What is the recommended management for an adult male with confirmed low testosterone and symptoms, including first‑line testosterone replacement therapy, dosing, monitoring, and contraindications?

Treatment of Low Testosterone in Adult Males

For adult males with confirmed hypogonadism (two morning testosterone measurements <300 ng/dL) and specific symptoms—particularly diminished libido or erectile dysfunction—testosterone replacement therapy is the first-line treatment, with transdermal gel preferred initially due to lower erythrocytosis risk, though intramuscular injections offer a cost-effective alternative. 1

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Diagnostic Confirmation Required Before Treatment

Before initiating any therapy, you must establish both biochemical and clinical hypogonadism:

• Obtain two separate fasting morning (8–10 AM) total testosterone measurements; both must be <300 ng/dL to confirm hypogonadism. 1, 2 Single measurements are unreliable due to diurnal variation and assay differences. 1

• Measure LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism—this distinction is critical because secondary hypogonadism patients desiring fertility require gonadotropin therapy instead of testosterone. 1, 2

• In borderline cases (total testosterone 231–346 ng/dL) or obese men, measure free testosterone by equilibrium dialysis and SHBG to differentiate true hypogonadism from SHBG-related alterations. 1, 3

• Qualifying symptoms are diminished libido and erectile dysfunction—these are the only symptoms with proven testosterone responsiveness. 1, 4 Fatigue, low energy, mood changes, and cognitive complaints show minimal to no improvement even with confirmed hypogonadism. 5

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First-Line Testosterone Replacement Options

Transdermal Testosterone Gel (Preferred Initial Formulation)

Start with transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied to shoulders and upper arms each morning. 1, 6

• Advantages: More stable day-to-day testosterone levels and markedly lower erythrocytosis risk (15.4%) compared to injectable testosterone (43.8%). 1

• Dosing adjustments: Check testosterone levels at 14 and 28 days after initiation, then every 3–6 months during the first year. 1, 6 Target mid-normal range (500–600 ng/dL). 1

• Dose titration algorithm: 6

  • If pre-dose morning testosterone >750 ng/dL → decrease by 20.25 mg
  • If 350–750 ng/dL → continue current dose
  • If <350 ng/dL → increase by 20.25 mg

• Critical safety warning: Children and women must avoid contact with application sites due to risk of virilization. 6 Patients must wash hands immediately after application and cover the area with clothing. 6

Intramuscular Testosterone (Cost-Effective Alternative)

Testosterone cypionate or enanthate 100–200 mg every 2 weeks (or 50–100 mg weekly for more stable levels). 1

• Advantages: Significantly lower annual cost ($156 vs. $2,135 for transdermal) with similar clinical effectiveness. 1

• Disadvantages: Higher erythrocytosis risk (43.8% vs. 15.4% with transdermal) due to supraphysiologic peaks 2–5 days post-injection. 1

• Monitoring timing: Measure testosterone levels midway between injections (days 5–7 for weekly dosing, days 7–10 for bi-weekly), targeting 500–600 ng/dL. 1 Do not draw at peak (days 2–5) or trough (days 13–14) to avoid misleading results. 1

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Absolute Contraindications to Testosterone Therapy

Do not initiate testosterone in men with: 1, 7, 3, 2

• Active desire for fertility preservation—testosterone causes prolonged azoospermia; use gonadotropin therapy (hCG + FSH) instead for secondary hypogonadism. 1

• Breast or prostate cancer (active or treated). 1, 7

• Hematocrit >54%—this is an absolute threshold requiring therapy withholding. 1

• PSA >4.0 ng/mL (or >3.0 ng/mL in high-risk men) without urologic evaluation and negative prostate biopsy. 1, 7

• Recent cardiovascular events (myocardial infarction or stroke within 3–6 months). 1, 2

• Untreated severe obstructive sleep apnea. 1, 7

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Mandatory Baseline Testing Before Initiation

Before starting testosterone, obtain: 1, 2

• Hematocrit/hemoglobin (contraindication if >54%)
• PSA in men >40 years (contraindication if >4.0 ng/mL without urologic clearance)
• Digital rectal examination to assess for prostate nodules or induration
• Fasting glucose and HbA1c to screen for diabetes
• Lipid profile for cardiovascular risk assessment
• Prolactin if LH/FSH are low/normal (if >1.5× upper limit, order pituitary MRI)
• Pituitary MRI if testosterone <150 ng/dL with LH/FSH <1.5 IU/L, regardless of prolactin level 1

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Monitoring Protocol During Treatment

First Year (Every 3–6 Months)

• Testosterone levels (timing depends on formulation—midway between injections for IM, anytime after 2–3 months for transdermal). 1, 2

• Hematocrit—withhold therapy immediately if >54% and consider therapeutic phlebotomy in high-risk patients. 1, 2 Injectable testosterone carries 43.8% erythrocytosis risk vs. 15.4% with transdermal. 1

• PSA in men >40 years—refer to urology if PSA rises >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter. 1, 2

• Digital rectal examination at each visit. 1

• Assess symptomatic response, particularly sexual function and libido. 1

After First Year (Annually)

Once stable, continue monitoring testosterone, hematocrit, PSA, and digital rectal examination yearly. 1, 2

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Expected Treatment Outcomes

Set realistic expectations with patients: 5, 1

• Sexual function and libido: Small but statistically significant improvement (standardized mean difference 0.35)—this is the primary proven benefit. 5

• Quality of life: Modest improvements confined mainly to sexual function domains. 5

• Energy, vitality, physical function, mood, and cognition: Little to no clinically meaningful effect (effect sizes 0.14–0.19). 5 Testosterone should not be prescribed for these symptoms alone. 5

• Metabolic benefits: Potential improvements in insulin resistance, triglycerides, and HDL cholesterol. 1

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

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Special Populations and Alternative Approaches

Men Desiring Fertility Preservation (Secondary Hypogonadism)

Testosterone is absolutely contraindicated. 1, 2 Instead:

• Use gonadotropin therapy (recombinant hCG + FSH) to stimulate endogenous testosterone production and maintain spermatogenesis. 1 This is the only evidence-based approach for fertility restoration in secondary hypogonadism. 1

Obesity-Associated Secondary Hypogonadism

Before initiating testosterone, attempt lifestyle modification: 1

• Hypocaloric diet (500–750 kcal/day deficit below maintenance)
• Structured exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2–3 times/week)
• Weight loss of 5–10% can significantly increase endogenous testosterone without medication. 1

If lifestyle modification fails after 3–6 months and symptoms persist with confirmed low testosterone, proceed with testosterone therapy. 1

Men with Borderline Testosterone (231–346 ng/dL)

• Measure free testosterone by equilibrium dialysis and calculate free androgen index (FAI = total testosterone ÷ SHBG × 100). 1
• If FAI <30 with diminished libido, consider a 4–6 month therapeutic trial after discussing risks and benefits. 1
• Continue beyond 6 months only if clinical benefit is demonstrated. 1

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Management of Erythrocytosis on Testosterone Therapy

Erythrocytosis is the most common serious adverse effect, particularly with injectable formulations. 1

Hematocrit-Based Algorithm

• Hematocrit 50–52%: Continue current therapy with closer monitoring; consider dose reduction if trending upward. 1

• Hematocrit 52–54%: Reduce testosterone dose by 25–50%; consider switching from injectable to transdermal formulation. 1

• Hematocrit >54%: Withhold testosterone immediately; consider therapeutic phlebotomy (500 mL every 1–2 weeks until hematocrit <52%) in high-risk patients. 1

If erythrocytosis develops on injectable testosterone, switch to transdermal gel, which provides more stable levels and lower erythrocytosis risk. 1

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Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or symptoms alone—require two morning values <300 ng/dL plus qualifying symptoms. 1, 2

• Do not omit LH/FSH testing after confirming low testosterone—the primary vs. secondary distinction directs treatment and fertility counseling. 1, 2

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

• Do not prescribe testosterone for weight loss, energy enhancement, or athletic performance—these are not evidence-based indications. 1

• Do not continue testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy. 1

• Do not ignore mild erythrocytosis (hematocrit 50–52%) in elderly or cardiovascular-high-risk patients—even modest elevations increase thrombotic risk. 1

• Approximately 25–30% of men receiving testosterone do not meet diagnostic criteria for hypogonadism, highlighting the need for strict adherence to testing protocols. 1, 8

• Nearly 50% of men on testosterone therapy never have their levels rechecked, representing a dangerous safety gap. 1