What are the long-term effects of Testosterone Replacement Therapy (TRT)?

Long-Term Effects of Testosterone Replacement Therapy

Evidence regarding long-term benefits and harms of TRT remains inadequate, with small improvements limited to sexual function and quality of life, while serious cardiovascular and mortality risks appear neutral but require ongoing monitoring for polycythemia, prostate changes, and other adverse effects. 1

Established Long-Term Benefits

Sexual Function and Quality of Life

• TRT produces small but consistent improvements in sexual function and self-reported quality of life in men with documented hypogonadism 1
• Erectile dysfunction improves modestly, particularly when TRT is used as first-line treatment in hypogonadal men with mild ED 1
• Libido and sexual function improvements are among the most reliable benefits, though effect sizes remain modest 2, 3

Bone Health

• Lumbar spine trabecular volumetric bone mineral density increases by 7% after 1 year of treatment 4
• Cortical volumetric BMD increases by 3% after 2 years, providing bone micro-architectural benefits 4
• Despite these improvements, conventional anti-osteoporosis medications should be used as primary treatment for osteoporosis, regardless of TRT initiation 4

Minimal or No Benefits for Common Aging Symptoms

• TRT provides little to no benefit for fatigue, decreased energy, reduced physical function, or cognitive decline 1
• Physical function improvements from self-reported measures show no clinically meaningful difference 1
• Vitality and fatigue improve by less than a small amount (effect size 0.17) 1
• Depressive symptoms improve minimally (effect size 0.19), though most studied men did not have baseline depression 1
• TRT should not be used to improve cognition, vitality, or physical strength in aging men 1

Long-Term Cardiovascular Safety

Current Evidence

• Low-certainty evidence from 14 trials showed small increase to no difference in adverse cardiovascular events (odds ratio 1.22) 1
• The TRAVERSE trial (mean follow-up 33 months) confirmed no difference in cardiovascular events between testosterone and placebo groups 1
• Observational studies with follow-up ranging from 0.73 to 10.3 years showed no increased risk for cardiovascular events 1
• Evidence remains inadequate to make definitive conclusions about long-term cardiovascular harms 1

Important Caveat

• Most trials excluded men with recent cardiovascular disease, limiting generalizability to higher-risk populations 1
• No evidence supports TRT safety in men with history of heart failure, suggesting cautious approach in this population 2

Long-Term Hematologic Effects

Erythrocytosis Risk

• Polycythemia occurs in 3-18% of patients on transdermal formulations and up to 44% on injectable testosterone 5, 6
• Hemoglobin and hematocrit levels must be checked periodically to detect polycythemia 6
• Long-term studies have not reported significant adverse events from erythrocytosis (e.g., stroke, thromboembolism), but monitoring remains essential 7

Long-Term Prostate Safety

Prostate Cancer Risk

• The TRAVERSE trial found no difference in prostate cancer incidence between testosterone and placebo groups at mean 33-month follow-up 1
• Meta-analyses of prostate cancer survivors suggest no increased recurrence risk, though evidence quality is poor 1
• TRT should be avoided in advanced prostate cancer 1
• Prostate cancer survivors require thorough counseling regarding unknown long-term effects 1

Prostate-Related Monitoring

• PSA levels and prostate volume increase with TRT but typically remain within clinically acceptable ranges 8, 7
• TRT is safe and does not worsen lower urinary tract symptoms significantly except in men with severe symptoms 1
• Baseline and follow-up monitoring must include PSA, digital rectal examination, and voiding symptoms assessment 4

Other Long-Term Adverse Effects

Reproductive Effects

• TRT is absolutely contraindicated in men seeking fertility due to suppression of spermatogenesis 1, 4, 9
• Oligospermia may occur after prolonged administration 6
• Testicular atrophy and azoospermia are recognized long-term risks 1

Metabolic and Endocrine Effects

• Elevated prostate-specific antigen levels occur but typically remain manageable 1
• Increased blood pressure is documented, particularly with oral formulations 1
• Fluid retention and gynecomastia are recognized long-term risks 1
• Lipid profiles remain largely neutral with physiologic testosterone replacement 5

Sleep Apnea

• TRT may initially worsen obstructive sleep apnea in some men, though this is not a longstanding effect 7
• Evidence suggests TRT does not worsen sleep apnea long-term 1
• Combined CPAP and testosterone gel therapy showed better outcomes than CPAP alone 1
• Baseline and follow-up monitoring should include sleep apnea history assessment 4

Dermatologic and Transfer Risks

• Skin reactions to transdermal products occur 1
• Risk for transfer to others of transdermal preparations poses virilization risk in women or children 1

Mortality Data

Current Evidence

• Pooled analysis of 12 studies showed fewer deaths among testosterone-treated patients (0.4%) versus placebo (1.5%), with odds ratio 0.47 1
• However, trials were not powered for mortality differences and excluded men at higher risk for death 1
• Definitive conclusions about testosterone's effect on mortality cannot be made due to few deaths and exclusion of highest-risk patients 1
• Findings do not suggest increased risk for death with testosterone treatment 1

Monitoring Requirements for Long-Term Safety

Initial Follow-Up

• First follow-up at 1-2 months to assess efficacy 4
• Subsequent monitoring every 3-6 months for the first year, then annually 4

Required Monitoring Parameters

• Hematocrit/hemoglobin levels at baseline and follow-up 4, 6
• PSA levels and digital rectal examination 4
• Voiding symptoms assessment 4
• Sleep apnea history 4
• Target testosterone levels should be mid-range (350-600 ng/dL) rather than high-normal to minimize adverse effects 4

Critical Clinical Pitfalls

Inappropriate Use

• TRT should never be used in eugonadal men for any purpose 1, 4
• TRT should not be prescribed to reduce weight or enhance cardiometabolic status 1
• TRT should not be used for joint pain management as there is insufficient evidence supporting efficacy for this indication 4

Treatment Interruption Consequences

• TRT interruption results in worsening of symptoms, including obesity parameters, voiding function, and erectile function 8
• Hypogonadism may require lifelong TRT, as withdrawal reverses benefits 8

Absolute Contraindications

• Men trying to conceive 1, 4
• Active or treated male breast cancer 1, 4
• Severe lower urinary tract symptoms (relative contraindication) 4