What are the differences between primary and secondary hypogonadism (testosterone deficiency) in terms of testosterone replacement therapy (TRT) and necessary monitoring?

From the Guidelines

Testosterone replacement therapy (TRT) should be considered for both primary and secondary hypogonadism, with a focus on addressing the underlying cause and monitoring for potential side effects, as evidenced by the American College of Physicians' clinical practice guideline 1. The approach to TRT differs based on the underlying cause of hypogonadism. Primary hypogonadism results from testicular failure, characterized by elevated LH/FSH with low testosterone, whereas secondary hypogonadism stems from hypothalamic-pituitary dysfunction, marked by low/normal LH/FSH with low testosterone. For primary hypogonadism, TRT is the standard treatment, as the testes cannot produce adequate testosterone. In contrast, secondary hypogonadism may require addressing the underlying cause, such as prolactinoma, obesity, or medication effects, which may restore natural testosterone production. However, TRT is often necessary if the underlying cause cannot be corrected. Common TRT options include:

• Intramuscular testosterone cypionate (50-200mg every 1-2 weeks)
• Testosterone enanthate (50-200mg every 1-2 weeks)
• Topical gels (AndroGel, Testim 50-100mg daily)
• Transdermal patches (Androderm 2-6mg daily)
• Subcutaneous pellets (Testopel 150-450mg every 3-6 months) Monitoring should include:
• Total testosterone levels (target: 400-700 ng/dL)
• Complete blood count (for polycythemia)
• Lipid panel
• Liver function tests
• PSA (in men >40) at baseline, 3-6 months after starting therapy, and annually thereafter Digital rectal exam should be performed annually in men over 40. Patients should be monitored for side effects, including erythrocytosis, sleep apnea, acne, fluid retention, and prostate issues. Fertility concerns should be addressed before starting TRT, as it suppresses spermatogenesis, as noted in the clinical guideline by the American College of Physicians 1.

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). Hypogonadotropic hypogonadism (congenital or acquired). Prior to initiating testosterone gel 1.62%, 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 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 dose should be titrated based on the pre-dose morning serum testosterone concentration at approximately 14 days and 28 days after starting treatment or following dose adjustment. Additionally, serum testosterone concentration should be assessed periodically thereafter.

Testosterone Replacement Therapy is indicated for primary hypogonadism and hypogonadotropic hypogonadism.

• The diagnosis of hypogonadism should be confirmed by measuring serum testosterone levels on at least two separate days.
• Dose adjustment should be based on pre-dose morning serum testosterone concentration at approximately 14 days and 28 days after starting treatment or following dose adjustment.
• Serum testosterone concentration should be assessed periodically thereafter 2.

From the Research

Testosterone Replacement Therapy

• Testosterone replacement therapy (TRT) is used to treat hypogonadal men, with benefits including improved sexual function, increased lean body mass, and increased bone density 3, 4.
• The diagnosis of hypogonadism is based on clinical signs and symptoms, plus laboratory confirmation via the measurement of low morning testosterone levels on two different occasions 4.
• Serum luteinizing hormone and follicle-stimulating hormone levels distinguish between primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism 4.

Primary vs Secondary Hypogonadism

• Primary hypogonadism is characterized by high levels of luteinizing hormone and follicle-stimulating hormone, while secondary hypogonadism is characterized by low or normal levels of these hormones 4.
• Adult-onset hypogonadism (AOH) is a condition that can be associated with elements of both primary and secondary hypogonadism, and is characterized by low levels of testosterone, associated signs and symptoms of hypogonadism, and low or normal gonadotropin levels 5.

Monitoring Testosterone Replacement Therapy

• Patients undergoing TRT should be monitored regularly, with parameters for surveillance including well-being, libido and sexual activity, measurement of serum testosterone levels, haemoglobin and haematocrit, PSA and digital rectal examination, and bone mineral density 6.
• Monitoring should be done at regular intervals, such as 3,6, and 12 months after initiation, and then annually 6.
• The use of hepatotoxic androgens should be avoided, and dose adjustment is possible with most delivery methods, but may not be necessary in all hypogonadal men 7.