What is androgen hormone therapy?

What is Androgen Hormone Therapy?

Androgen hormone therapy is the administration of testosterone or its derivatives to replace deficient endogenous testosterone production, primarily used to treat male hypogonadism by restoring normal secondary sexual characteristics, sexual function, and physiological processes dependent on androgens. 1, 2

Primary Clinical Applications

Androgen therapy serves distinct purposes depending on the clinical context:

• Male hypogonadism replacement: The principal indication is treating testosterone deficiency in males with either primary testicular failure or secondary hypogonadotropic hypogonadism who are not immediately pursuing fertility 1, 3, 4
• Gender-affirming masculinization: Testosterone therapy induces masculine secondary sexual characteristics in transgender men and non-binary individuals assigned female at birth, achieving serum testosterone levels in the cisgender male reference range 1
• Pubertal induction: In adolescent boys with permanent or transient hypogonadism, testosterone initiates and maintains normal pubertal development including growth spurt, genital maturation, and secondary sexual characteristics 5

Mechanism of Action and Physiological Effects

Androgens exert their effects through multiple pathways:

• Cellular mechanism: Testosterone binds to cytosol receptor proteins, and in many tissues is converted to dihydrotestosterone, which has higher receptor affinity; the steroid-receptor complex translocates to the nucleus to initiate transcription and cellular changes 2
• Growth and development: Androgens drive growth and maturation of male sex organs (prostate, seminal vesicles, penis, scrotum), development of male hair distribution patterns, laryngeal enlargement with vocal cord thickening, and alterations in body musculature and fat distribution 2
• Metabolic effects: Testosterone increases protein anabolism, decreases protein catabolism, improves nitrogen balance when adequate calories and protein are provided, causes retention of nitrogen, sodium, potassium, and phosphorus, and stimulates red blood cell production through erythropoietic stimulation factor 2
• Bone effects: Androgens are responsible for the adolescent growth spurt but also cause epiphyseal fusion, terminating linear growth; prolonged use in children can cause disproportionate bone maturation 2

Standard Formulations and Administration

Long-acting parenteral testosterone esters (testosterone enanthate or cypionate) are the treatment of choice for androgen replacement therapy due to their effectiveness, safety, practicality, and low cost. 3, 4, 6

Injectable Preparations

• Testosterone cypionate or enanthate: 200 mg intramuscularly every 2 weeks or 300 mg every 3 weeks for adult males 3
• Pharmacokinetics: These esters are less polar than free testosterone and are absorbed slowly from the lipid phase after intramuscular injection, with testosterone cypionate having an approximate half-life of 8 days 2
• Metabolism: Approximately 98% of plasma testosterone is bound to sex hormone-binding globulin, with only 2% free; about 90% is excreted in urine as glucuronic and sulfuric acid conjugates, and 6% in feces 2

Alternative Delivery Systems

• Transdermal systems: Scrotal patches and testosterone gels provide alternatives to injections in selected patients, showing promise in adolescents for achieving adult body composition 4, 5
• Oral alkylated derivatives: These are generally too weak for adult male hypogonadism treatment but may have value when full androgenization is not desired, such as in adjuvant breast carcinoma treatment 3

Specific Clinical Contexts

Prostate Cancer Treatment (Androgen Deprivation)

In contrast to replacement therapy, androgen deprivation therapy (ADT) is used for androgen-sensitive metastatic or recurrent prostate cancer:

• Mechanism: Testosterone promotes prostate cancer growth via androgen receptor interactions; ADT works by either reducing testosterone production (castration) or blocking androgen receptors (antiandrogens) 1
• Methods: Bilateral orchiectomy rapidly reduces serum testosterone to castrate levels (<10 ng/mL), while LHRH agonists (goserelin, leuprolide) cause chemical castration within 3-4 weeks after initial testosterone surge 1
• Adverse effects: ADT causes weight gain, obesity, diabetes risk, cardiovascular disease, sexual dysfunction, osteoporosis, muscle loss, anemia, and cognitive changes 1

Gender-Affirming Therapy

Masculinizing hormone therapy for transgender individuals has distinct characteristics:

• Dosing: Standard testosterone doses achieve serum levels in the cisgender male reference range, with hemoglobin increasing to male reference range within 3 months 1
• Physical changes: Deepened voice, body and facial hair growth, menstrual suppression, clitoral growth, increased muscle mass, and reduced fat mass occur; voice changes and hair growth are irreversible even if testosterone is stopped 1
• Adverse effects: Polycythemia, reduced HDL cholesterol, androgenic alopecia, acne, pelvic pain, genital dryness, and potentially increased myocardial infarction risk 1
• Perioperative management: Testosterone therapy is generally continued perioperatively without routine discontinuation 1

Important Contraindications and Monitoring

When Androgens Should Not Be Used

• Lack of evidence: There is insufficient substantial evidence that androgens are effective for fractures, surgery recovery, convalescence, or functional uterine bleeding 2
• Prostate cancer: Testosterone replacement is contraindicated in men with prostate cancer, as androgens promote cancer growth 1

Monitoring Requirements

• Effectiveness: Plasma testosterone levels should be monitored to ensure adequate replacement, as testosterone esters must be hydrolyzed to free hormone before exerting cellular actions 6
• Adverse effects: Monitor for polycythemia (especially in transgender men), cardiovascular risk factors, bone density changes, and prostate health in cisgender men 1
• Fertility considerations: Exogenous testosterone inhibits endogenous testosterone release through pituitary LH feedback inhibition, and at large doses suppresses spermatogenesis through FSH inhibition 2

Alternative Approaches for Fertility Preservation

When fertility is desired in men with secondary hypogonadism:

• Gonadotropin therapy: hCG alone or combined with hMG can stimulate endogenous testosterone production and spermatogenesis, though this is more expensive and complex than testosterone replacement 4
• Pulsatile GnRH: Can stimulate both testosterone production and spermatogenesis in men with hypothalamic defects like Kallmann's syndrome 4
• Limitation: Testosterone replacement alone cannot induce or maintain normal spermatogenesis 6