How should low testosterone be confirmed, evaluated, and managed in a symptomatic adult male?

Confirmation, Evaluation, and Management of Low Testosterone in Symptomatic Adult Males

Diagnostic Confirmation

Hypogonadism requires both biochemical confirmation AND specific symptoms—never diagnose on a single testosterone measurement or symptoms alone. 1, 2

Laboratory Confirmation

• Obtain two separate fasting morning total testosterone measurements (8–10 AM) using the same laboratory and methodology 1, 2, 3, 4
• Both values must be < 300 ng/dL to establish biochemical hypogonadism 1, 2, 3, 4
• Morning timing is mandatory because testosterone peaks between 8–10 AM; later measurements risk false-positive diagnoses 1, 5
• Single measurements are insufficient due to significant intra-individual variability and assay differences 1, 2, 3

Additional Hormone Assessment

• Measure LH and FSH after confirming low testosterone to differentiate primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 1, 3, 4
• This distinction is critical because secondary hypogonadism can be treated with gonadotropin therapy to preserve fertility, whereas testosterone replacement causes azoospermia 1
• Measure free testosterone by equilibrium dialysis (gold standard) or calculate free androgen index in men with borderline total testosterone (231–346 ng/dL), obesity, or suspected SHBG abnormalities 1, 5, 3, 4
• Free androgen index = (total testosterone ÷ SHBG) × 100; values < 30 indicate true hypogonadism even when total testosterone is borderline-normal 1

When to Order Pituitary MRI

• Total testosterone < 150 ng/dL with LH and FSH < 1.5 IU/L (regardless of prolactin level) 1
• Prolactin > 1.5 × upper limit of normal (repeat to confirm, then order MRI) 1, 3, 4
• Visual field defects (bitemporal hemianopsia) or anosmia present 1

Symptom Assessment

Only diminished libido and erectile dysfunction justify testosterone therapy—these are the sole symptoms with proven responsiveness. 1, 6

Qualifying Symptoms (Small but Significant Benefit)

• Reduced libido (primary indication) 1, 6, 3, 4
• Erectile dysfunction 1, 6, 3, 4
• Decreased spontaneous/morning erections 1
• Standardized mean difference for sexual function improvement = 0.35 1

Non-Qualifying Symptoms (No Meaningful Benefit)

• Fatigue or low energy (SMD = 0.17, clinically insignificant) 1, 6
• Depressed mood (SMD = -0.19, "less-than-small") 1, 6
• Poor concentration or "brain fog" 1, 6
• Reduced physical strength or muscle mass 1, 6
• These symptoms show minimal correlation with testosterone levels and do not improve reliably with therapy 1, 6

Evaluation for Reversible Causes

Before initiating testosterone, systematically exclude treatable conditions that mimic or cause hypogonadism.

Obesity-Associated Secondary Hypogonadism

• Excess adipose tissue increases aromatization of testosterone to estradiol, suppressing LH secretion 1
• First-line treatment: hypocaloric diet (500–750 kcal/day deficit) plus ≥150 min/week moderate-intensity aerobic exercise and resistance training 2–3 times weekly 1
• Weight loss of 5–10% can significantly increase endogenous testosterone without medication 1, 6

Other Reversible Causes to Screen

• Hyperprolactinemia (measure prolactin) 1, 3, 4
• Hyperthyroidism (measure TSH) 1
• Hemochromatosis (iron saturation, ferritin) 1
• Diabetes mellitus (fasting glucose, HbA1c) 1, 2
• Chronic systemic illnesses (HIV, chronic kidney/liver disease) 1
• Medications that suppress testosterone (opioids, corticosteroids) 1
• Sleep disorders, particularly obstructive sleep apnea 1

Pre-Treatment Baseline Testing

Complete the following before initiating testosterone therapy:

• Hematocrit/hemoglobin (absolute contraindication if > 54%) 1, 7, 3, 4
• PSA in men > 40 years (> 4.0 ng/mL requires urologic evaluation and negative prostate biopsy before therapy; > 3.0 ng/mL in African-American men or those with first-degree relatives with prostate cancer) 1, 7, 3, 4
• Digital rectal examination to assess for palpable prostate nodules or induration 1, 3, 4
• Fasting glucose and HbA1c 1
• Lipid profile 1
• TSH 1

Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation (testosterone causes prolonged, potentially irreversible azoospermia; use gonadotropin therapy instead) 1, 6, 7, 3, 4
• Breast or prostate cancer 1, 6, 7, 3, 4
• Hematocrit > 54% 1, 6, 7, 3, 4
• Recent myocardial infarction or stroke within 3–6 months 1, 6
• Uncontrolled or severe heart failure (class III or IV) 1, 6, 3, 4
• Untreated severe obstructive sleep apnea 1, 7, 3, 4
• Severe lower urinary tract symptoms (IPSS > 19) 1, 3, 4

Treatment Selection

Transdermal testosterone gel is first-line due to stable serum levels and lower erythrocytosis risk compared with injectables. 1, 7

First-Line: Transdermal Testosterone Gel 1.62%

• Starting dose: 40.5 mg daily (2 pump actuations or one 40.5 mg packet) applied once daily in the morning 1, 7
• Apply to clean, dry, intact skin of shoulders and upper arms only (not abdomen, genitals, chest, armpits, or knees) 7
• Erythrocytosis incidence: approximately 15.4% 1
• Annual cost: approximately $2,135 1
• Patients must wash hands immediately with soap and water after application and cover application sites with clothing after gel dries 7
• Wash application site thoroughly with soap and water before any skin-to-skin contact with others 7

Second-Line: Intramuscular Testosterone Cypionate or Enanthate

• Dosing: 100–200 mg every 2 weeks or 50–100 mg weekly 1
• Weekly dosing reduces "roller-coaster" testosterone fluctuations compared with bi-weekly regimens 1
• Erythrocytosis incidence: approximately 43.8% (markedly higher than transdermal) 1
• Annual cost: approximately $156 (significantly more economical) 1
• Peak serum testosterone occurs days 2–5 post-injection; returns to baseline by days 10–14 1
• Measure testosterone levels midway between injections (days 5–7 for weekly dosing), targeting 500–600 ng/dL 1

Dose Adjustment Algorithm

• Measure testosterone at 2–3 months after initiation or dose change 1, 7
• If clinical response is adequate, no dose adjustment needed even if levels are low-normal 1
• If clinical response is suboptimal AND testosterone levels are low-normal or below, increase dose 1
• Gel can be adjusted between 20.25 mg (minimum) and 81 mg (maximum) daily 7

Monitoring Protocol

First Follow-Up (2–3 Months)

• Total testosterone (midway between injections for injectables) 1, 7
• Hematocrit/hemoglobin 1, 7, 3, 4
• PSA (men > 40 years) 1, 7, 3, 4
• Assess clinical response, particularly sexual function and libido 1

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

• Total testosterone 1, 7, 3, 4
• Hematocrit/hemoglobin (withhold therapy if > 54%; consider phlebotomy in high-risk cases) 1, 7, 3, 4
• PSA (refer to urology if increase > 1.0 ng/mL in first 6 months or > 0.4 ng/mL per year thereafter) 1, 3, 4
• Digital rectal examination 1, 3, 4
• Lipid profile 1

Discontinuation Criteria

• If no improvement in sexual function at 12 months, discontinue therapy to prevent unnecessary long-term exposure without benefit 1

Management of Erythrocytosis

Elevated hematocrit increases blood viscosity and thrombotic risk, particularly in elderly or cardiovascular-high-risk patients. 1

Hematocrit-Based Algorithm

• 50–52%: Continue therapy with closer monitoring; consider dose reduction if trending upward 1
• 52–54%: Reduce testosterone dose by 25–50%; consider switching from injectable to transdermal 1
• > 54%: Withhold testosterone immediately; consider therapeutic phlebotomy in high-risk patients 1, 7, 3, 4

Therapeutic Phlebotomy Protocol (When Indicated)

• Remove 500 mL blood every 1–2 weeks until hematocrit < 52% 1
• Monitor iron studies (ferritin, transferrin saturation) monthly to avoid iron deficiency 1
• Target ferritin 50–100 µg/L 1
• Reserve phlebotomy for hematocrit persistently > 54% despite dose reduction, high-risk patients with hematocrit 52–54%, or symptomatic hyperviscosity 1

Special Populations

Men Desiring Fertility Preservation

• Testosterone therapy is absolutely contraindicated 1, 6, 7, 3, 4
• Use gonadotropin therapy (recombinant hCG plus FSH) instead for secondary hypogonadism 1
• Combined hCG + FSH restores both testosterone production and spermatogenesis 1

Men with Diabetes

• Measure testosterone even in absence of hypogonadal symptoms 1
• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction ≈ 0.37%) 1
• Consider intensifying diabetes therapy with GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 1

Elderly Men or Those with Cardiovascular Risk

• Target mid-range testosterone levels (350–600 ng/dL) rather than upper-normal 1
• Use transdermal formulations preferentially over injectables 1
• Even modest hematocrit elevations (50–52%) increase thrombotic risk in this population 1

Critical Pitfalls to Avoid

• Never diagnose on a single testosterone measurement—two morning values are required 1, 2, 3, 4
• Never omit LH/FSH testing after confirming low testosterone—the primary vs. secondary distinction directs treatment and fertility counseling 1, 3, 4
• Never start testosterone without confirming the patient does not desire fertility—therapy causes prolonged azoospermia 1, 6, 7, 3, 4
• Never prescribe testosterone for weight loss, energy enhancement, or athletic performance—these are not evidence-based indications 1, 6
• Never continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy 1, 7, 3, 4
• Never measure testosterone outside 8–10 AM window—this increases false-positive rates 1, 2, 5
• Never diagnose based on symptoms alone without biochemical confirmation 1, 2, 6, 3, 4
• Approximately 20–30% of men receiving testosterone do not meet diagnostic criteria, and nearly 50% never have levels rechecked—highlighting widespread non-adherence to guidelines 1, 2