In an adult male with symptoms of testosterone deficiency, what Canadian laboratory criteria (two separate morning total testosterone measurements below 10 nmol/L) and baseline tests (CBC, total and free testosterone, luteinizing hormone, follicle‑stimulating hormone, prostate‑specific antigen, liver function tests, lipid profile, fasting glucose/HbA1c) are required to initiate testosterone replacement therapy, what are the target testosterone levels, monitoring schedule, first‑line formulations, contraindications, and alternative options such as clomiphene citrate?

Canadian Laboratory Criteria and Management for Testosterone Replacement Therapy

Diagnostic Laboratory Requirements

In Canada, you must document two separate morning total testosterone measurements below 10 nmol/L (approximately 290 ng/dL) drawn between 8–10 AM to establish biochemical hypogonadism. 1, 2, 3 This threshold aligns closely with international guidelines that use <300 ng/dL as the diagnostic cut-off. 1, 2, 3

Baseline Laboratory Panel Before Initiating TRT

Before starting testosterone therapy, obtain the following tests:

• Complete blood count (CBC) – Document baseline hemoglobin and hematocrit; hematocrit >50% requires investigation before therapy initiation. 2
• Total testosterone (morning, 8–10 AM) – Measured on two separate occasions to confirm persistent hypogonadism. 1, 2, 3
• Free testosterone by equilibrium dialysis – Essential in men with obesity, diabetes, or borderline total testosterone, as low SHBG can artificially lower total testosterone while free testosterone remains normal. 1, 4, 5
• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) – Mandatory to distinguish primary hypogonadism (elevated LH/FSH with low testosterone) from secondary hypogonadism (low or low-normal LH/FSH with low testosterone). 1, 2, 4 This distinction is critical for fertility counseling and treatment selection.
• Prostate-specific antigen (PSA) – Required in all men over 40 years; PSA >4.0 ng/mL mandates urologic evaluation and documented negative prostate biopsy before starting therapy. 1, 4, 6
• Liver function tests (ALT, AST, bilirubin) – Baseline hepatic function assessment. 1
• Lipid profile (total cholesterol, LDL, HDL, triglycerides) – Evaluate cardiovascular risk factors. 1, 2
• Fasting glucose or HbA1c – Screen for diabetes, which is common in hypogonadal men. 1, 2, 4

Additional Testing in Secondary Hypogonadism

If LH and FSH are low or low-normal with low testosterone, measure:

• Serum prolactin – Screen for hyperprolactinemia, a reversible cause of secondary hypogonadism. 1, 2, 4
• Iron saturation – Evaluate for hemochromatosis. 1
• Consider pituitary MRI – If prolactin is elevated or other pituitary dysfunction is suspected. 1

Target Testosterone Levels During Treatment

Aim for mid-normal testosterone levels of 14–17 nmol/L (approximately 400–500 ng/dL) during treatment. 1, 2, 4, 6 Targeting mid-normal rather than upper-normal ranges reduces the risk of erythrocytosis and other adverse effects while maintaining clinical benefit. 1

Monitoring Schedule

Initial Monitoring (First Year)

• Testosterone levels at 2–3 months after treatment initiation or dose adjustment, then every 6–12 months once stable. 1, 4, 6
  • For injectable testosterone (cypionate/enanthate), measure levels midway between injections (days 5–7) to avoid misleading peak or trough values. 1
  • For transdermal gel, measure at any time after 2–3 months of stable therapy. 1
• Hematocrit at 3 months, 6 months, and 12 months, then annually. 1, 2, 4 Withhold treatment if hematocrit exceeds 54% and consider phlebotomy in high-risk cases. 1, 2
• PSA at 3 months, 6 months, and 12 months in men over 40 years. 1, 4, 6 Refer for urologic evaluation if PSA increases >1.0 ng/mL in the first 6 months or >0.4 ng/mL per year thereafter. 1
• Digital rectal examination at each visit to assess for prostate abnormalities. 1, 2

Long-Term Monitoring (After First Year)

• Testosterone levels every 6–12 months once stable. 1, 4
• Hematocrit annually or more frequently if trending upward. 1, 2
• PSA annually in men over 40 years. 1, 4
• Assess clinical response, particularly sexual function and libido, at 12 months; discontinue if no improvement. 1

First-Line Testosterone Formulations

Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation because it provides stable day-to-day testosterone levels and carries a significantly lower risk of erythrocytosis (15.4%) compared to injectable testosterone (43.8%). 1, 7 Apply once daily in the morning to clean, dry, intact skin of the shoulders and upper arms—never to the abdomen, genitals, chest, armpits, or knees. 7

Dose Adjustment for Transdermal Gel

• Measure pre-dose morning testosterone at 14 days and 28 days after starting or adjusting dose. 7
• If testosterone >750 ng/dL (>26 nmol/L): Decrease dose by 20.25 mg. 7
• If testosterone 350–750 ng/dL (12–26 nmol/L): Continue current dose. 7
• If testosterone <350 ng/dL (<12 nmol/L): Increase dose by 20.25 mg. 7
• Maximum dose is 81 mg daily (four pump actuations or two 40.5 mg packets). 7

Alternative: Injectable Testosterone

Intramuscular testosterone cypionate or enanthate 100–200 mg every 2 weeks is a cost-effective alternative (annual cost approximately $156 vs. $2,135 for gel). 1, 8 However, injectable testosterone produces supraphysiologic peak levels 2–5 days post-injection and returns to baseline by days 10–14, resulting in fluctuating testosterone levels and a 43.8% incidence of erythrocytosis. 1, 2

Absolute Contraindications to Testosterone Therapy

Do not initiate testosterone therapy in men with:

• Active desire for fertility preservation – Testosterone suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 1, 4, 6 Use gonadotropin therapy (hCG plus FSH) instead for secondary hypogonadism. 1
• Active or treated male breast cancer. 1, 4, 6
• Prostate cancer or PSA >4.0 ng/mL without urologic clearance. 1, 4, 6
• Hematocrit >50% (some guidelines use >54%). 1, 2, 4, 6
• Untreated severe obstructive sleep apnea. 1, 4, 6
• Recent myocardial infarction or stroke (within 3–6 months). 1, 8, 6
• Severe/decompensated heart failure (NYHA class III or IV). 1, 8, 6

Alternative Option: Clomiphene Citrate

For men with secondary hypogonadism who desire fertility preservation, clomiphene citrate 25–50 mg three times weekly (off-label) stimulates endogenous testosterone production without suppressing spermatogenesis. 1 This selective estrogen receptor modulator blocks estradiol-mediated negative feedback on the hypothalamus, increasing LH and FSH secretion, which in turn stimulates testicular testosterone production and spermatogenesis. 1, 2

Clomiphene is particularly useful in:

• Young men with secondary hypogonadism who wish to preserve fertility. 1, 2
• Men with obesity-associated hypogonadism, where excessive aromatization of testosterone to estradiol suppresses LH secretion. 1

If clomiphene is ineffective or contraindicated, use gonadotropin therapy (recombinant hCG plus FSH) to directly stimulate the testes. 1, 4 This approach restores both testosterone levels and spermatogenesis in men with secondary hypogonadism. 1

Critical Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement – Two morning values are required due to assay variability and diurnal fluctuation. 1, 2, 3
• Never start testosterone without confirming the patient does not desire fertility – Testosterone causes azoospermia that may be irreversible. 1, 4, 6
• Never omit LH/FSH testing once low testosterone is confirmed – The distinction between primary and secondary hypogonadism directs therapy and fertility counseling. 1, 2, 4
• Never measure testosterone at random times of day – Afternoon or evening measurements are physiologically lower and lead to false-positive diagnoses. 2
• Never ignore mild erythrocytosis (hematocrit 50–52%) in elderly patients or those with cardiovascular disease – Even modest elevations increase blood viscosity and thrombotic risk. 1, 2
• Never continue full-dose testosterone when hematocrit exceeds 54% – This is an absolute indication to withhold therapy. 1, 2, 4

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 improvements primarily in sexual function domains. 1, 4, 9 However, testosterone provides little to no benefit for physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism. 1, 4, 9 Set realistic expectations with patients and reevaluate at 12 months; discontinue if no improvement in sexual function is seen. 1