What are the benefits and risks of exogenous testosterone therapy for men with documented symptomatic hypogonadism (total testosterone <300 ng/dL on at least two morning measurements)?

Risks and Benefits of Exogenous Testosterone Therapy

Diagnostic Requirements Before Initiating Therapy

Testosterone therapy should only be initiated in men with confirmed biochemical hypogonadism (total testosterone <300 ng/dL on two separate morning measurements between 8–10 AM) AND specific symptoms—primarily diminished libido and erectile dysfunction. 1

• Measure serum LH and FSH after confirming low testosterone to differentiate primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism, as this distinction is critical for treatment selection and fertility counseling 1
• In borderline cases (total testosterone 231–346 ng/dL) or obese men, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from functional low testosterone 1
• Approximately 25–30% of men receiving testosterone therapy do not actually meet diagnostic criteria for hypogonadism, highlighting the importance of strict adherence to testing protocols 1

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Proven Benefits of Testosterone Therapy

Sexual Function (Primary Indication)

• Small but statistically significant improvement in sexual function and libido with a standardized mean difference of 0.35 1
• Improvements in erectile function, particularly when combined with PDE5 inhibitors in men with both low testosterone and erectile dysfunction 1
• These sexual benefits represent the strongest evidence-based indication for therapy 1

Metabolic Parameters

• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 1
• Potential reduction in HbA1c of approximately 0.37% in hypogonadal men with type 2 diabetes 1
• Modest improvements in body composition with increased lean body mass and decreased visceral adiposity 1, 2

Bone Health

• Modest improvements in bone mineral density, with approximately 3.2% increase at the lumbar spine and 1.4% increase at the femoral neck 1

Hematologic Effects

• May help correct mild anemia in some patients 1

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Minimal or No Benefits (Critical to Communicate)

Testosterone therapy produces little to no clinically meaningful effect on the following, even in confirmed hypogonadism: 1

• Physical functioning and muscle strength – effect sizes are negligible 1
• Energy and vitality – standardized mean difference of only 0.17, clinically insignificant 1
• Depressive symptoms – less-than-small improvement with SMD of -0.19 1
• Cognition and memory – no measurable benefit 1
• Quality of life – improvements are modest and confined mainly to sexual function domains 1

These limitations must be discussed with patients to set realistic expectations. 1

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Risks and Adverse Effects

Erythrocytosis (Most Common Serious Risk)

• Injectable testosterone carries the highest risk: approximately 44% of users develop hematocrit >52% 1
• Transdermal preparations have lower risk: approximately 15% develop erythrocytosis 1
• Elevated hematocrit increases blood viscosity and can exacerbate coronary, cerebrovascular, and peripheral vascular disease, particularly in elderly patients 1
• Withhold therapy if hematocrit exceeds 54%; consider therapeutic phlebotomy in high-risk cases 1

Cardiovascular Considerations

• The 2023 TRAVERSE trial (5,246 men with pre-existing or high cardiovascular risk) showed no significant increase in major adverse cardiac events or stroke with transdermal testosterone gel versus placebo over 21.7 months 1
• However, some postmarketing studies have suggested increased risk of myocardial infarction and stroke 3
• Avoid initiating therapy within 3–6 months of a cardiovascular event 1
• Injectable testosterone may carry greater cardiovascular risk than transdermal preparations due to supraphysiologic peak levels 1

Fertility Suppression

• Exogenous testosterone causes azoospermia by suppressing the hypothalamic-pituitary-gonadal axis 1
• This effect can be prolonged and potentially irreversible 1
• Testosterone therapy is absolutely contraindicated in men desiring fertility preservation; gonadotropin therapy (hCG plus FSH) should be used instead in secondary hypogonadism 1

Prostate-Related Effects

• Potential worsening of benign prostatic hyperplasia (BPH) symptoms 1, 3
• Theoretical risk of prostate cancer stimulation, though evidence remains controversial 1
• Monitor PSA levels; refer to urology if PSA rises >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1

Other Adverse Effects

• Fluid retention, which may worsen congestive heart failure in susceptible patients 1, 3
• Gynecomastia 1
• Acne or oily skin 1
• Testicular atrophy 1
• Sleep apnea (may worsen in those with risk factors) 1, 3
• Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism 3

Secondary Exposure Risk

• Virilization has been reported in children secondarily exposed to testosterone gel 3
• Women and children should avoid contact with unwashed or unclothed application sites 3
• Patients must wash hands immediately after application and cover sites with clothing after gel dries 3

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Absolute Contraindications

Do not initiate testosterone therapy in men with: 1

• Active desire for fertility preservation (use gonadotropin therapy instead)
• Active or treated male breast cancer
• Known or suspected prostate cancer
• Hematocrit >54%
• Pregnancy in female partners (testosterone may cause fetal harm) 3
• Recent cardiovascular event within 3–6 months
• Severe untreated obstructive sleep apnea

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Monitoring Requirements

Baseline Assessment

• Hematocrit/hemoglobin 1
• PSA (in men >40 years) and digital rectal examination 1
• Fasting glucose and HbA1c 1
• Lipid profile 1

Follow-Up Schedule

• 2–3 months after initiation: measure testosterone (midway between injections for injectables, targeting 450–600 ng/dL), hematocrit, and PSA 1
• Every 3–6 months during first year: repeat testosterone, hematocrit, PSA, lipid profile, and digital rectal examination 1
• Annually thereafter once stable 1

Discontinuation Criteria

• If no improvement in sexual function after 12 months, discontinue therapy to prevent unnecessary long-term exposure without benefit 1

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Formulation Selection Considerations

Transdermal Testosterone Gel (First-Line)

• Preferred initial formulation due to more stable day-to-day testosterone levels 1
• Lower risk of erythrocytosis (15%) compared to injectables (44%) 1
• Typical starting dose: 40.5 mg daily (1.62% gel) 1, 3
• Disadvantages: higher cost ($2,135/year vs. $156/year for injectables), risk of transfer to others 1

Intramuscular Injections

• More economical option 1
• Typical dosing: 100–200 mg every 2 weeks or 50–100 mg weekly 1
• Higher risk of erythrocytosis due to supraphysiologic peaks 2–5 days post-injection 1
• Weekly dosing provides more stable levels than bi-weekly 1

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Critical Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement or symptoms alone—require two morning values <300 ng/dL plus specific sexual symptoms 1
• Never initiate therapy without confirming the patient does not desire fertility, as testosterone causes prolonged azoospermia 1
• Never prescribe testosterone for weight loss, energy enhancement, or athletic performance—these are not evidence-based indications 1
• Never continue therapy in men with hematocrit >54%—this is an absolute indication to withhold treatment 1
• Never ignore mild erythrocytosis (hematocrit 50–52%) in elderly or cardiovascular-risk patients, as even modest elevations increase thrombotic risk 1
• Nearly 50% of men on testosterone therapy never have their levels rechecked, representing a dangerous practice pattern 1

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Special Populations

Obesity-Associated Secondary Hypogonadism

• First-line treatment is weight loss through hypocaloric diet (500–750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2–3 times/week) 1
• Weight loss of 5–10% can significantly increase endogenous testosterone production 1
• Testosterone therapy should only be considered after lifestyle modification attempts if hypogonadism persists 1

Men with Diabetes

• Testosterone therapy may improve insulin resistance and glycemic control 1
• Androgens may decrease blood glucose and insulin requirements—monitor closely and adjust diabetes medications as needed 3

Elderly Men

• Target mid-range testosterone levels (350–600 ng/dL) rather than upper-normal 1
• Use transdermal formulations preferentially over injectables due to lower erythrocytosis risk 1
• Primary indication remains sexual dysfunction—minimal benefit for frailty, physical function, or cognition 1