Is there a role for testosterone replacement therapy (TRT) in patients with normal total testosterone but low free testosterone levels?

From the Guidelines

Testosterone replacement therapy (TRT) should be considered in men with normal total testosterone but low free testosterone levels, particularly if they have symptoms of testosterone deficiency, as it may improve their quality of life and reduce morbidity and mortality risks associated with hypogonadism. The decision to initiate TRT should be based on both laboratory values and clinical symptoms such as fatigue, decreased libido, erectile dysfunction, reduced muscle mass, or depressed mood 1. Free testosterone is the biologically active form of the hormone, so low levels can cause deficiency symptoms even when total testosterone appears normal. This occurs because conditions like obesity, aging, liver disease, or high sex hormone-binding globulin (SHBG) can reduce the available free testosterone while maintaining normal total levels.

Key Considerations for TRT

• The measurement of morning serum free testosterone is essential when evaluating low total testosterone clinically in a man with obesity 1.
• Testosterone replacement in men with obesity and hypogonadism has demonstrated favorable results, including weight loss, improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and lean body mass 1.
• The most common method of testosterone replacement is as a topical preparation, with transdermal testosterone preparations (gel, patch) favored over intramuscular injections due to the relative stability of testosterone levels from day-to-day 1.
• Monitoring should include periodic assessment of symptoms, testosterone levels, hematocrit, PSA, and liver function.

Potential Risks and Benefits

• Potential risks of TRT include polycythemia, sleep apnea, acne, and possible cardiovascular effects 1.
• However, testosterone replacement therapy has also been associated with cardiometabolic benefits, including improvements in glucose control, insulin sensitivity, and lipid profiles 1.
• The safety concerns regarding testosterone injections may be related to the increased time spent in both the supratherapeutic and subtherapeutic range in between injections compared with patients receiving transdermal testosterone preparations 1.

Treatment Options

• Treatment typically involves testosterone preparations such as injections (testosterone cypionate 50-200mg every 1-2 weeks), daily transdermal gels (AndroGel, Testim 50-100mg), patches (Androderm 2-6mg daily), or pellets (implanted every 3-6 months) 1.
• The method of testosterone replacement should be individualized for each patient, taking into account factors such as convenience, cost, and potential side effects 1.

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 These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range. • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation These men have low testosterone serum concentrations, but have gonadotropins in the normal or low range.

The FDA drug label does not answer the question.

From the Research

Testosterone Replacement Therapy

• The aim of testosterone replacement therapy (TRT) is to improve symptoms and signs of testosterone deficiency, including decreased libido, erectile dysfunction, and depressed mood, by increasing serum testosterone levels to a physiologic range 2.
• TRT has been used for over 70 years, and numerous preparations and formulations have been developed to improve pharmacokinetics and patient compliance 2.
• The indication of testosterone-replacement therapy (TRT) treatment requires the presence of low testosterone level and symptoms and signs of hypogonadism 3.

Low Free Testosterone

• A serum total testosterone level of less than 300 to 350 ng/dL on two separate morning blood samples is considered a low level 4.
• However, there is no direct evidence in the provided studies that addresses the role of TRT in patients with normal total testosterone but low free testosterone.
• The studies suggest that TRT is beneficial for men with hypogonadism, which is defined as a low serum testosterone level and signs or symptoms of hypogonadism 4, 3, 5.

Benefits and Risks of TRT

• TRT may produce a wide range of benefits for men with hypogonadism, including improvement in libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life, and cardiovascular disease 3.
• However, there are potential risks associated with TRT, such as worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea, or severe heart failure 3, 5.
• Long-term TRT has been shown to reduce fatigue in men with hypogonadism 6.