What are the physiological impacts of Testosterone Replacement Therapy (TRT)?

Physiological Impacts of Testosterone Replacement Therapy

Testosterone replacement therapy produces clinically meaningful improvements in sexual function, mood, muscle mass, bone density, and quality of life in hypogonadal men, while carrying manageable risks including erythrocytosis, potential prostate effects, and cardiovascular considerations that require systematic monitoring. 1

Primary Physiological Benefits

Sexual Function and Libido

• TRT significantly improves sexual function, libido, and erectile dysfunction in hypogonadal men, with maximal improvement typically occurring within 30 days of treatment initiation. 1, 2
• These improvements are sustained with continued therapy but do not increase further beyond the initial 30-day response period. 2

Musculoskeletal Effects

• Lean body mass increases by 1.3-2.7 kg within 90 days of treatment, with higher doses (100 mg/day gel) producing greater gains than lower doses (50 mg/day). 2
• Muscle strength improves significantly, particularly in lower extremity exercises, with leg press strength increasing by 11-13 kg within 90 days across all formulations. 2
• Bone density improves with TRT, though fracture data remains limited with only 6 fractures in testosterone groups versus 8 in placebo groups across multiple trials. 1
• Fat mass decreases by approximately 0.9-1.05 kg, with reductions correlating directly to achieved serum testosterone levels. 2

Mood and Cognitive Function

• TRT produces a small but clinically meaningful improvement in depressive symptoms (SMD -0.19), with maximal benefit occurring within 30 days. 1, 2
• Quality of life improves modestly, with men moving from moderate to mild symptom severity on validated scales (mean AMS score improvement of 3.3 points). 1
• Cognitive function shows no consistent improvement in men without baseline cognitive impairment, based on the 493-patient Cognitive Function Trial. 1
• Energy and vitality improve minimally (SMD 0.17), addressing one of the most commonly reported symptoms. 1

Hematologic Effects

• Erythropoiesis increases substantially, with erythrocytosis occurring in 43.8% of men receiving intramuscular injections versus 15.4% with transdermal patches. 3
• Hemoglobin and hematocrit rise predictably, with risk increasing dose-dependently: 2.8% at 5 mg/day transdermal, 11.3% at 50 mg/day gel, and 17.9% at 100 mg/day gel. 3
• This represents the most common clinically significant adverse effect requiring monitoring and potential intervention. 4, 5

Body Composition and Metabolic Effects

• TRT reduces abdominal girth and may improve metabolic parameters including blood glucose and HbA1c in men with type 2 diabetes. 6
• The therapy shows associations with reduced features of metabolic syndrome, though long-term cardiovascular protection remains unproven. 6
• Nitrogen retention increases along with retention of sodium, potassium, and phosphorus, while urinary calcium excretion decreases. 7, 8

Lipid Profile Considerations

HDL and Cholesterol Effects

• Physiologic testosterone replacement at standard doses (100-200 mg weekly intramuscular or equivalent transdermal) produces neutral to minimal effects on lipid profiles. 4
• HDL cholesterol shows minimal changes at physiologic doses, with reductions occurring in only 3 of 18 studies; significant HDL suppression occurs only with supraphysiologic doses (600 mg/week). 4
• Total cholesterol decreased in 5 studies, increased in 2, and remained unchanged in 12 studies across meta-analyses. 4
• LDL cholesterol remained unchanged or decreased in 14 of 15 analyzed studies. 4
• Transdermal testosterone demonstrates the most neutral lipid effects, with a 36-month placebo-controlled study showing no significant differences in any lipid parameters. 4

Cardiovascular and Thrombotic Considerations

Cardiovascular Risk Profile

• Observational studies with mean follow-up ranging from 0.73 to 10.3 years show no increased risk for mortality, cardiovascular events, or stroke, though most studies excluded men with recent cardiovascular disease. 1
• Some postmarketing studies have shown increased risk of myocardial infarction and stroke, creating ongoing controversy. 5
• TRT should not be commenced for 3-6 months in patients with recent cardiovascular events. 4
• Higher endogenous testosterone levels may actually have favorable effects on cardiovascular risk, contrary to historical assumptions. 1

Venous Thromboembolism

• Venous thromboembolism including deep vein thrombosis and pulmonary embolism have been reported in patients using testosterone products. 5
• Blood viscosity increases with elevated hematocrit, potentially aggravating vascular disease in coronary, cerebrovascular, or peripheral circulation, particularly in elderly patients. 3

Prostate Effects

Benign Prostatic Hyperplasia

• BPH symptoms may worsen in susceptible men, though this occurs rarely and is not typically clinically significant. 1, 5
• Prostate-specific antigen levels increase modestly within the normal range, with increases correlating to achieved serum testosterone levels. 2

Prostate Cancer Considerations

• No compelling evidence exists that testosterone causes de novo prostate cancer, though it may potentially stimulate growth of occult existing cancer. 1, 3
• The controversy regarding prostate cancer risk persists despite lack of supporting evidence for causation. 1, 9

Reproductive Effects

Fertility and Testicular Function

• Azoospermia commonly develops as exogenous testosterone suppresses endogenous testosterone release through feedback inhibition of pituitary LH. 5, 7
• Spermatogenesis becomes suppressed through feedback inhibition of pituitary FSH at higher doses. 7, 8
• Testicular atrophy occurs commonly, especially in younger men, but is usually reversible with cessation of treatment. 1

Other Physiological Effects

Fluid and Electrolyte Balance

• Edema may occur, particularly in patients with preexisting cardiac, renal, or hepatic disease, though it is rarely clinically significant. 1, 5

Sleep and Respiratory Effects

• Sleep apnea may develop or worsen in men with risk factors including obesity and pre-existing respiratory conditions. 1, 3, 5

Dermatologic Effects

• Skin reactions vary dramatically by formulation: up to 66% with patches, 5% with gel, and rare with injections. 1
• Acne and oily skin occur infrequently. 1
• Gynecomastia occurs rarely due to aromatization of testosterone to estradiol, and is usually reversible. 1, 3

Critical Monitoring Requirements

Essential Laboratory Surveillance

• Baseline and periodic monitoring must include: serum testosterone levels, PSA, hemoglobin/hematocrit, liver function tests, and lipid concentrations. 5
• Hematocrit requires closer monitoring than lipids, as polycythemia represents the most common adverse effect with indirect cardiovascular implications. 4
• Recheck lipids at 3-6 months after initiating therapy to confirm no worsening. 4

Dose Optimization Strategy

• Target testosterone levels in the middle tertile of normal range (450-600 ng/dL) to minimize HDL suppression and other adverse effects while maximizing symptom improvement. 4
• Use minimal dosing necessary to normalize testosterone levels and improve symptoms. 4

Management of Erythrocytosis

• When erythrocytosis develops, appropriate interventions include dose reduction, temporary withholding of testosterone, therapeutic phlebotomy, or blood donation. 3

Formulation-Specific Considerations

Route of Administration Differences

• Intramuscular injections produce a "roller coaster" effect with peak levels at 2-5 days and return to baseline at 10-14 days, causing alternating periods of symptomatic benefit and symptom return. 1
• Transdermal preparations provide more stable serum levels and lower erythrocytosis risk (15.4% vs 43.8% for injections). 3
• Never prescribe 17-alpha-alkylated androgens (methyltestosterone) due to hepatotoxicity and unfavorable lipid effects. 4

Special Population Considerations

Elderly Patients

• Elderly men face particularly high risk for erythrocytosis complications due to increased likelihood of underlying vascular disease. 3
• Men with high BMI and low testosterone have increased cardiovascular event risk; concurrent weight loss programs should be implemented. 4

Patients with Comorbidities

• Men with chronic obstructive pulmonary disease require extra vigilance due to baseline elevated hematocrit. 3
• Results in obese men or those with diabetes/metabolic syndrome mirror those of the overall population. 1