Pharmacology of testosterone and anabolic steroids

Physiological regulation and GnRH analogues

Normally, the hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile manner. It acts on the anterior pituitary, stimulating the release of gonadotropins: luteinizing hormone (LH), which triggers testosterone production, and follicle-stimulating hormone (FSH), which is responsible for estrogen secretion.

Pharmacological analogues of GnRH work differently: they create a stable concentration of the substance in the blood. The absence of physiological pulsation desensitizes receptors and inhibits the synthesis of gonadotropins by the pituitary gland, leading to a sharp decrease in androgen and estrogen production.

The drugs are administered subcutaneously or intramuscularly as depot formulations for long-term dose maintenance. They are indicated for hormone-dependent tumors (cancer of the prostate, uterus, and breast). Side effects are equivalent to castration: patients report impotence, hot flashes, and an increased risk of secondary tumors.

Classification of anabolic steroids

Anabolic steroids are synthetic derivatives of male sex hormones. Their main feature lies in the dissociation of effects: pronounced anabolic action prevails over residual androgenic activity.

Three main groups of drugs are distinguished:

• Native hormone: testosterone itself.
• Testosterone esters: testosterone propionate, testosterone isocaproate, mesterolone, as well as combination drugs (Omnadren, Andriol Testocaps).
• 17-alkylandrogens: methyltestosterone, methandienone, nandrolone (Retabolil).

The introduction of the 17-alkyl group makes the molecule resistant to hepatic degradation, which ensures high anabolic activity, but directly causes hepatotoxicity of drugs in this group.

Mechanism of action and pharmacologic effects

At the molecular level, steroids diffuse across the cell membrane and bind to androgen receptors in the cytoplasm. The resulting complex moves into the cell nucleus, where it interacts with chromatin enhancers. This alters messenger RNA (mRNA) transcription and powerfully stimulates the synthesis of enzyme and structural proteins.

Key pharmacological effects:

1. Activation of protein synthesis (growth of muscle and bone tissue).
2. Acceleration of bone calcification.
3. Stimulation of fat and glycogen formation.
4. Hypoglycemic effect (due to increased glucose uptake by peripheral tissues).

In clinical practice, these properties are used primarily for the treatment of muscular dystrophy and osteoporosis.

Side effects and systemic toxicity

Despite the predominance of the anabolic effect, the drugs cause severe adverse reactions that depend on the patient's sex and age.

• In men: depression and aggressiveness develop. Via negative feedback mechanisms through gonadotropins, spermatogenesis is suppressed and testicular atrophy occurs.
• In women: masculinization (virilization) is observed. It manifests as voice deepening, hirsutism, acne, alopecia, and menstrual irregularities.
• In children: the drugs provoke early puberty and premature closure of epiphyseal growth plates, leading to irreversible final height stunting.
• Systemic toxicity: includes arterial hypertension, hyperlipidemia, and marked hepatotoxicity (characteristic of 17-alkylated forms).

Steroid derivatives with specific action

Pharmacology also utilizes modified steroids with antihormonal activity, for example, in the treatment of endometriosis:

• Gestrinone (an ethynylnortestosterone derivative). Possesses antiestrogenic, antiprogestogen, and weak androgenic action. Suppresses LH and FSH secretion, reducing estradiol and progesterone levels by 50–70%, which causes endometrial atrophy. Side effects: weight gain, seborrhea, voice lowering, depression, and lipid profile changes (increased LDL, decreased HDL).
• Mifepristone. A synthetic progesterone inhibitor with a strong antiglucocorticoid effect. Possesses direct antiangiogenic action — sharply reduces the production of vascular endothelial growth factor (VEGF). With prolonged use of high doses, it can provoke endometrial hyperplasia.

Class and exam questions

What else to study on this topic

• Use of aromatase and prostaglandin synthesis inhibitors in pathogenetic therapy
• Symptomatic therapy of hormone-dependent conditions (NSAIDs, antispasmodics, iron preparations)
• Surgical aspects and prevention of implantation spread in endometriosis
• Effect of gestrinone on the lipid profile (HDL and LDL)
• Antiangiogenic action of mifepristone and effect on vascular endothelial growth factor

Other topics in the "Additional Topics" section

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