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

Laboratory Confirmation Steps:

• Measure morning total testosterone (drawn between 8 AM and 10 AM) on at least two separate occasions to confirm levels below 300 ng/dL 1, 2
• If total testosterone is borderline or the patient has obesity, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin level 2
• Once low testosterone is confirmed, measure serum LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 2
• Elevated LH/FSH with low testosterone indicates primary hypogonadism, while low or low-normal LH/FSH indicates secondary hypogonadism 2

Qualifying Symptoms:

• Primary symptoms with proven benefit: Diminished libido and erectile dysfunction 1
• Secondary symptoms with weaker evidence: Diminished sense of vitality 2
• Symptoms with minimal or no proven benefit: Fatigue, low energy, depressed mood, reduced physical function, or cognitive complaints 1

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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. 1

Alternative Formulations Based on Specific Circumstances:

• For cost concerns: Intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks (annual cost ~$156 vs ~$2,135 for transdermal) 1
• For elderly men (>65 years): Transdermal preparations are strongly preferred over injections due to lower erythrocytosis risk 1
• For patients with absorption concerns: Testosterone undecanoate 750 mg initially, repeat at 4 weeks, then every 10 weeks 3

Application Instructions for Transdermal Gel:

• Apply to clean, dry, intact skin of the shoulders and upper arms only 4
• Do NOT apply to abdomen, genitals, chest, armpits, or knees 4
• Wash hands immediately with soap and water after application 4
• Cover application sites with clothing after gel has dried 4
• Wash application site thoroughly with soap and water before any skin-to-skin contact with others 4

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Absolute Contraindications to TRT

Do not initiate testosterone therapy in men with any of the following conditions: 1, 5

• Active desire for fertility preservation (testosterone causes azoospermia; use gonadotropin therapy instead) 1, 2
• Active or treated male breast cancer 1
• Prostate cancer or PSA >4.0 ng/mL without urologic evaluation 5
• Hematocrit >54% 1, 3
• Untreated severe obstructive sleep apnea 5
• Myocardial infarction or stroke within the past 6 months 5
• Uncontrolled heart failure 5

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Expected Treatment Outcomes

Benefits with Strong Evidence:

• Sexual function and libido: Small but significant improvements (standardized mean difference 0.35) 1
• Quality of life: Modest improvements, primarily in sexual function domains 1
• Metabolic effects in diabetic men: Improved insulin resistance, glycemic control, and HbA1c reduction ~0.37% 1

Minimal or No Benefit:

• Physical functioning: Little to no effect 1
• Energy and vitality: Minimal improvement (SMD 0.17) 1
• Depressive symptoms: Less-than-small improvement (SMD -0.19) 1
• Cognition: No substantial benefit 1

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Monitoring Requirements

Initial Monitoring (First 3 Months):

• Measure testosterone levels at 2-3 months after treatment initiation, targeting mid-normal levels (500-600 ng/dL) 1, 2
• For injectable testosterone: measure levels midway between injections (days 5-7 after injection) 2
• For transdermal gel: measure pre-dose morning levels 1

Ongoing Monitoring (Every 6-12 Months Once Stable):

• Testosterone levels every 6-12 months 2
• Hematocrit/hemoglobin at each visit—withhold treatment if >54% and consider phlebotomy 1, 3
• 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 1
• Digital rectal examination to assess for prostate abnormalities 1
• Blood pressure monitoring 1

Dose Adjustment Criteria:

• If testosterone >750 ng/dL: Decrease daily dose by 20.25 mg 1
• If testosterone 350-750 ng/dL: Continue current dose 1
• If testosterone <350 ng/dL: Increase daily dose by 20.25 mg 1

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Special Population: Men Desiring Fertility

Testosterone therapy is absolutely contraindicated in men seeking fertility preservation, as it suppresses spermatogenesis and causes azoospermia. 1, 2

Alternative Treatment for Secondary Hypogonadism with Fertility Concerns:

• Mandatory treatment: Gonadotropin therapy with recombinant hCG plus FSH 1
• This stimulates the testes directly and can restore both testosterone levels and fertility potential 2
• Testosterone can be withdrawn later and gonadotropins initiated if fertility becomes a concern 6, 7

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Cardiovascular Safety Considerations

• The FDA issued a safety announcement in 2015 regarding possible increased risk of heart attack and stroke with TRT 1
• Patients should be advised of these possible risks before initiating therapy 1
• Baseline cardiovascular risk should be assessed, and men with recent cardiovascular events (within 3-6 months) should delay TRT initiation 1
• Injectable testosterone may carry higher cardiovascular risk than transdermal preparations due to fluctuating levels 1

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Critical Pitfalls to Avoid

• Never initiate TRT based on symptoms alone without confirmed biochemical hypogonadism (two morning testosterone measurements <300 ng/dL) 1, 2
• Never start TRT in eugonadal men (normal testosterone levels), even if symptomatic or for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1, 2
• Never assume age-related decline justifies treatment—safety and efficacy in "age-related hypogonadism" have not been established 4
• Never skip fertility counseling before initiating TRT in men of reproductive age 2
• Never continue TRT beyond 12 months without symptomatic improvement in sexual function 1
• Children and women must avoid contact with unwashed or unclothed application sites to prevent secondary exposure and virilization 4

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Discontinuation Criteria

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, to prevent unnecessary long-term exposure to potential risks without benefit. 1