Androgens

Mechanism of action and pathways

Testosterone exerts its biological effects in the body through three main pathways:

1. Independently, as a native molecule.
2. Through conversion into a more active metabolite — dihydrotestosterone (DHT).
3. Through conversion (aromatization) into the female sex hormone — estradiol.

Regardless of the metabolic pathway, the mechanism of action remains general and characteristic of steroids. Hormones penetrate inside the cell and interact with specific intracellular androgen receptors. The resulting complex activates gene expression, leading to the synthesis of proteins that determine the final biological effect.

Physiological effects of hormones

The action of androgens strictly depends on the form in which the hormone is present:

• Native testosterone: during the prenatal period, it is responsible for the formation of internal genitalia in the male fetus. During puberty, it provides an anabolic effect (stimulates muscle mass growth), and also forms libido and potency. In addition, testosterone has a hematological effect — it stimulates erythropoiesis.
• Dihydrotestosterone (DHT): is irreversibly formed under the action of the enzyme $5\alpha$-reductase (the process takes place in the prostate gland, liver, and external genitalia). DHT has a higher affinity for receptors. Prenatally, it ensures the differentiation of external genitalia, and during puberty, their maturation and male-pattern hair growth. The pathophysiological role of DHT lies in the fact that its excess leads to prostate hyperplasia (adenoma, cancer).
• Estradiol: is formed under the action of the enzyme aromatase in the liver, adipose tissue, ovaries, and central nervous system. In men, it is necessary to maintain bone mineral density and the closure of epiphyseal growth plates (cessation of longitudinal bone growth) at the end of puberty.

Classification and pharmacokinetics of drugs

The main pharmacokinetic problem of native testosterone is the first-pass effect. With conventional oral administration, it is instantly destroyed in the liver into inactive metabolites without achieving a therapeutic concentration in the blood. Therefore, three groups of agents are used in clinical practice:

1. Native testosterone. Used in forms that bypass the liver — transdermal patches and gels. Daily application provides a stable hormone concentration without peak fluctuations.
2. Testosterone esters. Created by esterifying the hydroxyl group at the 17th position. This sharply increases the lipophilicity of the molecule. Upon intramuscular injection of oil solutions, the drug creates a depot in adipose tissue and gradually hydrolyzes, releasing the hormone. Examples: testosterone propionate (short-acting, administered daily), testosterone isocaproate (long-acting, once every 3–4 weeks), and combined ester mixtures (Omnadren). There are also oral capsules (Andriol TK) and DHT derivatives (mesterolone).
3. 17-alpha androgens (anabolic steroids). Synthetic molecules resistant to hepatic degradation. Their main feature is the dissociation of effects: the anabolic action prevails over the androgenic action. Representatives: methyltestosterone (used sublingually) and nandrolone (Retabolil, administered intramuscularly once every 3–4 weeks).

Indications and side effects

The main indication for prescribing androgens to men is hormone replacement therapy (HRT) for hypogonadism (testosterone deficiency). In women, drugs may be prescribed for hormone-dependent tumors (breast cancer).

Side effects of therapy:

• Water and electrolyte disturbances: retention of sodium ions ($Na^+$) and water, leading to edema formation.
• In men: excessive sexual arousal and prostate hypertrophy.
• In pediatrics: in the treatment of boys with delayed puberty, accelerated closure of the epiphyseal growth plates of tubular bones is possible, leading to premature growth cessation.
• In women: the development of virilization (masculinization), which manifests as voice deepening and male-pattern facial hair growth.

An absolute contraindication to the prescription of androgens is prostate cancer, as this is an androgen-dependent tumor.

Class and exam questions

What else to study on this topic

• Negative feedback mechanism in sex hormone secretion
• The role of $5\alpha$-reductase in the development of prostate hyperplasia and cancer
• Pharmacokinetics of testosterone esters and the mechanism of depot formation in adipose tissue
• Features of androgen use in pediatric practice
• Mechanism of development of virilization in women upon administration of androgenic drugs

Other topics in the section "Hormone preparations, their synthetic substitutes, and antagonists"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.