What are the causes of secondary adrenal insufficiency (Adrenal Insufficiency)?

From the Guidelines

Secondary adrenal insufficiency is primarily caused by dysfunction of the pituitary gland or hypothalamus, resulting in inadequate ACTH (adrenocorticotropic hormone) production, with the most common cause being prolonged use of exogenous glucocorticoids, as stated in the guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK 1. The causes of secondary adrenal insufficiency can be categorized into several groups, including:

• Prolonged use of exogenous glucocorticoids, such as prednisone, dexamethasone, or hydrocortisone, which suppresses the hypothalamic-pituitary-adrenal axis 1
• Pituitary tumors (adenomas), pituitary surgery or radiation, traumatic brain injury affecting the pituitary, pituitary apoplexy (bleeding into the pituitary) 1
• Infiltrative diseases, such as sarcoidosis, hemochromatosis, infections, such as tuberculosis, histoplasmosis, autoimmune hypophysitis, and congenital defects like POMC (pro-opiomelanocortin) deficiency 1 Unlike primary adrenal insufficiency, secondary adrenal insufficiency does not affect mineralocorticoid production since the renin-angiotensin-aldosterone system remains intact. Patients typically present with fatigue, weakness, anorexia, and weight loss, but do not develop hyperpigmentation or severe electrolyte abnormalities characteristic of primary adrenal insufficiency. Treatment involves glucocorticoid replacement therapy, typically with hydrocortisone 15-25 mg daily in divided doses, and addressing the underlying cause when possible, as recommended by the guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK 1.

From the FDA Drug Label

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness The causes of secondary adrenal insufficiency include:

• Drug-induced secondary adrenocortical insufficiency, which may occur with the use of corticosteroids like hydrocortisone 2
• Pituitary unresponsiveness, which can occur particularly in times of stress, such as trauma, surgery, or illness 2

From the Research

Causes of Secondary Adrenal Insufficiency

The causes of secondary adrenal insufficiency can be attributed to several factors, including:

• Pituitary destruction due to masses, inflammation, or infiltration 3
• Certain medications, such as long-term glucocorticoid therapy, which can suppress the hypothalamic pituitary adrenal axis through negative feedback 4
• Hypopituitarism, which can result from central nervous system injury, such as tumors, radiation, or surgery 4
• Certain germline variants, although this is a rare cause 3
• Autoimmune mechanisms, which may play a significant role in the pathogenesis of isolated adrenocorticotropic hormone deficiency 5

Underlying Mechanisms

The underlying mechanisms of secondary adrenal insufficiency involve:

• Insufficient stimulation of the adrenal glands due to inadequate secretion or synthesis of adrenocorticotropic hormone (ACTH) 4, 6
• Lack of stimulation via pituitary adrenocorticotropic hormone or hypothalamic corticotropin-releasing hormone 6
• Suppression of the hypothalamic pituitary adrenal axis, which can lead to variable recovery times after cessation of glucocorticoids 4