From the Guidelines
Testosterone therapy should only be prescribed for conditions like congenital hypogonadism and Klinefelter syndrome, as well as other forms of primary and secondary hypogonadism, due to the lack of long-term efficacy and safety data in other populations. The American College of Physicians' clinical practice guideline, based on a systematic review of the evidence 1, found that testosterone therapy may provide small improvements in sexual functioning and quality of life in older men with low testosterone levels, but the long-term efficacy and safety are unknown.
Key considerations for prescribing testosterone therapy include:
- Comprehensive evaluation of patients before initiating therapy, including morning total testosterone levels, luteinizing hormone, follicle-stimulating hormone, and prolactin measurements
- Restoration of testosterone levels to the mid-normal range (400-700 ng/dL) while monitoring for potential side effects
- Regular follow-up with testosterone level checks, complete blood counts, and prostate-specific antigen testing
- Contraindications, such as breast or prostate cancer, untreated severe sleep apnea, severe heart failure, or erythrocytosis, should be carefully considered before initiating therapy.
The current evidence suggests that testosterone therapy should not be prescribed for nonspecific symptoms, such as decreased energy, sexual function, and mobility, in the absence of a well-established medical condition known to cause hypogonadism 1. The restriction to only treating congenital hypogonadism and Klinefelter syndrome may be overly limiting, but the lack of strong evidence supporting the use of testosterone therapy in other populations warrants a cautious approach.
From the FDA Drug Label
INDICATIONS AND USAGE Males Testosterone Enanthate Injection, USP is indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired) – Testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy Hypogonadotropic hypogonadism (congenital or acquired) – Gonadotropin or luteinizing hormone‑releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.
INDICATIONS AND USAGE Testosterone cypionate injection is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired)-testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy. Hypogonadotropic hypogonadism (congenital or acquired)-idiopathic gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.
The policy of not prescribing testosterone outside of congenital hypogonadism and Klinefelter disease is more restrictive than the FDA-approved indications for testosterone therapy, which include:
- Primary hypogonadism (congenital or acquired)
- Hypogonadotropic hypogonadism (congenital or acquired) This policy may not be supported by the FDA drug label, as the label does not explicitly state that testosterone should only be prescribed for these two conditions 2, 3, 4.
From the Research
Testosterone Prescription Guidelines
- Testosterone therapy is typically prescribed for patients with congenital hypogonadism and Klinefelter disease, as well as for hypoactive sexual desire disorder in postmenopausal women and to produce physical male sex characteristics in female-to-male transgender patients 5.
- The U.S. Food and Drug Administration warns that testosterone therapy may increase the risk of cardiovascular complications, and other possible risks include rising prostate-specific antigen levels, worsening lower urinary tract symptoms, polycythemia, and increased risk of venous thromboembolism 5.
Klinefelter Disease and Testosterone Therapy
- Klinefelter syndrome is associated with increased morbidity and mortality, and the mainstay of medical treatment is testosterone replacement therapy to attenuate acute and long-term consequences of hypogonadism and possibly prevent frequent comorbidity 6, 7.
- Testosterone replacement therapy is the mainstay of treatment in hypogonadal Klinefelter syndrome patients, but randomized trials are needed to determine optimal therapeutic regimens and follow-up schedules 7.
Diagnosis and Evaluation of Male Hypogonadism
- Clinical practice guidelines recommend that testosterone levels be measured on ≥2 occasions to confirm a diagnosis of hypogonadism, and gonadotropins be measured to determine whether hypogonadism is primary or secondary 8.
- However, the use of hormone testing as recommended by guidelines is not routinely performed in real-world clinical practice, increasing the possibility of overdiagnosis of male hypogonadism, underdiagnosis of secondary hypogonadism, and inappropriate testosterone therapy use and management 8.
Special Considerations
- Patients with Klinefelter syndrome may experience symptoms of gonadal failure, which can precipitate gender identity challenges, and treatment with testosterone replacement therapy can combat these symptoms and enhance quality of life 9.
- However, there is a concern that the application of exogenous testosterone may increase the risk of prostate adenocarcinoma development and progression, and patients with Klinefelter syndrome who are diagnosed with prostate adenocarcinoma may face challenges when balancing a rising prostate-specific antigen level and risk of cancer recurrence with their quality of life 9.