What is the appropriate evaluation and management of an adult male with suspected hypogonadism, including diagnostic work‑up, testosterone replacement therapy options, monitoring, and fertility‑preserving treatment alternatives?

Evaluation and Management of Adult Male Hypogonadism

Diagnostic Work-Up

Diagnosis requires both biochemical confirmation (two separate morning total testosterone measurements <300 ng/dL drawn between 8-10 AM) and specific symptoms—primarily diminished libido and erectile dysfunction. 1, 2

Initial Laboratory Assessment

• Obtain two fasting morning total testosterone levels (8-10 AM) on separate days; single measurements are insufficient due to diurnal variation and assay variability 1, 2
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) in men with obesity, diabetes, or borderline total testosterone (231-346 ng/dL) 1, 2
• After confirming low testosterone, measure serum LH and FSH to distinguish primary (elevated LH/FSH) from secondary (low or low-normal LH/FSH) hypogonadism—this distinction is critical for treatment selection and fertility counseling 1, 2

Additional Testing Based on Hypogonadism Type

For secondary hypogonadism (low/normal LH-FSH):

• Measure serum prolactin; if >1.5× upper limit of normal, order pituitary MRI 1, 2
• Order pituitary MRI immediately if testosterone <150 ng/dL with LH/FSH <1.5 IU/L, even without elevated prolactin 2
• Screen for reversible causes: TSH (thyroid), fasting glucose/HbA1c (diabetes), iron studies (hemochromatosis), assess for obesity/metabolic syndrome, chronic illness, medications affecting the HPG axis 1, 2

For all patients before initiating therapy:

• Baseline hematocrit/hemoglobin (absolute contraindication if >54%) 1, 2
• PSA and digital rectal exam in men >40 years (PSA >4.0 ng/mL requires urologic evaluation and negative biopsy before therapy) 1, 2
• Lipid profile 2

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Treatment Selection Algorithm

Step 1: Address Reversible Causes First

For obesity-associated secondary hypogonadism, attempt weight loss through low-calorie diets (500-750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic plus resistance training 2-3×/week) before initiating testosterone. Weight loss of 5-10% can significantly increase endogenous testosterone and normalize gonadotropins. 1, 2

Step 2: Determine Fertility Goals

If the patient desires fertility preservation now or in the future, testosterone replacement therapy is absolutely contraindicated because it suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 1, 2, 3

For secondary hypogonadism with fertility concerns:

• Use gonadotropin therapy (recombinant hCG plus FSH) as first-line treatment; combined therapy provides optimal outcomes for both testosterone restoration and spermatogenesis 1, 2
• This is the only evidence-based approach that maintains fertility while normalizing testosterone 1, 2

For primary hypogonadism:

• Gonadotropins are ineffective because the testes cannot respond; testosterone replacement is the only option, but it permanently compromises fertility 1, 2

Step 3: Select Testosterone Formulation (If Fertility Not Desired)

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 markedly lower erythrocytosis risk (15.4%) compared with injectable testosterone (43.8%). 1, 2, 3

Alternative formulations:

• Intramuscular testosterone cypionate/enanthate 100-200 mg every 2 weeks is a cost-effective alternative ($156/year vs. $2,135/year for gel) but carries higher erythrocytosis risk 1, 2
• Peak levels occur days 2-5 post-injection, return to baseline by days 10-14, creating a "roller-coaster" effect 1, 2
• Testosterone undecanoate 750 mg IM initially, repeat at 4 weeks, then every 10 weeks provides fewer yearly injections with more stable levels but requires 30-minute post-injection observation for serious pulmonary oil microembolism (POME) reactions 2, 4

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Monitoring Protocol

Initial Phase (First 12 Months)

At 2-3 months after initiation:

• Measure testosterone levels (midway between injections for injectables, targeting 500-600 ng/dL mid-normal range) 1, 2
• Check hematocrit/hemoglobin 1, 2
• Measure PSA in men >40 years 1, 2
• Assess clinical response, particularly sexual function and libido 2

Every 3-6 months during year 1:

• Repeat testosterone, hematocrit, PSA, lipid profile 1, 2
• Perform digital rectal examination 2
• Evaluate symptomatic response 2

Long-Term Monitoring (After Year 1)

Annually once stable:

• Testosterone level 2
• Hematocrit/hemoglobin 2
• PSA and digital rectal exam in men >40 years 2
• Lipid profile 2

Safety Thresholds Requiring Action

• Hematocrit >54%: withhold testosterone immediately; consider therapeutic phlebotomy (500 mL every 1-2 weeks until <52%) in high-risk patients 1, 2
• PSA rise >1.0 ng/mL within first 6 months OR >0.4 ng/mL per year thereafter: refer to urology 1, 2
• No improvement in sexual function at 12 months: discontinue therapy to prevent unnecessary long-term exposure without benefit 1, 2

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Expected Treatment Outcomes

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

Testosterone therapy provides little to no clinically meaningful benefit for:

• Physical functioning, muscle strength, or frailty 1, 2
• Energy, vitality, or fatigue (effect size 0.17—clinically insignificant) 1, 2
• Depressive symptoms (effect size -0.19—less than small) 1, 2
• Cognition or memory 1, 2

Additional metabolic benefits may include:

• Improvements in insulin resistance, fasting glucose, triglycerides, and HDL cholesterol 2
• Modest increases in bone mineral density (3.2% lumbar spine, 1.4% femoral neck) 2

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Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation 1, 2, 3
• Active or treated male breast cancer 1, 2
• Hematocrit >54% 1, 2
• Untreated severe obstructive sleep apnea 2
• Recent cardiovascular events within past 3-6 months (myocardial infarction, stroke) 2
• Prostate cancer on active surveillance or androgen deprivation therapy 2

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Critical Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement or symptoms alone; require two morning values <300 ng/dL plus specific sexual symptoms 1, 2
• Never 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, as this causes prolonged azoospermia 1, 2
• Never prescribe testosterone for weight loss, energy enhancement, athletic performance, or cognition—these are not evidence-based indications 1, 2
• Never test testosterone outside 8-10 AM window, as this increases false-positive rates 1, 2
• Never continue testosterone when hematocrit exceeds 54%; this is an absolute indication to withhold therapy 1, 2
• Never assume age-related decline in young men; always investigate for secondary causes of hypogonadism, as reversible conditions must be addressed first 2
• Approximately 25-30% of men receiving testosterone do not meet diagnostic criteria for hypogonadism, and nearly 50% never have their levels rechecked—highlighting the need for strict adherence to diagnostic and monitoring protocols 2