What is the recommended approach to managing hypogonadism in a male patient in his 50s or 60s with a decline in testosterone levels from 495 ng/dl to 288 ng/dl over 6 years, presenting with symptoms such as brain fog, anxiety, and anhedonia?

Management of Declining Testosterone in a Male Patient in His 50s-60s

Direct Recommendation

You should initiate testosterone replacement therapy given confirmed biochemical hypogonadism (288 ng/dL) with specific symptoms of brain fog, anxiety, and anhedonia, though you must set realistic expectations: testosterone provides only small improvements in sexual function but minimal to no benefit for cognitive symptoms, energy, or mood. 1, 2

Diagnostic Confirmation Required Before Treatment

Critical first step: Confirm hypogonadism with a second morning testosterone measurement (8-10 AM) to establish persistent low levels, as single measurements are insufficient due to assay variability and diurnal fluctuation. 2

• Your patient's decline from 495 ng/dL to 288 ng/dL over 6 years represents true biochemical hypogonadism (threshold <300 ng/dL). 2
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from SHBG-related decreases. 2
• Obtain LH and FSH levels to differentiate primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism—this distinction has critical treatment implications for fertility preservation. 2

Setting Realistic Expectations: What Testosterone Will and Won't Do

Here's the evidence-based reality you must communicate:

Minimal to No Benefit for Your Patient's Primary Complaints:

• Brain fog/cognition: Testosterone produces little to no effect on cognitive function, even in confirmed hypogonadism. 1, 2
• Anxiety/mood: Only "less-than-small improvement" in depressive symptoms (standardized mean difference -0.19), with effect sizes too small to be clinically meaningful. 1, 3
• Anhedonia/energy: Minimal improvements in vitality and fatigue (standardized mean difference 0.17)—barely distinguishable from placebo. 1, 3

Small Benefits You Can Expect:

• Sexual function: Small but significant improvements in libido and erectile function (standardized mean difference 0.35). 1, 2
• Quality of life: Modest improvements, primarily driven by sexual function domains rather than energy or mood. 2
• Metabolic effects: Improvements in insulin resistance, triglycerides, and HDL cholesterol. 2

Treatment Algorithm

Step 1: Address Reversible Causes First

Before initiating testosterone, evaluate and treat:

• Weight loss if obese: Low-calorie diets and exercise can improve testosterone levels in obesity-associated secondary hypogonadism without medication. 2
• Sleep disorders, thyroid dysfunction, anemia, vitamin D deficiency. 2
• Metabolic syndrome and cardiovascular risk factors. 2

Step 2: Pre-Treatment Safety Screening (Absolute Requirements)

• Hematocrit/hemoglobin: Contraindicated if hematocrit >50-54%. 2, 3
• PSA and digital rectal exam (for men over 40): PSA >4.0 ng/mL requires urologic evaluation before starting. 2
• Fertility counseling: Testosterone is absolutely contraindicated if the patient desires fertility preservation—use gonadotropin therapy (hCG plus FSH) instead. 2
• Cardiovascular history: Recent cardiovascular events within 3-6 months warrant delaying initiation. 2

Step 3: Formulation Selection

Intramuscular testosterone cypionate or enanthate is preferred over transdermal preparations due to significantly lower cost ($156.24 vs $2,135.32 annually) with similar clinical effectiveness and harms. 1, 2, 3

Dosing:

• Start with testosterone cypionate 100-200 mg every 2 weeks or 50-100 mg weekly. 2
• Target mid-normal testosterone levels (500-600 ng/dL) when monitoring. 2, 3
• Measure testosterone levels midway between injections (days 5-7 after injection). 2

Alternative if cost is not a concern:

• Transdermal testosterone gel 1.62% at 40.5 mg daily provides more stable day-to-day levels and lower erythrocytosis risk. 2, 4

Step 4: Monitoring Protocol

Initial monitoring (critical for safety):

• Testosterone levels at 2-3 months after initiation or dose change. 2
• Once stable, monitor every 6-12 months. 2

Ongoing safety monitoring:

• Hematocrit periodically: Withhold treatment if >54% and consider phlebotomy in high-risk cases. 2
• PSA levels (men over 40): Urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter. 2

Step 5: Reassessment and Discontinuation Criteria

Reevaluate symptoms at 12 months. 1, 2

Discontinue testosterone if:

• No improvement in sexual function (the only domain with proven benefit). 1, 2
• Hematocrit exceeds 54% despite dose adjustment. 2
• Development of contraindications (prostate cancer, severe cardiovascular events). 2

Critical Pitfalls to Avoid

Do not prescribe testosterone based on symptoms alone without confirmed biochemical hypogonadism (two measurements <300 ng/dL)—approximately 20-30% of men receiving testosterone in the US violate this guideline. 2, 3

Do not assume testosterone will improve brain fog, anxiety, or anhedonia—the evidence shows minimal to no benefit for these symptoms, and you risk exposing the patient to unnecessary risks (erythrocytosis, cardiovascular events) without benefit. 1, 3, 5

Never start testosterone without confirming the patient does not desire fertility—exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia. 2

Do not skip investigation for secondary causes of hypogonadism in a man in his 50s-60s—measure prolactin, iron saturation, and consider pituitary imaging if secondary hypogonadism is confirmed. 2

Alternative Approach: Non-Hormonal Management

Given the lack of evidence for testosterone improving your patient's primary complaints (brain fog, anxiety, anhedonia), consider:

• PDE5 inhibitors (sildenafil, tadalafil) for erectile dysfunction, which can be combined with testosterone for optimal results. 2
• Cognitive-behavioral therapy or antidepressants for anxiety and anhedonia—these have stronger evidence than testosterone for mood disorders. 2
• Exercise programs for fatigue and vitality—physical activity improves sexual function and testosterone levels. 2

Cardiovascular Safety Considerations

The 2024 TRAVERSE trial (the largest randomized trial to date) showed testosterone does not increase the risk of myocardial infarction or stroke, even in high-risk patients. 6 However, low-certainty evidence suggests a possible small increase in adverse cardiovascular events (Peto odds ratio 1.22). 1, 5 Injectable testosterone may carry higher cardiovascular risk than transdermal preparations due to supraphysiologic and subtherapeutic fluctuations. 2

Long-Term Safety Concerns

Long-term safety and efficacy beyond 36 months have not been established, particularly concerning for elderly patients. 5 Erythrocytosis occurs in 2.8-44% of patients depending on formulation, with higher rates in injectable testosterone. 2, 5 While some pooled analyses showed fewer deaths with testosterone, the evidence was too imprecise to draw firm conclusions about mortality. 5