What are the qualifications for a male patient to undergo testosterone replacement therapy (TRT) for hypogonadism?

Testosterone Replacement Therapy Qualifications

A male patient qualifies for testosterone replacement therapy when he has BOTH 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

Diagnostic Requirements

Biochemical Confirmation

• Measure morning total testosterone (between 8-10 AM) on at least two separate days to establish persistent hypogonadism, as single measurements are insufficient due to assay variability and diurnal fluctuation 1, 2
• Testosterone must be below 300 ng/dL (some guidelines use 275-350 ng/dL threshold) to establish hypogonadism 1, 2
• Measure free testosterone by equilibrium dialysis in men with borderline total testosterone, obesity, or diabetes, where low SHBG may artificially lower total testosterone while free testosterone remains normal 1
• Measure sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from low SHBG-related decreases in total testosterone 1

Determine Type of Hypogonadism

• Measure serum LH and FSH after confirming low testosterone to distinguish primary from secondary hypogonadism, which has critical treatment implications 1, 2
• Elevated LH/FSH with low testosterone indicates primary (testicular) hypogonadism, while low or low-normal LH/FSH with low testosterone indicates secondary (hypothalamic-pituitary) hypogonadism 1
• For secondary hypogonadism, measure serum prolactin to investigate for hyperprolactinemia, which can cause secondary hypogonadism 1
• Consider pituitary MRI if secondary hypogonadism is confirmed to identify etiology of hypothalamic/pituitary dysfunction 1

Qualifying Symptoms

Primary Indications (Strong Evidence for Benefit)

• Diminished libido and sexual desire are the primary symptoms warranting treatment 1, 3
• Erectile dysfunction that may be testosterone-related, particularly when PDE5 inhibitors have failed 1
• Approximately 36% of men seeking consultation for sexual dysfunction have hypogonadism, and testosterone replacement improves response to PDE5 inhibitors 1

Secondary Symptoms (Weaker Evidence)

• Diminished sense of vitality, though evidence for improvement is weaker 4
• Muscle weakness and reduced muscle mass 5
• Mood changes and depressive symptoms, though improvements are minimal (SMD -0.19) 1, 3

Symptoms with Minimal or No Proven Benefit

The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men 1. Even in confirmed hypogonadism:

• Fatigue and low energy show minimal improvement (SMD 0.17) 1, 3
• Physical functioning shows little to no improvement 1, 3
• Cognitive complaints show no benefit 1, 3

Absolute Contraindications

Testosterone therapy must NOT be initiated if any of the following are present:

• Active desire for fertility preservation - testosterone causes azoospermia and suppresses spermatogenesis; gonadotropin therapy (hCG plus FSH) is mandatory instead 1, 2
• Active or treated male breast cancer 1, 2
• Known or suspected prostate cancer 2
• Hematocrit >54% 1, 2
• Untreated severe obstructive sleep apnea 1, 2
• Unstable cardiovascular conditions (recent MI or stroke within 3-6 months) 1
• Pregnancy in female partners - women who are pregnant should not be exposed to testosterone 2

Pre-Treatment Evaluation

Required Laboratory Tests

• Baseline hematocrit or hemoglobin to monitor for potential erythrocytosis during treatment 1, 6
• PSA level and digital rectal examination in men over 40 years, with PSA >4.0 ng/mL requiring urologic evaluation and documented negative prostate biopsy before initiating therapy 1
• Fasting glucose to exclude diabetes 1

Special Population Considerations

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 1
• Excessive aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion 1

Men with Diabetes:

• Measure morning total testosterone using an accurate assay in diabetic men with symptoms or signs of hypogonadism 1
• Measure free or bioavailable testosterone in diabetic men with total testosterone near the lower limit 1

Young Men with Secondary Hypogonadism:

• Never start testosterone without confirming the patient does not desire fertility 1
• Never skip investigation for secondary causes of hypogonadism, as reversible conditions must be addressed first 1
• Gonadotropin therapy is first-line treatment for men with secondary hypogonadism who desire fertility preservation 1

Men Using Opioids:

• Opioids can cause secondary hypogonadism, making it essential to evaluate the cause of low testosterone levels 6
• Consider whether opioid-induced hypogonadism might improve with opioid dose reduction or discontinuation before committing to lifelong testosterone therapy 6

Critical Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without confirmed biochemical testing 1
• Never use screening questionnaires or symptoms alone to diagnose hypogonadism due to lack of specificity 1
• Approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation, representing inappropriate prescribing 1, 3
• Never assume age-related decline in young men - investigate for secondary causes 1
• Do not attempt to diagnose the type of hypogonadism based on gonadotropin levels while the patient is on testosterone therapy, as results will be misleading 1

Expected Treatment Outcomes

Realistic Expectations to Discuss with Patients

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 3
• Modest quality of life improvements, primarily in sexual function domains 1, 3
• Little to no effect on physical functioning, energy, vitality, or cognition even in confirmed hypogonadism 1, 3
• Minimal improvements in depressive symptoms (SMD -0.19) 1, 3
• Potential improvements in metabolic syndrome markers, including insulin sensitivity 4, 3
• Increased lean body mass by approximately 2078 grams over 40 weeks 3

Long-Term Considerations

• Long-term efficacy and safety data are limited, particularly beyond 36 months 3
• Cardiovascular safety data are insufficient, with trials not powered to assess heart attacks or strokes 3
• Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen 1