosterone levels remain within an optimal range for physiological function.