What are the options, required laboratory tests, and primary care considerations for a male patient with low testosterone levels considering Hormone Replacement Therapy (HRT), including those with a history of prostate cancer, sleep apnea, or cardiovascular disease?

Male Hormone Replacement Therapy: Treatment Options, Laboratory Monitoring, and Primary Care Essentials

Treatment Options

Transdermal testosterone gel (1.62% formulation at 40.5 mg daily) is the preferred first-line treatment for male hypogonadism due to more stable day-to-day testosterone levels and lower risk of erythrocytosis compared to injectable formulations. 1

Available Formulations

Transdermal preparations:

• Testosterone gel 1.62%: Starting dose 40.5 mg daily, provides stable levels with only 5% experiencing skin reactions 2, 1
• Patches: Associated with higher skin reaction rates (up to 66% experience erythema or pruritus) 2
• Annual cost approximately $2,135, but 71% of patients prefer gels for convenience and ease of use 2, 1

Injectable testosterone:

• Testosterone cypionate or enanthate: 100-200 mg every 2 weeks or 50-100 mg weekly 2, 1
• Peak levels occur days 2-5 after injection, return to baseline by days 10-14 2, 1
• Annual cost approximately $156, making it the most economical option 2, 1
• Higher risk of erythrocytosis (43.8%) compared to transdermal (15.4%) 3
• Measure testosterone levels midway between injections (days 5-7), targeting 500-600 ng/dL 1

Long-acting injectable:

• Testosterone undecanoate: 750 mg initially, repeat at 4 weeks, then every 10 weeks 1
• Provides fewer yearly injections with more stable levels 1

Oral formulation:

• Jatenzo (oral testosterone undecanoate): FDA-approved dosing, measure levels 4-6 hours after morning dose 1

Patient Selection Considerations

Cost-conscious patients: Injectable testosterone is significantly more economical at $156/year versus $2,135/year for transdermal 2, 1

Elderly patients or those with chronic illness: Use easily titratable formulations (gel, spray, patch) rather than long-acting injectables to reduce erythrocytosis risk 3

Patients prioritizing convenience: 71% prefer topical gel over injections for ease of use and non-staining properties 2

Required Laboratory Tests

Baseline Testing (Before Initiating Therapy)

Diagnostic confirmation requires:

• Two separate morning total testosterone measurements (8-10 AM) below 300 ng/dL 2, 1
• Free testosterone by equilibrium dialysis in men with borderline total testosterone, obesity, or diabetes where SHBG abnormalities are suspected 1
• Sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from SHBG-related decreases 1
• LH and FSH levels to distinguish primary (elevated LH/FSH) from secondary (low/low-normal LH/FSH) hypogonadism 2, 1

Mandatory safety screening:

• Hemoglobin/hematocrit: Withhold therapy if hematocrit >50% until etiology investigated 2, 3
• PSA level in men over 40 years: Levels >4.0 ng/mL require urologic evaluation before starting therapy 2, 1
• Digital rectal examination: Assess for palpable prostate nodules or induration 2
• Fasting glucose: Exclude diabetes, as testosterone may improve insulin resistance 1
• Lipid panel: Optional but recommended to assess cardiovascular risk 2

Additional screening:

• History of sleep apnea: Testosterone may potentiate sleep apnea, especially in obese patients 2
• Voiding symptoms assessment: Use International Prostatic Symptoms Score 2
• Prolactin level: If loss of libido is prominent or testosterone is very low 1

Monitoring During Therapy

Initial follow-up at 1-2 months:

• Testosterone levels: Assess efficacy and consider dose escalation if suboptimal 2, 1
• Hematocrit/hemoglobin: Monitor for erythrocytosis 2
• Clinical symptom response: Particularly sexual function and libido 1

Subsequent monitoring every 3-6 months for first year, then annually:

• Testosterone levels: Target mid-normal range (500-600 ng/dL) 2, 1
• Hematocrit: Withhold treatment if >54% and consider phlebotomy 2, 3
• PSA levels in men over 40: Refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 2, 1
• Digital rectal examination: Assess for prostate abnormalities 2
• Voiding symptoms: Monitor for worsening benign prostatic hyperplasia 2

Primary Care Provider Essentials

Absolute Contraindications

Never initiate testosterone therapy in men with:

• Active desire for fertility preservation: Testosterone causes azoospermia through suppression of FSH; use gonadotropin therapy (hCG plus FSH) instead 2, 1
• Active or treated male breast cancer 2, 1
• Prostate cancer on active surveillance or androgen deprivation therapy 2, 1
• Hematocrit >54% 2, 3
• Untreated severe obstructive sleep apnea 2, 4
• Recent cardiovascular events within past 3-6 months 1
• PSA >4.0 ng/mL without urologic clearance 2, 1

Realistic Treatment Expectations

Benefits with strong evidence:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 2, 1
• Modest quality of life improvements, primarily in sexual function domains 2, 1
• Improvements in bone mineral density and lean body mass 2, 1
• Potential improvements in fasting glucose, insulin resistance, and lipid profile 1

Minimal or no proven benefits:

• Little to no effect on physical functioning (SMD 0.15) 2, 1
• Minimal improvements in energy and vitality (SMD 0.17) 2, 1
• Less-than-small improvements in depressive symptoms (SMD -0.19), and most men in studies did not have baseline depression 2, 1
• No differences in cognitive function 2, 1

Discontinue therapy if no improvement in sexual function after 12 months to prevent unnecessary long-term exposure without benefit 1

Critical Safety Concerns

Erythrocytosis:

• Most common serious adverse effect, particularly with injectable testosterone (43.8% vs 15.4% with transdermal) 3
• Hematocrit >54% warrants immediate intervention: temporarily withhold therapy, reduce dose, or perform therapeutic phlebotomy 2, 3
• Increased blood viscosity impairs microcirculation, particularly dangerous in elderly patients or those with vascular disease 3

Cardiovascular considerations:

• Low-certainty evidence shows small increase to no difference in adverse cardiovascular events (Peto odds ratio 1.22) 2
• FDA warning exists regarding possible increased cardiovascular risk, though data remain inconclusive 5, 6
• Use cautiously in men with congestive heart failure or renal insufficiency due to fluid retention risk 2

Prostate monitoring:

• No definitive evidence that testosterone stimulates prostate cancer growth, but monitoring remains mandatory 2
• Increased PSA (>1.0 ng/mL in first 6 months or >0.4 ng/mL per year) requires urologic referral 1

Fertility impact:

• Exogenous testosterone suppresses spermatogenesis through negative feedback on pituitary FSH 2, 1, 5
• Recovery of spermatogenesis is highly variable and may take months to years after discontinuation 2
• Counsel all men of reproductive age about fertility implications before starting therapy 2

Common Pitfalls to Avoid

Diagnostic errors:

• Never diagnose hypogonadism based on symptoms alone without confirmed low testosterone on two separate morning measurements 1
• Never start testosterone in eugonadal men (normal testosterone levels), even if symptomatic—approximately 20-30% of men receiving testosterone in the US lack documented low testosterone 1
• Don't measure testosterone while patient is on therapy to diagnose type of hypogonadism—requires 2-4 week washout period 1
• In men with borderline total testosterone, always measure free testosterone by equilibrium dialysis, as 26.3% of men over 60 have normal total but low free testosterone 1

Treatment errors:

• Never prescribe testosterone to men actively seeking fertility—use gonadotropin therapy (hCG plus FSH) instead 2, 1
• Don't draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable formulations—measure midway between injections 2, 1
• Don't assume age-related decline justifies treatment—requires both biochemical confirmation and specific symptoms (primarily sexual dysfunction) 1
• Nearly half of men on testosterone therapy never have their levels checked—this is dangerous practice 1

Monitoring failures:

• Don't skip hematocrit monitoring—erythrocytosis is the most common serious adverse effect requiring intervention 2, 3
• Don't continue therapy beyond 12 months without documented improvement in sexual function 1
• Don't ignore PSA increases—refer for urologic evaluation with increases >1.0 ng/mL in first 6 months 1

Special Populations

Men with obesity-associated secondary hypogonadism:

• First attempt weight loss through low-calorie diets and regular exercise, which can improve testosterone levels without medication 1
• Excessive aromatization in adipose tissue converts testosterone to estradiol, causing negative feedback on LH secretion 1

Men with diabetes:

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction of approximately 0.37%) 1
• Optimize diabetes management concurrently, considering GLP-1 receptor agonists or SGLT2 inhibitors for cardiovascular benefits 1

Men with history of prostate cancer:

• Post-radical prostatectomy with favorable pathology (negative margins, undetectable PSA): Testosterone can be considered after careful discussion 2
• Post-radiation therapy: Limited data suggest safety, but requires close PSA monitoring 2
• Active surveillance or metastatic disease: Testosterone remains contraindicated 2, 1

Men with sleep apnea:

• Testosterone may worsen sleep apnea, especially in obese patients or those with chronic lung disease 2, 5, 4
• Untreated severe obstructive sleep apnea is an absolute contraindication 2, 4

Secondary Hypogonadism Considerations

When secondary hypogonadism is confirmed (low testosterone with low/low-normal LH/FSH):

• Investigate underlying causes: Measure prolactin, consider pituitary function testing, evaluate for sleep disorders, thyroid dysfunction, anemia, vitamin D deficiency 1
• Consider MRI of sella turcica to identify hypothalamic/pituitary dysfunction etiology 1
• For men desiring fertility: Gonadotropin therapy (hCG plus FSH) is mandatory—testosterone is absolutely contraindicated 2, 1
• Alternative to testosterone: Clomiphene citrate 25-50 mg three times weekly (off-label) stimulates endogenous testosterone production while preserving fertility 1