What are the guidelines for initiating testosterone replacement therapy (TRT) in adult males with diagnosed hypogonadism in a primary care setting?

Guidelines for Testosterone Replacement Therapy in Primary Care

Diagnostic Requirements Before Initiating TRT

Testosterone replacement therapy should only be initiated in adult males with confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1, 2

Laboratory Confirmation

• Measure morning total testosterone (drawn between 8-10 AM) on at least two separate occasions to confirm levels below 300 ng/dL 2, 3
• If total testosterone is borderline (275-350 ng/dL), measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in men with obesity or diabetes 2
• Once low testosterone is confirmed, measure serum LH and FSH to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 2
  • Elevated LH/FSH with low testosterone = primary hypogonadism 2
  • Low or low-normal LH/FSH with low testosterone = secondary hypogonadism 2

Critical Pre-Treatment Assessments

• Document baseline hematocrit/hemoglobin (treatment contraindicated if hematocrit >54%) 2, 3
• Perform digital rectal examination and measure PSA in men over 40 years (PSA >4.0 ng/mL requires urologic evaluation before initiating therapy) 2
• Screen for fertility desires (testosterone therapy is absolutely contraindicated in men seeking fertility—offer gonadotropin therapy instead) 2, 4
• Assess cardiovascular risk factors and ensure blood pressure is adequately controlled 3

Who Should NOT Receive TRT

Absolute Contraindications

• Active male breast cancer or prostate cancer 2, 4
• Men actively seeking fertility preservation (testosterone causes azoospermia) 2, 4
• Hematocrit >54% 2, 4
• Age-related low testosterone without structural or genetic etiologies (FDA-mandated restriction) 3

Strong Recommendations Against TRT

• Eugonadal men (normal testosterone levels), even if symptomatic, for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 2
• Men with age-related low-normal testosterone to improve energy, vitality, or physical function (produces little to no effect on these outcomes) 1, 5

First-Line Treatment Selection

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 lower erythrocytosis risk compared to injections. 2, 6

Alternative Formulations Based on Patient Factors

If cost is a primary concern:

• Intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks (annual cost ~$156 vs ~$2,135 for transdermal) 2
• Monitor testosterone levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL 2

If patient prefers less frequent dosing:

• Testosterone undecanoate 750 mg initially, repeat at 4 weeks, then every 10 weeks 2
• Measure trough levels before next injection 4

Oral testosterone undecanoate:

• Starting dose: 200 mg twice daily with food 3
• Adjust based on testosterone drawn 3-5 hours after morning dose at least 7 days after starting 3
• FDA boxed warning: Can cause blood pressure increases that increase risk of major adverse cardiovascular events 3

Expected Treatment Outcomes

Realistic Benefits to Discuss with Patients

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 2, 5
• Modest quality of life improvements, primarily in sexual function domains 1, 2
• Potential improvements in bone mineral density in men with osteoporosis 1
• Improvements in insulin sensitivity, triglycerides, and HDL cholesterol in men with metabolic syndrome 1, 2

Minimal or No Benefits

• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition 1, 5
• Energy/fatigue improvements are minimal (SMD 0.17) 2
• Depressive symptom improvements are "less-than-small" (SMD -0.19) 2

Monitoring Requirements

Initial Monitoring

• Measure testosterone levels 2-3 months after treatment initiation and after any dose change 2, 4
• Target mid-normal testosterone levels (500-600 ng/dL) 2, 4

Ongoing Monitoring (Every 6-12 Months Once Stable)

• Testosterone levels 2, 4
• Hematocrit/hemoglobin (withhold treatment if hematocrit >54%; consider phlebotomy in high-risk cases) 2, 4
• PSA in men over 40 years (refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter) 2
• Blood pressure monitoring (especially with oral formulations) 3
• Clinical symptom response, particularly sexual function 2

When to Discontinue Treatment

• If no improvement in sexual function after 12 months, discontinue treatment to prevent unnecessary long-term exposure to potential risks without benefit 2
• If hematocrit remains >54% despite dose adjustment 2, 4
• If significant PSA elevation occurs 2

Special Populations and Clinical Scenarios

Men with Secondary Hypogonadism Desiring Fertility

• Gonadotropin therapy (recombinant hCG plus FSH) is mandatory—testosterone is absolutely contraindicated 2
• Combined hCG and FSH therapy provides optimal outcomes for fertility preservation 2

Men with Obesity-Associated Secondary Hypogonadism

• Attempt weight loss through low-calorie diets and regular exercise BEFORE initiating testosterone, as this can improve testosterone levels without medication 2

Men with Diabetes

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction ~0.37%) 2
• Consider intensifying diabetes therapy concurrently with GLP-1 receptor agonist or SGLT2 inhibitor 2

Elderly Men (>65 Years)

• Use transdermal preparations over injections due to more stable levels and lower erythrocytosis risk 5
• Target mid-normal testosterone levels (350-600 ng/dL) 2
• Be aware that long-term safety beyond 36 months has not been established 5
• Low-certainty evidence suggests possible small increase in adverse cardiovascular events (Peto odds ratio 1.22) 5

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility 2
• Never diagnose hypogonadism based on symptoms alone without confirmed low testosterone on two separate morning measurements 2
• Never use testosterone in eugonadal men, even for symptomatic complaints 2
• Never assume age-related decline in young men—investigate for secondary causes of hypogonadism 2
• Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable formulations—measure midway between injections 2
• Never skip monitoring hematocrit—nearly half of men on testosterone therapy never have their levels checked, which is dangerous practice 2
• Do not expect meaningful improvements in energy, physical function, or cognition even with confirmed hypogonadism 1, 5

Cardiovascular Safety Considerations

The FDA issued a safety announcement in 2015 cautioning about possible increased risk of heart attack and stroke with TRT 1. However, level 1 trials have shown conflicting results, with most finding no difference in cardiovascular adverse events compared to placebo 1. Patients starting or currently prescribed TRT should be advised of these possible risks 1. Before initiating therapy, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled 3.