What is the recommended starting dose and regimen for testosterone replacement therapy in adult men with confirmed hypogonadism?

Starting Dose for Testosterone Replacement Therapy in Men with Confirmed Hypogonadism

For adult men with confirmed hypogonadism, start with transdermal testosterone gel 1.62% at 40.5 mg (2 pump actuations) applied once daily to the shoulders and upper arms, or alternatively, intramuscular testosterone cypionate/enanthate 100–200 mg every 2 weeks (or 50–100 mg weekly for more stable levels). 1, 2, 3

Diagnostic Confirmation Required Before Initiating Therapy

Before prescribing any testosterone formulation, you must confirm biochemical hypogonadism with two separate fasting morning total testosterone measurements (8–10 AM) both < 300 ng/dL, plus the presence of specific symptoms—primarily diminished libido and erectile dysfunction. 1, 3 Single measurements are insufficient due to diurnal variation and assay variability. 1

Additionally, measure serum LH and FSH after confirming low testosterone to distinguish primary (elevated gonadotropins) from secondary (low/normal gonadotropins) hypogonadism, as this distinction is critical for treatment selection and fertility counseling. 1

First-Line Formulation: Transdermal Testosterone Gel

Starting Dose and Administration

The recommended starting dose is testosterone gel 1.62% at 40.5 mg (2 pump actuations or one 40.5 mg packet) applied topically once daily in the morning to the shoulders and upper arms. 3 This formulation is preferred as first-line therapy because it provides more stable day-to-day testosterone levels and carries a significantly lower risk of erythrocytosis (15.4%) compared with injectable preparations (43.8%). 1, 4

Apply the gel to clean, dry, intact skin of the upper arms and shoulders only—do not apply to the abdomen, genitals, chest, armpits, or knees. 3 The application area should be limited to what will be covered by a short-sleeve t-shirt. 3 Once dry, cover the site with clothing, wash hands thoroughly with soap and water, and avoid swimming or showering for at least 2 hours after application. 3

Dose Titration

The dose can be adjusted between a minimum of 20.25 mg (1 pump actuation) and a maximum of 81 mg (4 pump actuations) based on pre-dose morning serum testosterone measured at approximately 14 days and 28 days after starting treatment. 3 Target mid-normal testosterone levels of 450–600 ng/dL. 1, 2

• If testosterone > 750 ng/dL: decrease by 20.25 mg 3
• If testosterone 350–750 ng/dL: continue current dose 3
• If testosterone < 350 ng/dL: increase by 20.25 mg 3

Alternative First-Line Option: Injectable Testosterone

Starting Dose and Administration

Intramuscular testosterone cypionate or enanthate: start at 100–200 mg every 2 weeks or 50–100 mg weekly. 1, 2 Weekly dosing (50–100 mg) provides more stable testosterone levels and reduces the risk of erythrocytosis compared with biweekly administration, though both are acceptable. 2

Injections can be self-administered in the anterolateral thigh or given by another person via gluteal intramuscular injection using a 21–23 gauge, 1–1.5 inch needle. 2 The maximum safe volume for gluteal injection is 3 mL per site. 2

Monitoring and Dose Adjustment

Measure testosterone levels midway between injections (days 5–7 for weekly dosing, days 7–10 for biweekly dosing) at 2–3 months after initiation, targeting mid-normal values of 500–600 ng/dL. 1, 2 Peak levels occur 2–5 days post-injection, with return to baseline by days 10–14. 1

Important Caveat on Injectable Formulations

Injectable testosterone carries a markedly higher risk of erythrocytosis (43.8% vs. 15.4% with transdermal) due to supraphysiologic peak levels followed by subtherapeutic troughs. 4 This elevated hematocrit can aggravate vascular disease in coronary, cerebrovascular, or peripheral circulation, particularly in elderly patients or those with cardiovascular risk factors. 4 Therefore, transdermal preparations are strongly preferred for patients with cardiovascular disease, diabetes, hypertension, or advanced age. 4

Formulation Selection Algorithm

Choose transdermal gel when:

• Patient has cardiovascular risk factors (elderly, diabetes, hypertension, known CAD) 4
• Patient prefers convenience and ease of use (71% of patients prefer gel) 4
• Minimizing erythrocytosis risk is a priority 4

Choose injectable testosterone when:

• Cost is a primary concern (annual cost ≈$160 for injectable vs. ≈$2,135 for transdermal) 1, 4
• Patient refuses topical application or has concerns about secondary transfer 4
• Patient has a history of significant skin reactions to adhesives 4

Absolute Contraindications Before Starting Any Formulation

Never initiate testosterone therapy if the patient:

• Actively desires fertility preservation (testosterone causes prolonged azoospermia; use gonadotropin therapy instead) 1
• Has active or treated male breast cancer 1
• Has hematocrit > 54% 1
• Has untreated severe obstructive sleep apnea 1
• Has had a recent cardiovascular event within the past 3–6 months 1

Baseline Testing Required Before Initiation

Before starting therapy, obtain:

• Hematocrit/hemoglobin (contraindication if > 54%) 1
• PSA in men > 40 years (if > 4.0 ng/mL, requires urologic evaluation and negative prostate biopsy before therapy) 1
• Digital rectal examination to assess for palpable prostate nodules 1
• Fasting glucose and HbA1c to exclude diabetes 1
• Lipid profile 1

Monitoring Schedule After Initiation

Early Follow-Up (First Year)

• 2–3 months: measure testosterone (midway between injections for injectables), hematocrit, and PSA; assess clinical response 1, 2
• Every 3–6 months during year 1: repeat testosterone, hematocrit, PSA, lipid profile, and digital rectal examination 1

Long-Term Monitoring (After First Year)

• Annually: repeat testosterone, hematocrit, PSA, lipid profile, and digital rectal examination once stable 1

Safety Thresholds

• Withhold testosterone if hematocrit > 54% and consider therapeutic phlebotomy in high-risk cases 1
• Refer to urology if PSA increases > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter 1

Expected Treatment Outcomes

Testosterone therapy produces small but statistically significant improvements in sexual function and libido (standardized mean difference ≈ 0.35), with modest quality-of-life improvements primarily in sexual function domains. 1 However, there is little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism. 1 Therefore, the primary therapeutic indication is sexual dysfunction (low libido, erectile dysfunction), not fatigue, low energy, or mood disturbances. 1

Discontinue therapy at 12 months if there is no documented improvement in sexual function, as continuing treatment without benefit exposes the patient to unnecessary risks. 1

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or symptoms alone—require two fasting morning values < 300 ng/dL plus specific sexual symptoms 1
• Do not measure testosterone outside the 8–10 AM window, as this increases false-positive rates 1
• Always obtain LH and FSH after confirming low testosterone—the primary vs. secondary distinction guides therapy and fertility counseling 1
• Never initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone suppresses spermatogenesis and can cause prolonged azoospermia 1
• Do not prescribe testosterone for weight loss, general energy enhancement, or athletic performance—these are not evidence-based indications 1
• Do not ignore mild erythrocytosis (hematocrit 50–52%) in elderly patients or those with cardiovascular disease, as even modest elevations increase blood viscosity and thrombotic risk 1