Mechanism of Action and Pathways
Testosterone exerts its biological effects in the body through three main pathways:
- Directly, as a native molecule.
- Through conversion into a more potent metabolite — dihydrotestosterone (DHT).
- Via conversion (aromatization) into the female sex hormone — estradiol.
Regardless of the metabolic pathway, the mechanism of action remains characteristic of steroid hormones. The hormones penetrate the cell membrane and bind to specific intracellular androgen receptors. The resulting hormone-receptor complex activates gene expression, leading to the synthesis of proteins that determine the final biological effect.
Physiological Effects of the Hormones
The effects of androgens strictly depend on the form of the hormone:
- Native testosterone: During the prenatal period, it is responsible for the formation of internal male reproductive organs. During puberty, it provides an anabolic effect (stimulating muscle mass growth) and establishes libido and potency. Additionally, testosterone has a hematological effect, stimulating erythropoiesis.
- Dihydrotestosterone (DHT): Irreversibly formed by the enzyme $5\alpha$-reductase (occurring in the prostate gland, liver, and external genitalia). DHT has a higher affinity for androgen receptors. Prenatally, it ensures the differentiation of external genitalia, and during puberty, it drives their maturation and male-pattern hair growth. The pathophysiological role of DHT is that its excess leads to prostate hyperplasia (benign prostatic hyperplasia, prostate cancer).
- Estradiol: Formed via the aromatase enzyme in the liver, adipose tissue, ovaries, and central nervous system. In males, it is necessary to maintain bone mineral density and promote epiphyseal plate closure (halting longitudinal bone growth) at the end of puberty.
Classification and Pharmacokinetics of Medications
The primary pharmacokinetic challenge of native testosterone is the first-pass effect. When taken orally, it is rapidly degraded in the liver into inactive metabolites, failing to achieve therapeutic blood concentrations. Therefore, clinical practice utilizes three main groups of agents:
- Native testosterone: Administered via non-oral routes that bypass the liver — transdermal patches and gels. Daily application provides a stable hormone concentration without peak fluctuations.
- Testosterone esters: Created by esterifying the hydroxyl group at the 17th carbon position, which drastically increases the molecule's lipophilicity. When administered intramuscularly as oil solutions, the drug forms a depot in adipose tissue and gradually hydrolyzes to release the hormone. Examples include testosterone propionate (short-acting, administered daily), testosterone isocaproate (long-acting, administered every 3–4 weeks), and combined ester mixtures (Omnadren). Oral capsules (Undestor/Andriol) and DHT derivatives (mesterolone) are also available.
- 17-$\alpha$-alkylated androgens (anabolic steroids): Synthetic molecules resistant to hepatic degradation. Their main feature is the dissociation of effects: the anabolic action predominates over the androgenic action. Examples include methyltestosterone (administered sublingually) and nandrolone (administered intramuscularly every 3–4 weeks).
Indications and Adverse Effects
The primary indication for prescribing androgens in men is hormone replacement therapy (HRT) for hypogonadism (testosterone deficiency). In women, these medications may be used for hormone-dependent tumors (such as breast cancer).
Adverse effects of therapy:
- Fluid and electrolyte disturbances: Retention of sodium ions ($Na^+$) and water, leading to edema.
- In men: Excessive sexual arousal and prostatic hypertrophy.
- In pediatrics: Treatment of boys with delayed puberty can cause accelerated closure of the epiphyseal growth plates of tubular bones, leading to premature growth cessation.
- In women: Development of virilization (masculinization), manifesting as voice deepening and male-pattern facial hair growth.
An absolute contraindication to androgen therapy is prostate cancer, as it is an androgen-dependent malignancy.