What is the recommended approach to testosterone replacement therapy (TRT) in a patient with symptoms of low testosterone, such as low libido, fatigue, or erectile dysfunction, and how should it be monitored and managed?

Testosterone Replacement Therapy: Diagnosis, Treatment, and Monitoring

Diagnostic Confirmation Required Before Treatment

Testosterone replacement therapy should only be initiated in men with both biochemically confirmed hypogonadism (two separate morning total testosterone measurements below 300 ng/dL drawn between 8-10 AM) AND specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1, 2, 3

Essential Baseline Testing

• Repeat morning testosterone measurement (8-10 AM) on a separate occasion to confirm persistent hypogonadism, as single measurements are insufficient due to assay variability and diurnal fluctuation 1, 4
• Free testosterone by equilibrium dialysis in men with borderline total testosterone or obesity, as analog methods have limited reliability 1, 4
• Sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from low SHBG-related decreases in total testosterone 1, 4
• Serum LH and FSH to differentiate primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism—this distinction is critical for treatment selection and fertility preservation 1, 5
• Serum prolactin if LH is low or low-normal, as hyperprolactinemia can cause secondary hypogonadism 4, 5

Pre-Treatment Safety Screening

• Baseline hematocrit or hemoglobin to monitor for erythrocytosis during treatment 6, 1
• PSA and digital rectal examination in men over 40 years 6, 1
• Assessment of voiding symptoms using history or International Prostatic Symptoms Score 6
• Screen for sleep apnea history 6

Absolute Contraindications to Testosterone Therapy

Testosterone therapy is absolutely contraindicated in the following situations: 1, 4

• Active desire for fertility preservation (testosterone suppresses spermatogenesis and causes prolonged azoospermia)
• Active or treated male breast cancer
• Prostate cancer on active surveillance or androgen deprivation therapy
• Hematocrit >54% (or >50% per some guidelines)
• Untreated severe obstructive sleep apnea
• Severe heart failure (use cautiously due to fluid retention risk)

Critical Fertility Consideration

For men with secondary hypogonadism who desire fertility preservation, gonadotropin therapy (recombinant hCG plus FSH) is mandatory and testosterone is absolutely contraindicated. 1, 5 Men with primary hypogonadism cannot respond to gonadotropin stimulation and can only receive testosterone, which permanently compromises fertility. 1

Treatment Selection Algorithm

First-Line Formulation

Transdermal testosterone gel (1.62% at 40.5 mg daily) is the preferred first-line formulation due to more stable day-to-day testosterone levels and lower erythrocytosis risk compared to intramuscular injections. 1

Alternative Formulations

Intramuscular testosterone cypionate or enanthate (100-200 mg every 2 weeks or 50 mg weekly) is a more economical alternative, with annual costs of $156.24 versus $2,135.32 for transdermal preparations. 1, 2, 3 Peak serum levels occur 2-5 days after injection, with return to baseline by 10-14 days. 6, 1

For injectable testosterone, measure levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL. 1

Formulation Selection Considerations

• Transdermal preparations: More stable levels, lower erythrocytosis risk, but higher cost and potential skin reactions (patches up to 66%, gels 5%) 6, 1
• Intramuscular injections: More economical, but higher erythrocytosis risk and fluctuating levels with potential for supraphysiologic peaks 6, 1
• Patient preference regarding convenience, cost, and administration method should guide selection 1

Expected Treatment Outcomes

Realistic Benefits

Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference 0.35), with modest quality of life improvements primarily in sexual function domains. 1, 7

Testosterone therapy produces little to no effect on physical functioning, energy and vitality (SMD 0.17), depressive symptoms (SMD -0.19), or cognition, even in confirmed hypogonadism. 1, 4

Additional Potential Benefits

• Improved bone mineral density 1
• Increased lean body mass and decreased body fat 1
• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 1
• Correction of mild anemia 1

Time to Symptomatic Improvement

Symptomatic benefits may not manifest for several weeks to many months after treatment initiation. 8

Monitoring During Therapy

Initial Follow-Up

First follow-up visit at 1-2 months to assess efficacy, with consideration of dose escalation if inadequate clinical response with suboptimal testosterone levels. 6

Testosterone levels should be tested 2-3 months after treatment initiation and/or after any dose change. 1

Ongoing Monitoring Schedule

Once stable levels are confirmed, monitoring every 6-12 months is typically sufficient, then yearly thereafter. 6, 1

Parameters to Monitor at Each Visit

• Symptomatic response to treatment, voiding symptoms, and sleep apnea assessment 6
• Serum testosterone levels targeting mid- to upper-normal range (500-600 ng/dL) 6, 1
• Hematocrit or hemoglobin: Withhold treatment if hematocrit >54% and consider phlebotomy in high-risk cases 6, 1
• PSA levels in men over 40 years: Urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1
• Digital rectal examination 6

Dose Adjustment Algorithm

If adequate clinical response with testosterone levels in low-normal range: No dosage adjustment needed. 6

If suboptimal clinical response with testosterone levels in low-normal range: Increase testosterone dosage. 6

If maximal recommended transdermal dose achieved without adequate serum levels: Consider changing to intramuscular injection therapy. 6

For injectable testosterone, interpret blood test results based on interval since most recent injection, recognizing peak levels at 2-5 days and return to baseline by 10-14 days. 6

Potential Risks and Side Effects

Common Side Effects

• Skin reactions (erythema, pruritus): Patches up to 66%, gels 5% 6
• Local injection site reactions: Pain, soreness, bruising, erythema, swelling, nodules, furuncles 6
• Breast tenderness and swelling in small number of men 6
• Testicular atrophy and compromised fertility due to gonadotropin down-regulation 6
• Fluid retention: Uncommon and generally mild, but use cautiously in heart failure or renal insufficiency 6

Serious Risks Requiring Monitoring

• Erythrocytosis: Higher risk with injectable testosterone compared to transdermal preparations 1
• Cardiovascular events: FDA warns of possible increased risk, though evidence is conflicting and multiple professional societies support appropriate use 1, 9
• Prostate concerns: Theoretical risk of stimulating occult prostate cancer, though no evidence supports this risk 6, 10
• Worsening benign prostatic hyperplasia symptoms 1

Treatment Discontinuation Criteria

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, to prevent unnecessary long-term exposure to potential risks without benefit. 1

Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

Attempt weight loss through low-calorie diets and regular exercise before initiating testosterone therapy, as this can improve testosterone levels without medication. 1, 5 Weight loss and lifestyle modifications can be combined with testosterone therapy for better outcomes in symptomatic patients. 5

Borderline Testosterone Levels (231-346 ng/dL)

A 4-6 month trial of testosterone therapy may be considered after careful discussion of risks and benefits, with continuation beyond 6 months only if clinical benefit is demonstrated. 1

Men with Diabetes

Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction of approximately 0.37%) in hypogonadal men with type 2 diabetes. 1 Consider intensifying diabetes therapy concurrently with GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits. 1

Common Pitfalls to Avoid

Never start testosterone without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis and prolonged azoospermia. 1

Never diagnose hypogonadism based on symptoms alone without confirmed biochemical testing, as symptoms are non-specific and approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation. 1, 4

Never attempt to diagnose primary versus secondary hypogonadism while patient is on testosterone therapy, as exogenous testosterone suppresses LH and FSH, making results misleading. 1 Testosterone must be discontinued with adequate washout (2-4 weeks) before diagnostic testing. 1

Never use testosterone therapy in eugonadal men (normal testosterone levels), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men. 1

Never assume age-related decline in young men—always investigate for secondary causes of hypogonadism, as reversible conditions must be addressed first. 1