Testosterone Replacement Therapy: Risks and Benefits

Primary Recommendation

Testosterone replacement therapy should be initiated only in men with confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND associated symptoms—primarily diminished libido and erectile dysfunction—with the understanding that benefits are modest for sexual function and quality of life, while effects on energy, physical function, and cognition are minimal to absent. 1, 2, 3

Diagnostic Requirements Before Initiating Therapy

Biochemical Confirmation

Measure morning total testosterone (8-10 AM) on two separate occasions to confirm persistent hypogonadism, as single measurements are unreliable due to assay variability and diurnal fluctuation 2, 3, 4
Testosterone levels below 300 ng/dL (some guidelines use 275-350 ng/dL threshold) establish biochemical hypogonadism 1, 2, 3
Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) in men with borderline total testosterone or obesity 2, 5
Obtain LH and FSH levels to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism, which has critical treatment implications for fertility preservation 2, 5, 4

Symptom Requirements

Primary indication: Diminished libido and erectile dysfunction 2, 3
Secondary symptoms that may support treatment: Decreased energy, depressed mood, reduced muscle mass, decreased bone density 1, 2, 3
Critical caveat: Approximately 20-30% of men receiving testosterone in the United States lack documented low testosterone before treatment initiation—a practice that violates evidence-based guidelines 2

Expected Benefits: Setting Realistic Expectations

Sexual Function (Primary Benefit)

Small but significant improvement in global sexual function and libido (standardized mean difference 0.35) 1, 2, 3
Modest improvement in erectile function (SMD 0.27) 1
These represent the strongest and most consistent benefits of testosterone therapy 1, 2, 6

Quality of Life

Small improvement in quality of life scores (SMD 0.33 on Aging Males' Symptoms scale), primarily driven by sexual function improvements rather than energy or mood 1, 2
This translates to moving from "moderate to mild symptom severity" on average 2

Energy, Vitality, and Mood (Minimal Benefits)

Less-than-small improvement in energy and fatigue (SMD 0.17)—barely distinguishable from placebo 1, 2
Less-than-small improvement in depressive symptoms (SMD 0.19), though most men in studies did not have baseline depression 1, 2
Little to no effect on physical functioning, even with objective measures like walk tests 1, 2

Metabolic and Body Composition

May improve insulin resistance, fasting glucose, triglycerides, and HDL cholesterol 5, 6
In conjunction with lifestyle programs, testosterone therapy reversed or reduced incident type 2 diabetes in high-risk men 6
Increases lean body mass and reduces body fat percentage 3, 7

Bone Health

Increases bone mineral density and bone strength 3, 7, 6
Paradoxically increased risk of fractures typically attributable to trauma in recent trials, despite improved bone density 6
Did not reduce falls or typical osteoporotic fractures 6

Cognitive Function

No evidence of benefit for cognitive function or prevention of cognitive decline 1, 2, 8

Risks and Adverse Effects

Cardiovascular Risk (Most Controversial)

Low-certainty evidence shows small increase to no difference in adverse cardiovascular events (Peto odds ratio 1.22) 1
FDA required labeling changes in 2015 regarding possible increased risk of myocardial infarction and stroke 9
Epidemiologic studies and randomized trials have been inconclusive for determining cardiovascular risk 9, 10
Some studies report increased risk, while others show neutral or possibly beneficial effects 1, 2, 9
Injectable testosterone may carry higher cardiovascular risk than transdermal preparations due to supraphysiologic and subtherapeutic fluctuations 2

Erythrocytosis (Most Common Serious Risk)

Wide range of risk depending on formulation: 3-18% with transdermal administration, up to 44% with intramuscular injections 1, 2, 3
Elevated hematocrit increases risk of thromboembolic events 2, 9
Monitoring requirement: Check hematocrit periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases 2, 5

Prostate-Related Concerns

Controversial and uncertain level of risk for prostate cancer stimulation 1, 7
May worsen benign prostatic hyperplasia (BPH) symptoms, though rarely of clinical significance 1, 9
Monitoring requirement: PSA and digital rectal examination for men over 40-50 years 2, 5, 3, 4
Withhold treatment if PSA increases significantly or exceeds 4.0 ng/mL on repeated testing 5, 9

Fertility Suppression

Common and potentially irreversible, especially in young men 1, 9
Exogenous testosterone suppresses spermatogenesis through feedback inhibition of pituitary FSH, leading to azoospermia 9, 7
Absolute contraindication in men actively seeking fertility preservation 2, 5, 3

Other Adverse Effects

Fluid retention: May worsen congestive heart failure in men with preexisting cardiac, renal, or hepatic disease 1, 9
Sleep apnea: May potentiate sleep apnea in men with risk factors such as obesity or chronic lung diseases 1, 9
Gynecomastia: Rare, usually reversible 1, 9
Skin reactions: High incidence with patches (up to 66%), low incidence with gels (5%), rare with injections 1
Acne or oily skin: Infrequent 1

Mortality

Pooled analysis showed fewer deaths among testosterone-treated patients (0.4%) versus placebo (1.5%), but evidence graded as low certainty due to very serious imprecision and low event rates 1
Insufficient evidence to draw conclusions about mortality 1

Absolute Contraindications

Breast or prostate cancer (active or treated) 2, 5, 3, 9
Active desire for fertility preservation—use gonadotropin therapy (hCG plus FSH) instead 2, 5, 3
Pregnancy (women)—testosterone causes fetal harm 9
Hematocrit >54% 2, 5
Recent myocardial infarction or stroke (within 4 months) 8
Severe or decompensated heart failure 8
Untreated severe obstructive sleep apnea 2, 5

Treatment Selection Algorithm

First-Line: Transdermal Testosterone Gel

Preferred initial formulation due to stable day-to-day testosterone levels and lower erythrocytosis risk 2, 5, 3
Starting dose: 40.5 mg daily (testosterone gel 1.62%) 5, 9
Advantages: Convenience, ease of use, stable levels 2, 5
Disadvantages: Higher cost (annual cost ~$2,135), risk of secondary exposure to women and children 2, 9
Critical safety warning: Virilization reported in children secondarily exposed; patients must wash hands immediately and cover application sites 9

Second-Line: Intramuscular Testosterone Injections

Testosterone cypionate or enanthate 100-200 mg every 2 weeks (or 50-400 mg every 2-4 weeks per FDA labeling) 2, 5, 9
Advantages: Low cost (annual cost ~$156), high peak serum levels 1, 2, 5
Disadvantages: Pain of injection, "roller coaster" effect with fluctuating levels, higher risk of erythrocytosis (up to 44%) 1, 2, 5
Peak levels occur 2-5 days after injection; return to baseline by 10-14 days 1, 5

Third-Line: Testosterone Undecanoate (Long-Acting Injectable)

Dosing: 750 mg initially, repeat at 4 weeks, then every 10 weeks 2
Advantages: Fewer yearly injections, more stable levels 2

Patient Preference Considerations

53% of patients prefer injectable testosterone over gel due to lower cost 1
71% of patients who used both formulations prefer topical gel for convenience and ease of use 1, 2

Monitoring Requirements

Initial Monitoring (First 3-6 Months)

Testosterone levels at 2-3 months after initiation or dose adjustment, targeting mid-normal range (500-600 ng/dL) 2, 5, 3
For injectable testosterone: measure levels midway between injections 5
Hematocrit for detection of erythrocytosis 2, 5, 3, 4
PSA and digital rectal examination for men over 40-50 years 2, 5, 3, 4

Long-Term Monitoring (Every 6-12 Months)

Testosterone levels once stable 5, 3
Hematocrit annually or after therapy changes 2, 5, 4
PSA annually 2, 5, 3
Blood pressure 2
Lipid profile 1, 3
Liver function tests 3
Bone density assessment in selected patients 4, 8

Reassessment of Treatment Benefit

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function, to prevent unnecessary long-term exposure without benefit 2, 5

Special Populations and Clinical Scenarios

Older Men (Age >65 Years)

Primary indication remains sexual dysfunction—not energy, vitality, physical function, or cognition 2, 8
Consider in combination with proven treatment strategies for osteoporosis or persistent mild depressive symptoms 8
May be offered to men with severe insulin resistance or pre-diabetes 8
Avoid in frail older men with recent cardiovascular events or severe heart failure 8

Men with Obesity-Associated Secondary Hypogonadism

First-line approach: Weight loss through low-calorie diets and regular exercise, which can improve testosterone levels without medication 2, 8
If lifestyle modifications fail and symptoms persist with confirmed low testosterone, consider testosterone therapy 2, 8

Men with Diabetes

Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction ~0.37%) 2, 5
Optimize diabetes management concurrently; consider adding GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 2

Young Men with Secondary Hypogonadism

Critical distinction: Men with secondary hypogonadism can achieve both fertility preservation and normal testosterone with gonadotropin therapy (hCG plus FSH), whereas testosterone therapy causes azoospermia 2, 5
Always confirm fertility intentions before initiating testosterone 2, 5

Men with Erectile Dysfunction

Approximately 36% of men seeking consultation for sexual dysfunction have hypogonadism 2
Combination therapy with PDE5 inhibitors (sildenafil, tadalafil) and testosterone improves outcomes in men with low testosterone 2
A minimal level of testosterone is required for complete effect of PDE5 inhibitor therapy 2

Common Pitfalls to Avoid

Never diagnose hypogonadism based on symptoms alone without biochemical confirmation on two separate occasions 2, 3
Never start testosterone without confirming the patient does not desire fertility, as suppression may be prolonged or irreversible 2, 5
Never use testosterone in eugonadal men (normal testosterone levels) for weight loss, muscle building, anti-aging, or cognitive enhancement—this violates evidence-based guidelines 2, 3, 8
Never attempt to diagnose primary versus secondary hypogonadism while the patient is on testosterone therapy, as exogenous testosterone suppresses LH and FSH 2
Never assume age-related decline justifies treatment in older men without confirmed low testosterone and specific symptoms 2, 8
Never skip investigation for reversible secondary causes of hypogonadism (sleep disorders, thyroid dysfunction, anemia, vitamin D deficiency, metabolic syndrome) 2

Long-Term Safety Considerations

Long-term safety data is limited, with few trials exceeding 1-3 years duration 1, 10, 8, 6
No large-scale, long-term studies have definitively assessed cardiovascular and prostate cancer risks 1, 9, 10
Treatment should continue for as long as the man feels benefits outweigh risks, with decisions made on an individual basis 8
Withdrawal should be considered when hypogonadism is reversed after resolution of underlying disorder 8

What are the risks and benefits of testosterone therapy, particularly in older men or those with significant medical histories, for treating hypogonadism?

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