What are the guidelines for testosterone replacement therapy in patients with low testosterone levels?

Testosterone Replacement Therapy Guidelines

Diagnostic Criteria

Testosterone replacement therapy should only be initiated when a patient has both confirmed biochemical hypogonadism (total testosterone <300 ng/dL on two separate morning measurements) AND specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1

Required Laboratory Confirmation

• Obtain two separate total testosterone measurements between 8 AM and 10 AM on different days, both showing levels <300 ng/dL 1, 2
• Use the same laboratory and methodology for both measurements to ensure consistency 1
• Measure serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after confirming low testosterone to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 1, 2
• Elevated LH/FSH with low testosterone indicates primary hypogonadism; low or low-normal LH/FSH with low testosterone indicates secondary hypogonadism 2

Clinical Symptoms to Document

• Sexual symptoms: reduced libido, erectile dysfunction, decreased sexual function 1
• Energy-related: reduced energy, reduced endurance, diminished work/physical performance, fatigue 1
• Cognitive/mood: depression, reduced motivation, poor concentration, impaired memory, irritability 1

Physical Examination Findings

• Evaluate body habitus, virilization status (body hair patterns in androgen-dependent areas), body mass index or waist circumference 1
• Assess for gynecomastia, testicular size/consistency/masses, varicocele presence, prostate size and morphology 1

Additional Testing Requirements

Mandatory Adjunctive Tests

• Measure serum prolactin in patients with low testosterone combined with low or low-normal LH levels to screen for hyperprolactinemia 1
• If prolactin is elevated, repeat measurement; persistently elevated levels require endocrinology referral for possible pituitary tumor evaluation 1
• Men with total testosterone <150 ng/dL combined with low or low-normal LH should undergo pituitary MRI regardless of prolactin levels 1

Condition-Specific Screening

Measure testosterone even without symptoms in men with: 1

• Unexplained anemia
• Bone density loss
• Diabetes
• Exposure to chemotherapy or testicular radiation
• HIV/AIDS
• Chronic narcotic use
• Male infertility
• Pituitary dysfunction
• Chronic corticosteroid use

Treatment Selection Algorithm

First-Line Therapy

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 compared to injections. 2

• Apply to clean, dry, intact skin of upper arms and shoulders only 3
• Cover application site with clothing after gel dries 3
• Avoid swimming or showering for minimum 2 hours after application 3
• Annual cost approximately $2,135 1

Alternative: Intramuscular Injections

If cost is a primary concern, intramuscular testosterone cypionate or enanthate 50-400 mg every 2-4 weeks is more economical (annual cost approximately $156). 1, 4

• Peak serum levels occur 2-5 days after injection, with return to baseline by days 10-14 2, 4
• Measure testosterone levels midway between injections, targeting mid-normal value (500-600 ng/dL) 2
• Higher risk of erythrocytosis compared to transdermal preparations 2, 5

Absolute Contraindications

Testosterone therapy is absolutely contraindicated in the following situations: 2, 4, 3

• Men actively seeking fertility (use gonadotropin therapy instead: hCG plus FSH) 1, 2
• Active or treated male breast cancer 2, 4
• Known or suspected prostate cancer 4, 3
• Pregnancy in female partners (risk of fetal virilization) 3

Monitoring Requirements

Initial Monitoring (First 2-3 Months)

• Check testosterone levels 2-3 months after treatment initiation or any dose change 2
• For injection patients, measure midway between injections 2
• For transdermal patients, measure morning levels 2

Ongoing Monitoring (Every 6-12 Months)

Once stable testosterone levels are confirmed, monitor the following every 6-12 months: 2

• Hematocrit/hemoglobin: withhold treatment if hematocrit >54% and consider phlebotomy in high-risk cases 2
• PSA levels in men over 40 years 2
• Prostate examination for benign prostatic hyperplasia symptoms 2
• Symptom assessment, particularly sexual function 1

Expected Outcomes and Realistic Expectations

Documented Benefits

Testosterone therapy produces small but significant improvements in sexual function (SMD 0.35) and quality of life. 1, 5

• Improved libido and sexual function 1, 2
• Small improvements in vitality and fatigue (SMD 0.17) 1
• Modest improvements in depressive symptoms (SMD 0.19 lower), though most men in studies did not have baseline depression 1

Limited or No Benefits

Little to no effect has been demonstrated on: 1, 5

• Physical functioning
• Energy and vitality (beyond small improvements noted above)
• Cognitive function
• Work performance

Treatment Discontinuation Criteria

If no improvement in sexual function is observed after 12 months of therapy, discontinue treatment to prevent unnecessary long-term exposure to potential risks without benefit. 2

Critical Fertility Preservation Considerations

For men with secondary hypogonadism who desire fertility preservation: 1, 2

• Testosterone therapy is absolutely contraindicated as it suppresses spermatogenesis and causes prolonged azoospermia 1
• Use gonadotropin therapy (recombinant hCG plus FSH) instead, which stimulates testes directly and can restore both testosterone levels and fertility potential 2, 6
• Selective estrogen receptor modulators may be considered for patients with low/normal LH who wish to preserve fertility 1

Safety Concerns and Risk Mitigation

Cardiovascular and Mortality

• Low-certainty evidence suggests possible small increase in adverse cardiovascular events (Peto odds ratio 1.22) 5
• Evidence on mortality is too imprecise to draw firm conclusions, though some pooled analyses showed fewer deaths with testosterone treatment 1, 5
• Most studies excluded men with recent cardiovascular disease 1

Hematologic Risks

• Erythrocytosis occurs in 2.8-17.9% of patients depending on formulation, with up to 44% risk with injections 5
• Monitor hemoglobin and hematocrit periodically 5

Prostate-Related Concerns

• Current evidence fails to definitively support concerns about prostate cancer development, though monitoring remains appropriate 1
• Patients with benign prostatic hyperplasia are at increased risk for worsening signs and symptoms 3

Common Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone or using screening questionnaires 1, 2
• Never start testosterone without confirming the patient does not desire fertility 2
• Never attempt to diagnose type of hypogonadism (primary vs. secondary) while patient is on testosterone therapy, as results will be misleading 2
• Never use testosterone therapy in eugonadal men (normal testosterone levels), even if symptomatic or for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 2
• Never assume age-related decline in young men without investigating for secondary causes of hypogonadism 2

Special Population: Elderly Men

In elderly men with symptomatic hypogonadism, testosterone therapy should be initiated primarily to improve sexual function, not for energy, vitality, physical function, or cognition. 1

• Long-term safety and efficacy beyond 36 months have not been established 5
• Consider non-hormonal alternatives for specific symptoms (e.g., PDE5 inhibitors for erectile dysfunction, exercise for fatigue) if contraindications exist 5