What is the management of testosterone replacement therapy (TRT)?

From the Guidelines

Testosterone therapy management should prioritize individualized dosing and regular monitoring to optimize benefits while minimizing risks, with a focus on improving sexual function and quality of life in men with low testosterone levels. The most recent and highest quality study, 1, found that testosterone treatment in adult men with age-related low testosterone showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolism or deep venous thrombosis. However, evidence for long-term safety is lacking, and most studies excluded men with recent cardiovascular disease.

Key Considerations

• Initial evaluation should include baseline total testosterone levels, complete blood count, prostate-specific antigen (PSA), and metabolic panel.
• Treatment typically begins with testosterone cypionate or enanthate injections (50-100mg weekly or 100-200mg every 2 weeks), transdermal gel (AndroGel, Testim 50-100mg daily), or patches (Androderm 2-6mg daily).
• Target testosterone levels should be in the mid-normal range (400-700 ng/dL).
• Follow-up testing should occur at 3-6 months after starting therapy, then annually, including testosterone levels, hematocrit (discontinue if >54%), PSA (refer to urology if increase >1.4 ng/mL in 12 months), and lipid profile.
• Common side effects include acne, fluid retention, and sleep apnea.
• Testosterone therapy is contraindicated in men with breast or prostate cancer, untreated severe sleep apnea, heart failure, or hematocrit >54%.

Patient Preferences and Values

• A study found that 53% of patients receiving testosterone treatment preferred injectable testosterone over gel-based pellet regimens, mostly due to lower cost 1.
• Another study found that most patients (71%) preferred a topical gel over an injection or patch for reasons attributed to convenience, ease of use, and nonstaining of clothes, among others 1.
• Patients should be counseled that fertility may decrease during treatment, and that benefits typically appear gradually over 3-6 months.

Limitations and Future Directions

• Few trials exceeded a 1-year duration, and minimum important outcome differences were often not established or reported 1.
• Long-term efficacy and safety of testosterone therapy are unknown, and further studies are needed to assess the benefits and risks of testosterone-replacement therapy in men.

From the FDA Drug Label

Testosterone gel 1.62% is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: • Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation The recommended starting dose of testosterone gel 1.62% is 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet) applied topically once daily in the morning to the shoulders and upper arms. The dose can be adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20.25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets). To ensure proper dosing, the dose should be titrated based on the pre-dose morning serum testosterone concentration from a single blood draw at approximately 14 days and 28 days after starting treatment or following dose adjustment.

Testosterone Therapy Management:

• Indications: Testosterone gel 1.62% is indicated for replacement therapy in adult males with primary or hypogonadotropic hypogonadism.
• Dosage: The recommended starting dose is 40.5 mg of testosterone applied topically once daily, with adjustments made based on serum testosterone concentrations.
• Administration: Apply to clean, dry, intact skin of the upper arms and shoulders, avoiding other areas of the body.
• Dose Adjustment: Titrate dose based on pre-dose morning serum testosterone concentration, with adjustments made at 14 and 28 days after starting treatment or following dose adjustment 2.

From the Research

Testosterone Therapy Management

• Testosterone replacement therapy (TRT) is prescribed to men diagnosed with hypogonadism to alleviate symptoms, improve quality of life, and improve overall health 3.
• The selection of the method depends on the patient's preference with advice from the physician, and dose adjustment is possible with most delivery methods but may not be necessary in all hypogonadal men 4.
• The use of hepatotoxic androgens must be avoided, and testosterone treatment induces reversible suppression of spermatogenesis; if fertility is desired in the near future, human chronic gonadotropin, selective estrogen receptor modulator, estrogen antagonist, or an aromatase inhibitor that stimulates endogenous testosterone production may be used 4.

Treatment Patterns and Outcomes

• High discontinuation rates were observed in patients using topical TRT or short-lasting TRT injections, with approximately 40% to 50% of patients in each cycle experiencing an attrition rate 3.
• The treatment pattern of TRT may be related to the disease state rather than dosing, daily use, or mode of administration 3.
• Testosterone replacement therapy can restore normal serum testosterone concentrations and relieve symptoms in most hypogonadal men, but the accuracy of diagnosis and appropriateness of treatment, along with proper follow-up, are increasingly important given the large increase in testosterone prescriptions and the recent concern for cardiovascular (CV) risk associated with TTh 5.

Monitoring and Minimizing Side Effects

• Testosterone can trigger several side effects, including increases in hematocrit and hemoglobin levels, and exogenous testosterone tends to increase erythropoiesis 6.
• The way of administration of testosterone seems to strongly influence the extent of hematocrit increases and can therefore be minimized by choosing the right testosterone preparation 6.
• Elevations in hematocrit levels triggered by testosterone therapy seem to be controversial, some studies advocate noninferior effects as compared to placebo while others found adverse side effects on cardiovascular health 6.

Guidelines for Testosterone Replacement Therapy

• The Society for Endocrinology commissioned a new guideline to provide all care providers with a multidisciplinary approach to treating patients with male hypogonadism, including a patient perspective to help clinicians best manage MH 7.
• These guidelines provide expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices 7.