What is the recommended treatment for testosterone replacement therapy (TRT) in men with confirmed hypogonadism?

From the Guidelines

Testosterone replacement therapy (TRT) is recommended for men with confirmed hypogonadism, with treatment options including injectable testosterone, transdermal testosterone, and subcutaneous implants, aiming to restore physiological testosterone levels and improve symptoms. The goal of TRT is to alleviate symptoms such as low libido, fatigue, and decreased muscle mass, while also improving overall quality of life. According to the American College of Physicians guideline 1, testosterone therapy may provide small improvements in sexual functioning and quality of life in older men with low testosterone levels.

Treatment Options

• Injectable testosterone cypionate or enanthate is commonly prescribed at 50-100 mg weekly or 100-200 mg every two weeks, administered intramuscularly.
• Transdermal options include testosterone gel (typically 50-100 mg daily applied to shoulders, upper arms, or abdomen) or patches (2-6 mg daily applied to non-genital skin).
• Testosterone pellets (subcutaneous implants providing 150-450 mg testosterone lasting 3-6 months) offer longer-term treatment.
• Oral testosterone undecanoate (typically 120-240 mg daily) is available in some countries but less common due to potential liver effects.

Monitoring and Individualization

Treatment should be individualized based on patient preference, cost considerations, and specific health factors. Regular monitoring is essential, including testosterone levels (aiming for mid-normal range), hematocrit (to watch for polycythemia), PSA (for prostate cancer risk), and symptom improvement, as recommended by the American College of Physicians guideline 1.

Patient Preferences

Patient preferences play a significant role in treatment selection, with some studies suggesting that patients prefer injectable testosterone over gel-based regimens due to lower cost 1, while others prefer topical gels for convenience and ease of use. The most bothersome symptoms for men with hypogonadism include lack of energy, decreased strength and endurance, and deterioration in work performance 1.

Safety and Efficacy

While the long-term efficacy and safety of TRT are unknown, evidence from observational studies suggests no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolism or deep venous thrombosis 1. However, treatment should be approached with caution, and patients should be closely monitored for potential adverse effects.

From the FDA Drug Label

Testosterone gel 1.62% is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired). 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. Dose adjustment: testosterone gel 1.62% can be dose 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).

The recommended treatment for testosterone replacement therapy (TRT) in men with confirmed hypogonadism is testosterone gel 1.62%. The starting dose is 40.5 mg of testosterone, applied topically once daily in the morning. The dose can be adjusted between 20.25 mg and 81 mg of testosterone based on the pre-dose morning serum testosterone concentration. Key considerations for treatment include:

• Diagnosis confirmation: Confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range.
• Dose titration: Titrate the dose based on the pre-dose morning serum testosterone concentration at approximately 14 days and 28 days after starting treatment or following dose adjustment.
• Monitoring: Monitor patients for signs and symptoms of adverse reactions, such as virilization, benign prostatic hyperplasia (BPH), and venous thromboembolism (VTE) 2.

From the Research

Testosterone Replacement Therapy (TRT) for Men with Confirmed Hypogonadism

• TRT should be offered to symptomatic older men with confirmed low testosterone concentrations after explaining the uncertainties regarding the long-term safety of this treatment 3.
• The treatment may be offered to men with severe hypogonadism and erectile dysfunction to improve sexual desire, erectile, and orgasmic function 3.
• TRT should also be considered in hypogonadal men with severe insulin resistance or pre-diabetes mellitus 3.
• It may also be considered, in combination with proven treatment strategies, for osteoporosis, or for selected patients with persistent mild depressive symptoms and/or low self-perceived quality of life, combined with standard medical care for each condition 3.

Contraindications and Precautions

• TRT is contraindicated in hypogonadal men actively seeking fertility treatment 3.
• Due to a lack of data, TRT should not be routinely used in older men to improve exercise capacity/physical function, improve cognitive function, or prevent cognitive decline 3.
• TRT must be avoided in older, frail men with known breast cancer or untreated prostate cancer and all men who have had myocardial infarction or stroke within the last four months, and those with severe or decompensated heart failure 3.

Monitoring and Treatment Duration

• Older men on TRT should be monitored at 3,6, and 12 months after initiation and at least yearly thereafter, or earlier and more frequently if indicated 3.
• Evaluation should include assessment of the clinical response, and measurement of total testosterone, haematocrit, and prostate-specific antigen (PSA) concentrations 3.
• Any limits on duration of use are arbitrary, and treatment should continue for as long as the man feels the benefits outweigh the risks for him, and decisions must be made on an individual basis 3.

Forms of Testosterone Replacement Therapy

• Natural testosterone should be used and not modified molecules 4.
• Testosterone is currently available in oral, intramuscular, subcutaneous and transdermal preparations 4.
• Recent advances in testosterone replacement therapy include testosterone gels which provide flexibility in dosing and minimal skin irritation resulting in good compliance, and the development of longer acting intramuscular preparations which result in more stable testosterone levels with longer injection intervals 4.

Alternative Treatments

• Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections 5.
• Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs 5.
• However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient 5.