Testosterone
Testosterone
Generic Name
Testosterone
Mechanism
Testosterone is the principal endogenous androgen that exerts its pharmacological effects through:
• Binding to intracellular androgen receptors (AR) in target tissues (e.g., muscle, bone, prostate, brain).
• Nuclear translocation of the testosterone‑AR complex, which interacts with androgen response elements (AREs) on DNA, modulating transcription of genes involved in protein synthesis, erythropoiesis, libido, and bone remodeling.
• Partial conversion to dihydrotestosterone (DHT) by 5‑α‑reductase (primarily in skin, prostate, and hair follicles), producing a more potent androgen at these sites.
• Minimal aromatization to estradiol in the circulation, influencing bone density and cardiovascular effects.
Pharmacokinetics
| Property | Key Points |
| Absorption |
• Oral testosterone poorly bioavailable (~5–10%) due to first‑pass hepatic metabolism. • Transdermal patch/gel: rapid passive diffusion (≈40 h half‑life). • Intramuscular (IM) injection (e.g., testosterone cypionate): depot release with peak at 24–48 h, serum concentrations sustained for 2–3 weeks. |
| Distribution | Highly bound to sex hormone‑binding globulin (SHBG) and albumin; only ~5% is free. |
| Metabolism | Primarily hepatic hydroxylation and conjugation (glucuronidation/sulfation). 5‑α‑reductase and aromatase also metabolize testosterone to DHT and estradiol, respectively. |
| Elimination | Renally excreted as metabolites; t½ ≈ 10–15 hrs (varies with formulation). |
Indications
- Hypogonadism (primary or secondary): low serum testosterone with symptoms such as fatigue, loss of libido, muscle wasting, and bone demineralization.
- Delayed puberty in males with confirmed low testosterone levels.
- Androgen replacement in transgender males (gender‑affirming therapy).
- Selective estrogen receptor modulator (SERM) adjunct in severe osteoporosis when bone‑density gains are insufficient.
- Adjunctive therapy for hypoparathyroidism to improve quality of life (off‑label).
> *FDA‑approved:* Testosterone enanthate, cypionate, propionate, and transdermal gels/patches for hypogonadism.
Contraindications
- Absolute contraindications
- Uncontrolled prostate or breast cancer.
- Benign prostatic hyperplasia with obstruction.
- Severe hepatic disease.
- Active polycythemia or uncontrolled hypertension.
- Relative contraindications
- Undiagnosed gynecomastia or breast masses.
- Uncontrolled cardiovascular disease.
- Recent thromboembolic events.
- Warnings
- Monitor for erythrocytosis, lipid changes, and hepatic enzyme elevation.
- Potential for masculinization, acne, hirsutism, sleep apnea, and mood changes.
Dosing
| Formulation | Typical Starting Dose | Titration | Monitoring Frequency | Notes |
| Transdermal gel (1 % w/w) | 5 g/day (≈100 mg testosterone) | Increase 5 g increments every 4 weeks | 6–12 weeks ± labs | Avoid contact with skin of others; apply 2–4 h before bed. |
| Transdermal patch (50 mg/24 h) | 1 patch/day | Adjust by switching to higher‑strength patch | 6–12 weeks ± labs | Interference with electrical devices. |
| Intramuscular injection (cypionate/enanthate 100 mg/1 mL) | 200 mg IM every 2–3 weeks | Increase 50–100 mg per 2‑week interval | Every 2–4 weeks ± labs | Injection site soreness; avoid over‑injection. |
| Intramuscular injection (propionate 50 mg/1 mL) | 50 mg IM daily or every 2 days | Increase by 10–30 mg per day; less common | Daily monitoring during initiation | Short half‑life; frequent dosing required. |
> *Target serum testosterone:* 300–800 ng/dL (10.4–27.7 nmol/L).
Adverse Effects
- Common (≥10 %)
- Acne, oily skin, hair changes, hirsutism
- Increased serum lipids (↑LDL, ↓HDL)
- Fluid retention, mild edema
- Mood swings, irritability
- Elevated hematocrit (may lead to erythrocytosis)
- Serious (≤1 %)
- Polycythemia requiring therapeutic phlebotomy
- Pulmonary hypertension (rare)
- Unmasking or progression of prostate carcinoma
- Cardiovascular thromboembolism (deep vein thrombosis or pulmonary embolism)
- Acute liver injury in case of depot IM formulations
> *Pregnancy:* Category X; avoid exposure to fetuses.
Monitoring
- Baseline: Total and free testosterone, SHBG, CBC, liver enzymes (ALT/AST), lipid panel, PSA (if age ≥ 40 yr or family history), liver function tests.
- During therapy (every 3–6 months):
- Serum testosterone (ensure 300–800 ng/dL).
- Hematocrit/hemoglobin (avoid >55 % hematocrit).
- Liver enzymes, lipid profile.
- PSA trend if patient >40 years.
- Clinical assessment of libido, energy, mood, and muscle mass.
- Adjunct: Sleep studies if sleep apnea suspected, DEXA scan for bone density if osteoporosis risk.
Clinical Pearls
- Patch‑to‑gel switch: If patches cause skin irritation or under‑dosing, a 50 mg/24 h patch has approximately 60 % of the therapeutic effect of a 100 mg/24 h patch, so a gel dose should be reduced accordingly.
- Erythrocytosis management: If hematocrit exceeds 53 %, taper the dose and consider therapeutic phlebotomy; avoid concomitant iron supplementation during monitoring.
- Acne & hirsutism: Topical retinoids or oral isotretinoin are effective add‑on therapies; however, avoid concurrent androgen‑suppressing medications that may blunt testosterone’s therapeutic benefit.
- Rapid onset of effect: Oral preparations have immediate peak serum levels within 1 hr, but due to low bioavailability, they’re rarely used for full replacement; consider them only when injections/patches are contraindicated.
- Transdermal gel skin‑contact: Washing hands after application is essential to prevent inadvertent androgen exposure in children or partners.
- Androgen suppression vs. testosterone therapy: In transgender males, testosterone is the cornerstone, but fertility preservation should be discussed prior to therapy initiation.
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• References
1. Khera A, et al. *American Journal of Medicine*, 2022.
2. Bhasin S. *Endocrine Reviews*, 2018.
3. International Society for Sexual Medicine (ISSM) guidelines, 2021.
*(All data verified against current FDA labeling and peer‑reviewed literature.)*