Testosterone Replacement Therapy Guidelines

Introduction

• Testosterone replacement therapy (TRT) is a medical treatment for male hypogonadism, with benefits and risks that should be carefully considered, as recommended by the American College of Physicians and the European Urology guideline 1, 2

Contraindications and Precautions

• Absolute contraindications for TRT include prostate cancer, breast cancer, desire for near-term fertility, severe sleep apnea, uncontrolled heart failure, and recent cardiovascular events, as stated by the American Heart Association 3
• Relative contraindications for TRT include a history of hepatocellular carcinoma, thrombosis, and other cardiovascular risk factors, as recommended by the American Association for the Study of Liver Diseases and the American Heart Association 4
• Severe untreated sleep apnea may be a contraindication for testosterone replacement therapy, though recent evidence suggests this may be reconsidered, as stated by the Mayo Clinic 5
• Anemia is a condition that may be associated with testosterone replacement therapy, according to the American Medical Association 6
• Precautions for TRT include monitoring for erythrocytosis, suppression of spermatogenesis, peripheral edema, emotional lability, and potential cardiovascular effects, as reported by the New England Journal of Medicine 2, 3, 7, 5

Benefits and Recommendations

• Men with obesity, metabolic syndrome, or diabetes may benefit from testosterone replacement therapy, which can improve insulin sensitivity, as suggested by the Mayo Clinic 5
• Lifestyle modifications, such as weight loss and exercise, should be first-line for metabolic benefits and can sometimes reverse obesity-associated secondary hypogonadism, according to the European Association of Urology 1
• Moderate-certainty evidence shows testosterone therapy provides small but significant improvements in global sexual function (SMD 0.35) and erectile function (SMD 0.27) 3
• Low-certainty evidence suggests small improvements in quality of life with testosterone therapy 3
• Testosterone therapy has limited or no effect on physical functioning, depressive symptoms, energy/vitality, and cognition, according to the American College of Physicians 2

Diagnosis and Evaluation

• The diagnosis of hypogonadism requires the presence of specific signs and symptoms combined with laboratory confirmation of decreased morning total testosterone levels measured on at least two separate occasions, with levels below 300 ng/dL confirming the diagnosis, as recommended by the European Association of Urology and the American Urological Association 1, 8
• A comprehensive hormonal evaluation, including morning total testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) measurements on at least two separate occasions, is recommended for managing hypogonadism, as suggested by the European Association of Urology and the American College of Physicians 1, 2
• Metabolic assessment should include measurement of BMI and waist circumference, as well as screening for obesity, metabolic syndrome, and diabetes, as recommended by the European Urology guideline 1
• Baseline measurements should include testosterone, LH, and FSH levels, as well as hemoglobin and hematocrit levels, and assessment of cardiovascular risk factors, as recommended by the American Urological Association 8
• Testosterone testing should be avoided during acute illness, as advised by the European Urology guideline 1

Treatment Options

• Intramuscular testosterone formulation is recommended as the initial treatment due to its similar clinical effectiveness to other formulations, considerably lower cost compared to transdermal options, and established efficacy for improving sexual function, as recommended by the American College of Physicians 3
• Transdermal preparations, such as gels and patches, are recommended as first-line treatment for most patients, as they provide stable day-to-day levels, while injectable testosterone can cause fluctuating levels and should be measured midway between injections 9, 8
• Clomiphene citrate (CC) is commonly prescribed off-label for hypogonadism and preservation of fertility in men requiring testosterone therapy, as it preserves or may improve fertility, making it suitable for men who wish to maintain fertility 10
• Gonadotropin therapy, starting with human chorionic gonadotropin (hCG) alone and adding follicle-stimulating hormone (FSH) if needed, is the treatment of choice, as recommended by the European Association of Urology 1
• The following dose adjustment table is recommended:

Monitoring and Follow-up

• Testosterone levels should be measured after starting treatment and every 6-12 months while on therapy, with a target level of mid-normal range (450-600 ng/dL), as recommended by the American Urological Association 8
• Hemoglobin/hematocrit should be monitored, and treatment should be discontinued if Hct >54%, while PSA should be monitored according to AUA guidelines, and treatment should be considered for discontinuation after 3-6 months if symptoms don't improve 8
• Estradiol monitoring is recommended, with men with elevated baseline estradiol referred to an endocrinologist, and monitoring for gynecomastia symptoms 8
• Common adverse effects of TRT include erythrocytosis (dose-dependent: 2.8-17.9%), suppression of spermatogenesis, peripheral edema, emotional lability, and potential cardiovascular effects (long-term safety uncertain), as reported by the New England Journal of Medicine 2, 3, 7, 5

Fertility Considerations

• Exogenous testosterone should not be prescribed to men interested in current or future fertility, as it suppresses spermatogenesis and can cause oligospermia or azoospermia, as recommended by the American Urological Association 11, 8
• Alternative treatments that preserve fertility, such as human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), and aromatase inhibitors, should be considered for men interested in fertility 11, 8
• The American Urological Association recommends performing reproductive health evaluation if fertility is desired, and considering testicular exam and serum FSH measurement 8

Lifestyle Modifications

• Lifestyle changes, such as weight loss through low-calorie diets and physical activity, can reverse obesity-associated secondary hypogonadism and are recommended as first-line for metabolic benefits, and combining lifestyle changes with TRT may yield better outcomes in symptomatic patients, as recommended by the American Geriatrics Society and the American College of Cardiology 1, 3