Introduction
Testosterone is a naturally occurring androgen hormone primarily produced by the testes in males and, to a lesser extent, by the ovaries in females and adrenal glands in both sexes. As a medication, testosterone replacement therapy is used to treat various hypogonadal conditions. Pharmaceutical testosterone preparations include esters for intramuscular injection, transdermal gels and patches, buccal systems, and subcutaneous implants.
Mechanism of Action
Testosterone exerts its effects through binding to and activating androgen receptors, which are intracellular transcription factors. This hormone-receptor complex translocates to the cell nucleus where it binds to specific DNA sequences, regulating the transcription of androgen-responsive genes. Testosterone promotes the development and maintenance of male sexual characteristics, supports spermatogenesis, increases muscle mass and strength, stimulates erythropoiesis, and influences bone mineralization.
Indications
- Primary hypogonadism (congenital or acquired)
- Hypogonadotropic hypogonadism (congenital or acquired)
- Delayed puberty in males
- Metastatic breast cancer in women (palliative treatment)
- Gender-affirming hormone therapy for transgender men
Dosage and Administration
Injectable esters (testosterone cypionate/enanthate): 50-400 mg IM every 2-4 weeks Transdermal gel: 50-100 mg applied daily to clean, dry skin Transdermal patch: 4-6 mg applied daily to torso, arms, or thighs Buccal system: 30 mg applied twice daily to gum region Subcutaneous pellet: 150-450 mg implanted every 3-6 months Special populations:- Geriatric patients: Use lowest effective dose
- Hepatic impairment: Use with caution, consider non-oral formulations
- Renal impairment: Dose adjustment not typically required
Pharmacokinetics
Absorption: Varies by formulation; IM esters have prolonged absorption, transdermal provides steady-state delivery Distribution: 98% bound to sex hormone-binding globulin and albumin Metabolism: Primarily hepatic via reduction and conjugation; some peripheral conversion to dihydrotestosterone and estradiol Elimination: Urine (90%) and feces (6%); half-life varies by formulation (10-100 minutes for native testosterone, longer for esters)Contraindications
- Known hypersensitivity to testosterone or product components
- Carcinoma of the breast in males
- Carcinoma of the prostate
- Pregnancy (may cause fetal harm)
- Severe cardiac, hepatic, or renal impairment
Warnings and Precautions
- Cardiovascular risk: May increase risk of myocardial infarction, stroke, and cardiovascular death
- Venous thromboembolism: Increased risk, especially in older men and those with thrombophilia
- Erythrocytosis: Monitor hematocrit regularly; may require dose reduction or discontinuation
- Sleep apnea: May induce or exacerbate sleep apnea
- Hepatic effects: May cause cholestatic hepatitis, jaundice, hepatic neoplasms
- Psychiatric effects: May increase aggression, irritability, or mood changes
- Priapism: Requires immediate medical attention
Drug Interactions
- Anticoagulants: May potentiate effects of warfarin
- Corticosteroids: May increase edema risk
- Insulin: May alter insulin requirements
- Cyclosporine: May increase cyclosporine levels
- Opioids: Chronic use may suppress hypothalamic-pituitary-gonadal axis
Adverse Effects
Common:- Acne
- Oiliness of skin
- Increased body/facial hair
- Erythrocytosis
- Weight gain
- Fluid retention
- Gynecomastia
- Myocardial infarction
- Stroke
- Venous thromboembolism
- Hepatotoxicity
- Prostate cancer (controversial)
- Sleep apnea
- Priapism
- Infertility/suppressed spermatogenesis
Monitoring Parameters
- Serum testosterone levels (target mid-normal range)
- Hematocrit/hemoglobin (baseline, 3-6 months, then annually)
- Lipid profile (baseline and periodically)
- Prostate-specific antigen (baseline, 3-6 months, then annually in men >40)
- Digital rectal exam (annually in men >40)
- Liver function tests (periodically)
- Bone mineral density (if indicated)
- Mood and behavioral changes
Patient Education
- Use exactly as prescribed; do not adjust dose without medical supervision
- Report any chest pain, shortness of breath, leg swelling, or neurological symptoms immediately
- Women should avoid skin contact with application sites of transdermal preparations
- Understand that fertility may be impaired during treatment
- Regular follow-up appointments and laboratory monitoring are essential
- Report any symptoms of priapism (prolonged, painful erections)
- Inform all healthcare providers about testosterone use
- Store medications properly and keep out of reach of children
References
1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. 2. FDA-approved prescribing information for various testosterone products 3. Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males. Andrology. 2020;8(5):970-987. 4. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200(2):423-432. 5. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624.