What are the common testosterone replacement therapy (TRT) regimens for men with hypogonadism?

Testosterone Replacement Therapy Regimens for Male Hypogonadism

Recommended Starting Regimen

For men with confirmed hypogonadism, transdermal testosterone gel is the preferred first-line formulation, starting at 40.5 mg daily (equivalent to 2 pump actuations or one 40.5 mg packet) applied to shoulders and upper arms each morning. 1, 2, 3

Diagnosis Confirmation Before Treatment

• Measure morning total testosterone (between 8-10 AM) on at least two separate days, confirming levels <300 ng/dL 2, 3
• Assess free testosterone by equilibrium dialysis and sex hormone-binding globulin, particularly in obese men 2
• Measure LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 2
• Document specific symptoms: diminished libido, erectile dysfunction, decreased vitality, or fatigue 2

Transdermal Testosterone Gel Regimens

Dosing Parameters

• Starting dose: 40.5 mg testosterone daily (2 pump actuations or one 40.5 mg packet) 2, 3
• Dose range: 20.25 mg to 81 mg daily (1-4 pump actuations) 2, 3
• Application site: Shoulders and upper arms only—never abdomen, genitals, chest, armpits, or knees 3
• Timing: Once daily in the morning 2, 3

Dose Titration Protocol

• Check testosterone levels at 14 days and 28 days after starting or after any dose change 2, 3
• Target mid-normal range: 500-600 ng/dL (or 350-750 ng/dL per guidelines) 2
• If testosterone >750 ng/dL: Decrease by 20.25 mg daily 3
• If testosterone 350-750 ng/dL: Continue current dose 3
• If testosterone <350 ng/dL: Increase by 20.25 mg daily 3
• Once stable, monitor every 6-12 months 2

Advantages of Transdermal Formulations

• Provide stable day-to-day testosterone levels without the fluctuations seen with injections 2, 4, 5
• Lower risk of erythrocytosis (3-18%) compared to intramuscular injections (up to 44%) 4, 6
• Minimal skin irritation (5.5% vs 66% with patches) 5
• Restore testosterone to mid-normal physiological values (14-17.5 nmol/L) 4

Intramuscular Injection Regimens

Standard Protocol

• Formulation: Testosterone cypionate or enanthate 2
• Dosing: Administered every 2-3 weeks 2
• Pharmacokinetics: Peak levels occur 2-5 days post-injection, return to baseline at 10-14 days 2
• Monitoring: Measure levels midway between injections, targeting 500-600 ng/dL 2

Advantages and Disadvantages

• Cost advantage: $156.24 annually vs $2,135.32 for transdermal gel 2, 4
• Higher erythrocytosis risk: Up to 44% with injections vs 3-18% with gel 4, 6
• Fluctuating levels: Causes mood and sexual function variability in some men 7
• Patient preference: Some prefer injections due to lower cost, others prefer gel for convenience 2

Alternative Regimens for Specific Situations

For Men Seeking Fertility Preservation

• Gonadotropin therapy is mandatory—TRT is absolutely contraindicated 1, 8
• Use recombinant human chorionic gonadotropin (hCG) plus FSH for secondary hypogonadism 1
• Combined hCG and FSH therapy provides optimal outcomes for fertility preservation 1

For Functional/Obesity-Related Hypogonadism

• Initiate weight loss through low-calorie diet—can increase testosterone by 1-2 nmol/L 1
• Add structured physical activity with duration correlating to testosterone improvement 1
• Consider combining lifestyle modifications with TRT for better symptomatic outcomes 1

Monitoring Requirements During Treatment

Testosterone Levels

• Initial assessment at 2-3 months after starting treatment 2, 4
• Reassess at 14 and 28 days after any dose adjustment 2, 3
• Once stable on a given dose, monitor every 6-12 months 2

Safety Monitoring

• Hematocrit: Check periodically; withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 6
• PSA levels: Monitor in men over 40 years; significant increases require treatment adjustment 1, 4
• Prostate examination: Assess for benign prostatic hyperplasia symptoms 1, 3
• Cardiovascular assessment: Monitor for fluid retention, especially in men with preexisting cardiac disease 3

Absolute Contraindications

• Men actively seeking fertility (use gonadotropins instead) 1
• Active or treated male breast cancer 1
• Known or suspected prostate cancer 3
• Pregnancy in female partners (risk of fetal harm) 3

Critical Safety Warnings

Secondary Exposure Risk

• Children must avoid contact with unwashed or unclothed application sites 3
• Patients must wash hands immediately with soap and water after gel application 3
• Cover application sites with clothing after gel dries 3
• Wash application site thoroughly before any anticipated skin-to-skin contact 3

Treatment Discontinuation Criteria

• If no improvement in sexual function after 12 months, discontinue treatment 6
• Hematocrit persistently >54% despite dose reduction 1
• Development of significant PSA elevation or prostate abnormalities 1, 4

Important Clinical Caveats

The European Association of Urology strongly recommends against testosterone therapy in eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men. 1

• TRT produces only small improvements in sexual function (effect size 0.35) and quality of life 6
• Little to no effect on physical functioning, depressive symptoms, energy, or cognition 1, 6
• Long-term safety beyond 36 months remains uncertain 6
• Testosterone gel 1.62% is not interchangeable with other topical testosterone products due to different systemic exposure 3