Can exogenous testosterone (testosterone replacement therapy) use be a contributing factor to adrenal insufficiency?

Exogenous Testosterone and Adrenal Insufficiency

Exogenous testosterone therapy can contribute to adrenal insufficiency through suppression of the hypothalamic-pituitary-adrenal axis, particularly when used long-term or at supraphysiological doses.

Mechanisms of Testosterone-Induced Adrenal Insufficiency

• Exogenous testosterone suppresses the hypothalamic-pituitary axis through negative feedback, which can indirectly affect adrenal function by altering the normal hormonal regulation 1
• Testosterone replacement therapy (TRT) reduces natural intratesticular testosterone production, which can disrupt the balance of the entire endocrine system, including adrenal function 1
• Long-term use of exogenous testosterone can lead to tertiary adrenal insufficiency, similar to what is seen with other steroid hormones that affect the hypothalamic-pituitary-adrenal axis 2
• The risk of adrenal insufficiency increases with higher doses and longer duration of testosterone therapy, similar to patterns seen with other exogenous steroids 2

Clinical Presentation of Adrenal Insufficiency

• Patients with adrenal insufficiency may present with fatigue, weight loss, hypotension, hyponatremia, hyperkalaemia, and hyperpigmentation 3
• Laboratory findings often include low morning cortisol levels (<250 nmol/L) with increased ACTH in primary adrenal insufficiency, while tertiary adrenal insufficiency (from exogenous hormone use) typically shows low cortisol with low/normal ACTH 3
• Symptoms may be masked or attributed to other causes, making diagnosis challenging in patients on testosterone therapy 3
• Acute adrenal crisis can be precipitated by stress, illness, or surgery in patients with underlying adrenal insufficiency 3

Diagnostic Approach

• For suspected adrenal insufficiency in patients on testosterone therapy, paired measurement of serum cortisol and plasma ACTH is the recommended initial diagnostic test 3
• Morning cortisol <250 nmol/L with elevated ACTH suggests primary adrenal insufficiency, while low cortisol with low/normal ACTH suggests secondary/tertiary adrenal insufficiency 3
• In equivocal cases, a synacthen (tetracosactide) stimulation test with peak serum cortisol <500 nmol/L is diagnostic of adrenal insufficiency 3
• Patients with 0-minute cortisol >350 nmol/L typically pass synacthen stimulation tests, suggesting intact adrenal function 2

Management Considerations

• For patients requiring both testosterone and treatment for adrenal insufficiency, physiologic doses of steroids (hydrocortisone) should be used rather than supraphysiological doses 3
• All patients with confirmed adrenal insufficiency should wear medical alert identification and carry a steroid alert card 3
• Recovery of adrenal function after cessation of exogenous testosterone can take 6-12 months, similar to recovery patterns seen with other steroid hormones 4
• For men with hypogonadism who wish to maintain fertility, alternative treatments such as human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), or aromatase inhibitors should be considered instead of testosterone replacement 1, 3

Prevention Strategies

• Regular monitoring of adrenal function in patients on long-term testosterone therapy is recommended, particularly when used at higher doses 2
• Patients on testosterone therapy should be educated about the signs and symptoms of adrenal insufficiency 3
• During periods of stress, illness, or surgery, patients on testosterone therapy may require stress-dose steroids if adrenal insufficiency is suspected 3
• Gradual tapering of testosterone therapy rather than abrupt discontinuation may reduce the risk of precipitating adrenal insufficiency 4

Special Considerations

• Women produce approximately 300 micrograms of testosterone daily, with about half derived from the ovaries and half from the adrenal glands, making the relationship between exogenous testosterone and adrenal function particularly important in female patients 5
• In some experimental models, testosterone has shown protective effects against adrenal cortical damage, suggesting a complex relationship between testosterone and adrenal function 6
• Patients with pre-existing pituitary disorders may be at higher risk of developing adrenal insufficiency when treated with testosterone 3