Adrenal Insufficiency

The hypothalamus secretes corticotrophin releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropin (ACTH).  ACTH then stimulates the adrenal gland to produce cortisol and aldosterone. Cortisol exerts negative feedback effects both at the pituitary and the hypothalamic levels. ACTH has structureal similarities to melanocyte stimulating hormone. Elevated levels of ACTH can stimulate production of melanin by melanocytes, resulting in hyperpigmentation of the skin. pigmentation. 

Once cortisol is released into the circulation, 95% is bound to cortisol binding globulin or albumin and the remaining 5% circulates as free cortisol. The latter fraction is biologically active and binds to intracellular glucocorticoid receptors to induce gluconeogenesis, glycogenolysis, lipolysis, and proteolysis. 

Adrenal insufficiency may be caused by primary adrenal disease or by ACTH deficiency which produces secondary adrenal deficiency. Primary adrenal insufficiency can occur acutely or chronically.  Primary acute adrenal insufficiency or adrenal crisis occurs in a variety of clinical settings:

• Patients with chronic adrenal insufficiency are subjected to any form of stress.
• Patients maintained on exogenous coricosteroids  have therapy withdrawn too quickly.
• Patients develop massive adrenal hemorrhage.
• Patients develop DIC and hemorrhagic infarction of adrenals.

Primary chronic adrenal insufficiency is called Addison disease. Clinical manifestations do not occur until >90% of the adrenal cortex has been destroyed. Many diseases can affect the adrenal glands including metastatic cancer, tuberculosis, lymphomas, amyloidosis, sarcoidosis, hemochromatosis, fungal infections and hemorrhage. However, autoimmune adrenalitis accounts for most of the cases. In about half of these autoimmune cases, only the adrenal glands are involved.  However, in the other 50% of cases other autoimmune diseases coexist. Examples include Hashimoto disease, pernicious anemia, type 1 diabetes, and hypoparathyroidism.  

Primary adrenal insufficiency results in deficiency of all adrenocorticol hormones including, cortisol, aldosterone, dehydroepiandrosterone (DHEA) and adrostenedione. ACTH is markedly elevated due to decreased negative feedback. 

Patients can present with ill defined fatigue, weakness, depression, anorexia, vomiting, unexplained weight loss, hypotension, hyperpigmentation, hypoglycemia, hyponatremia or hyperkalemia. 

Any disorder of the hypothalamus or pituitary that reduces ACTH secretion can lead to secondary adrenal insufficiency.  It is characterized by deficient cortisol and androgen secretion but normal aldosterone secretion.  Hyponatremia and hyperkalemia are not as severe in secondary adrenal insufficiency as in primary disease. 

Cortisol and corticotropin production follow a circadian rhythm. Peak levels occur in the early morning, just before waking, and then gradually decline throughout the day. They reach a nadir overnight when sleeping. An early morning measurement of plasma cortisol is the recommended initial test to evaluate for adrenal insufficiency. Guidelines from the European Society of Endocrinology and the Endocrine Society state that an early morning cortisol greater than 10 ug/dL indicates normal hypothalmic-pituitary-adrenal axis function and rules out adrenal insufficiency. Conversely an early morning plasma cortisol of less than 5 ug/dL in patients with clinical features of adrenal insufficiency is considered highly probable of adrenal insufficiency.

Another alternative initial test for adrenal insufficiency is an early-morning salivary free cortisol. Samples can be collected at home and sent to the laboratory. A salivary free cortisol levels greater than 180 ng/dL excludes adrenal insufficiency with a sensitivity of 95%. 

The ACTH (corticotropin) stimulation test is helpful in diagnosing adrenal insufficiency in those patients with equivocal levels of early morning cortisol (5-10 ug/dL). It is performed in the following manner. After obtaining a basal cortisol level, 250 ug of cosyntropin (Corticotropin 1-24 or ACTH 1-24) is given IM or IV.  Plasma samples are then drawn at 30 and 60 minutes. In normal subjects, baseline cortisol levels exceed 5 ug/dL.  Following administration of cosyntropin, plasma cortisol levels should rise at least 7 ug/dL and peak at greater than 18 ug/dL. A normal response rules out primary disorders of the adrenal gland, but does not exclude partial ACTH deficiency with impaired reserve.  

Subsequent measurement of plasma ACTH level, determines whether adrenal insufficiency is primary  (Addison's disease) or secondary. Nearly all patients with primary adrenal insufficiency have elevated plasma ACTH, greater than 100 pg/mL (reference range is 15-65 pg/mL). In contrast, patients with secondary and glucocorticoid-induced adrenal insufficiency have ACTH concentrations that are below 20 pg/mL. 

More than 90% of patients with primary adrenal insufficiency have circulating 21-hydroxylase antibodies. Detection of these antibodies confirms the diagnosis of autoimmune adrenalitis.

References

Vaidya A, et al. Adrenal Insufficiency in Adults: A Review. JAMA, published online June 16, 2025,  JAMA.doi:10.1001/jama.2025.5485.

Beuschlein F, etal. European Society of Endocrinology and Endocrine Society joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal insufficiency. Eur J Endocrinol. 2024;190(5):G25-G51.doi:10.1093/ejendo/lvae029.

Husni H et al. Cortiso values during the standard-dose cosyntropin stimulation test: personal experience with Elecsys cortisol II assay. Front Endocrinol.2022;13:978238.

Ospina NS et al. ACTH stimulation test for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab.2016;10(12):427-434.