What are the recommended steps and monitoring for initiating testosterone replacement therapy in an adult male with confirmed testosterone deficiency?

Best Practices for Initiating Testosterone Replacement Therapy

Diagnostic Confirmation Requirements

Before initiating testosterone therapy, you must document two separate fasting morning (8–10 AM) total testosterone measurements both < 300 ng/dL using a highly accurate assay certified by the CDC Hormone Standardization Program. 1, 2, 3, 4 A single measurement is insufficient due to significant diurnal variation and assay variability. 1, 3

• Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after confirming low testosterone to differentiate primary (testicular) hypogonadism—characterized by elevated LH/FSH—from secondary (hypothalamic-pituitary) hypogonadism—characterized by low or inappropriately normal LH/FSH. 1, 2, 4

• In men with total testosterone in the "gray zone" (231–346 ng/dL) or those with obesity, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from functional low testosterone due to altered SHBG. 2, 3, 4

• Obtain serum prolactin in all men with secondary hypogonadism (low testosterone with low/normal LH-FSH); if prolactin exceeds 1.5 × the upper limit of normal, order pituitary MRI to exclude prolactinoma. 1, 2, 4

• Order pituitary MRI when testosterone is < 150 ng/dL with LH and FSH both < 1.5 IU/L, regardless of prolactin level, or when visual field defects or anosmia are present. 1, 2

Symptom Assessment and Treatment Indications

Testosterone therapy is justified only for men with diminished libido and/or erectile dysfunction as primary qualifying symptoms. 1, 2, 4 These specific sexual symptoms correlate with measurable benefit from testosterone replacement, producing a small but statistically significant improvement (standardized mean difference ≈ 0.35). 1, 2, 4

• Do not initiate therapy for nonspecific symptoms such as fatigue, low energy, depressed mood, or reduced physical function, as testosterone produces little to no clinically meaningful improvement in these domains even when hypogonadism is biochemically confirmed. 1, 2, 4

• Approximately 20–30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation, violating evidence-based guidelines. 2

Pre-Treatment Baseline Assessments

Mandatory Laboratory Tests

• Hemoglobin/hematocrit: Withhold testosterone if hematocrit exceeds 50% until the etiology is investigated; hematocrit > 54% is an absolute contraindication. 1, 2, 4

• Prostate-specific antigen (PSA) in men > 40 years: PSA > 4.0 ng/mL requires urologic evaluation and documented negative prostate biopsy before initiating therapy. 1, 2, 4 In high-risk groups (African-American men or those with a first-degree relative with prostate cancer), PSA > 3.0 ng/mL triggers further urologic work-up. 2

• Digital rectal examination to assess for palpable prostate nodules or induration. 1, 2, 4

• Fasting glucose and HbA1c to exclude diabetes. 2, 4

• Lipid profile as part of baseline metabolic assessment. 2, 4

• Thyroid-stimulating hormone (TSH) to exclude thyroid dysfunction that can mimic hypogonadal symptoms. 2

Fertility Counseling

Testosterone therapy is absolutely contraindicated in men actively seeking fertility, as exogenous testosterone suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 1, 2, 4 For men with secondary hypogonadism who desire fertility preservation, gonadotropin therapy (recombinant hCG plus FSH) is mandatory and directly stimulates the testes to restore both testosterone production and spermatogenesis. 1, 2

Formulation Selection and Dosing

First-Line: Transdermal Testosterone Gel

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 a markedly lower risk of erythrocytosis (≈ 15.4%) compared with injectable preparations (≈ 43.8%). 1, 2, 5, 4

• Apply to clean, dry, intact skin of the upper arms and shoulders only—not to the abdomen, genitals, chest, armpits, or knees. 5

• The application site should be limited to the area covered by a short-sleeve t-shirt. 5

• Cover the application site with clothing after the gel has dried; avoid swimming, showering, or washing the site for a minimum of 2 hours after application. 5

• Children and women must avoid contact with unwashed or unclothed application sites, as secondary exposure can cause virilization. 5

Alternative: Intramuscular Testosterone

Intramuscular testosterone cypionate or enanthate 100–200 mg every 2 weeks is a cost-effective alternative (annual cost ≈ $156 vs. ≈ $2,135 for transdermal gel), but carries a higher erythrocytosis risk. 2, 4

• Peak serum testosterone occurs 2–5 days after injection, often transiently exceeding the upper limit of normal, with return to baseline by days 10–14. 1, 2

• Measure testosterone levels midway between injections (days 5–7 for weekly dosing or days 7–10 for bi-weekly dosing), targeting mid-normal values of 500–600 ng/dL. 1, 2

• Weekly dosing (50–100 mg every 7 days) reduces testosterone fluctuations compared with bi-weekly regimens, minimizing the "roller-coaster" effect and associated erythrocytosis risk. 2

Monitoring Protocol

Initial Follow-Up (2–3 Months)

• Measure total testosterone (timed midway between injections for injectable preparations), hematocrit, and PSA. 2, 4

• Evaluate clinical response—particularly improvement in sexual function and libido—and adjust the dose if symptoms persist with sub-optimal hormone levels. 2, 4

Ongoing Monitoring (Every 3–6 Months During First Year, Then Annually)

• Repeat total testosterone, hematocrit, PSA, and lipid profile. 2, 4

• Perform digital rectal examination. 2, 4

• Withhold testosterone if hematocrit rises > 54%; consider therapeutic phlebotomy in high-risk individuals (elderly patients or those with cardiovascular disease). 1, 2, 4

• Refer to urology if PSA increases > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter, or if a palpable prostate nodule, induration, or asymmetry develops on digital rectal examination. 1, 2

Dose Adjustment Algorithm (for Transdermal Gel)

• Pre-dose morning total testosterone > 750 ng/dL: Decrease daily dose by 20.25 mg (1 pump actuation). 5

• Pre-dose morning total testosterone 350–750 ng/dL: Continue current dose. 5

• Pre-dose morning total testosterone < 350 ng/dL: Increase daily dose by 20.25 mg (1 pump actuation). 5

Absolute Contraindications

Do not initiate testosterone therapy in men with any of the following conditions: 1, 2, 5, 4

• Active desire for fertility preservation (use gonadotropin therapy instead)
• Breast or prostate cancer
• Hematocrit > 54%
• PSA > 4.0 ng/mL (or > 3.0 ng/mL in high-risk groups) without urologic evaluation
• Untreated severe obstructive sleep apnea
• Severe lower urinary tract symptoms (International Prostate Symptom Score > 19)
• Uncontrolled heart failure or myocardial infarction/stroke within the past 3–6 months
• Thrombophilia or recent venous thromboembolism

Expected Treatment Outcomes

Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference ≈ 0.35), with modest quality-of-life gains confined mainly to sexual-function domains. 1, 2, 4

• There is little to no clinically relevant effect on energy, vitality, physical functioning, depressive symptoms, or cognition; effect sizes for these outcomes are negligible (e.g., energy improvement standardized mean difference ≈ 0.17). 1, 2, 4

• Discontinue therapy at 12 months if there is no documented improvement in sexual function, as continuing treatment without benefit exposes patients to potential risks without therapeutic gain. 1, 2

Critical Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement or on symptoms alone; require two fasting morning values < 300 ng/dL plus specific sexual symptoms. 1, 2, 3, 4

• Never omit LH/FSH testing after confirming low testosterone; the primary vs. secondary distinction guides therapy and fertility counseling. 1, 2, 4

• Never initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone causes prolonged azoospermia. 1, 2, 4

• Never prescribe testosterone for weight loss, general energy enhancement, or athletic performance, as these are not evidence-based indications. 1, 2

• Nearly 50% of men on testosterone therapy never have their levels re-checked, representing a significant safety gap. 2