What are the pros and cons of testosterone supplementation in adult males with diagnosed hypogonadism or significantly low testosterone levels?

Testosterone Supplementation: Pros and Cons

Testosterone replacement therapy should be initiated in adult men with confirmed hypogonadism (low morning testosterone on two separate days) who have symptoms such as decreased libido, erectile dysfunction, reduced muscle mass, fatigue, or diminished bone density, as the benefits of improved sexual function, bone density, and quality of life outweigh the risks when properly monitored. 1, 2

Diagnostic Requirements Before Considering Treatment

• Measure morning total testosterone levels on at least two separate days using an accurate assay, with levels below the normal range (typically <300 ng/dL or 10.4 nmol/L) required for diagnosis 3, 1
• Confirm the presence of symptoms: decreased libido, erectile dysfunction, reduced muscle mass, fatigue, depressed mood, impaired cognition, or diminished bone density 4, 5
• If total testosterone is borderline, measure free testosterone through equilibrium dialysis or calculate it from total testosterone, sex hormone-binding globulin (SHBG), and albumin 2, 4
• Obtain luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to distinguish primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low or normal LH/FSH) 2, 5
• Do not treat asymptomatic men with low testosterone, as this remains controversial and lacks established benefit 2

Proven Benefits (PROS)

Sexual Function

• Moderate-certainty evidence demonstrates small but meaningful improvement in global sexual function (SMD 0.35 higher) and erectile function (SMD 0.27 higher) 4, 3
• Improved libido is consistently reported across studies 4, 6

Physical and Body Composition

• Increased lean body mass and muscle strength 4, 6
• Decreased body fat 5, 6
• Improved bone mineral density, reducing fracture risk in hypogonadal men 4, 7

Quality of Life and Mood

• Small improvement in quality of life as measured by validated scales (SMD 0.33 lower on AMS scale) 4
• Modest improvement in vitality and fatigue (SMD 0.17 higher) 4
• Less-than-small improvement in depressive symptoms (SMD 0.19 lower), though most studied men did not have baseline depression 4
• Enhanced sense of well-being and energy 4, 6

Other Benefits

• Improved erythropoiesis and correction of anemia associated with hypogonadism 4, 6

Risks and Adverse Effects (CONS)

Cardiovascular Concerns

• The 2024 American College of Cardiology guidelines note no conclusive evidence that testosterone supplementation increases cardiovascular risk in hypogonadal men 2
• However, the American Heart Association reports that testosterone replacement in older men has been associated with increased coronary artery plaque volume 2, 3
• Low-certainty evidence shows a small increase to no difference in adverse cardiovascular events (Peto odds ratio 1.22) 4, 3
• Most studies excluded men with recent cardiovascular disease, limiting generalizability to high-risk populations 4

Prostate-Related Risks

• Theoretical concern about stimulating occult prostate cancer, though no large-scale evidence confirms this risk 4
• Rarely causes clinically significant benign prostatic hyperplasia symptoms 4
• Requires monitoring with digital rectal examination and prostate-specific antigen (PSA) levels in men over 40-50 years 5, 7

Hematologic Effects

• Erythrocytosis risk varies by formulation: 3-18% with transdermal administration, up to 44% with intramuscular injections 4
• Requires monitoring of hematocrit at baseline and at least annually 7

Reproductive Effects

• Testicular atrophy and infertility are common, especially in younger men, but usually reversible with cessation 4

Other Adverse Effects

• Fluid retention (rarely clinically significant) 4
• Skin reactions: high incidence with patches (up to 66%), low with gel (5%), rare with injections 4
• Acne or oily skin (infrequent) 4
• Gynecomastia (rare, usually reversible) 4
• Sleep apnea worsening (infrequent) 4, 6
• Hepatotoxicity (limited to oral agents, which are infrequently used) 4

Serious Adverse Events and Mortality

• Moderate-certainty evidence found no increased risk of serious adverse events (Peto odds ratio 0.94) or withdrawals due to adverse events 4
• Pooled analysis showed fewer deaths with testosterone than placebo (0.4% vs 1.5%), though evidence certainty is low and event rates were too low for definitive conclusions 4

Critical Monitoring Requirements

• Measure serum testosterone at approximately 14 and 28 days after starting treatment or dose adjustment, then periodically thereafter 1
• Target pre-dose morning testosterone levels between 350-750 ng/dL 1
• Monitor hematocrit at baseline and at least annually or after dose changes 5, 7
• Measure PSA and perform digital rectal examination at baseline and annually in men ≥40-50 years 5, 7
• Assess symptom improvement in sexual function, energy, mood, and physical function 7

Important Caveats and Pitfalls

• Safety and efficacy in "age-related hypogonadism" (late-onset hypogonadism) have not been established 1
• Obesity is a major confounder for low testosterone in men, particularly those with diabetes; weight loss and exercise should be encouraged to increase endogenous testosterone 2, 3
• Never measure testosterone in the afternoon or evening, as levels vary diurnally; morning measurements are required 2
• Do not initiate therapy without proper cardiovascular risk assessment, particularly in men with established cardiovascular disease 2
• Topical testosterone products carry risk of secondary exposure to women and children; patients must wash hands after application and cover application sites 1
• Different testosterone formulations (gel, patch, injection) have different pharmacokinetics and are not interchangeable 1

Formulation Considerations

• Intramuscular injections (testosterone cypionate/enanthate): Low cost, high peak levels, but cause "roller coaster" effect with fluctuating symptoms and require frequent visits 4
• Transdermal gel: Favorable pharmacokinetics with stable levels, well-tolerated, but risk of transfer to others and requires daily application 8, 1
• Transdermal patches: Effective but high skin irritation rates (up to 66% with non-scrotal patches) 4, 8
• Testosterone undecanoate injection: Quarterly administration with stable levels, emerging as attractive option 8