Differential diagnosisĭifferential diagnoses include other causes of ACTH-independent CS (adrenal adenoma and carcinoma), ACTH-dependent CS including pituitary (Cushing disease) or extra-pituitary tumors (ectopic ACTH secretion see these terms), polycystic ovary syndrome and metabolic syndrome. Hormonal investigations can demonstrate aberrant receptor expression with abnormal stimulation of cortisol secretion by various hormones such as GIP in cases of food-dependent CS and gonadotropin-releasing hormone (GnRH) in cases of LH-dependent CS.

Diagnosis can be confirmed by histological examination. Radiological imaging is helpful, but occasionally nodularity is indistinguishable from that in normal elderly persons. Diagnosis is often difficult because hypercortisolism usually develops slowly over years, may be cyclical and is often associated with subtle CS. Diagnostic methodsĭiagnosis is based on the clinical picture of CS, the demonstration of ACTH-independent hypercortisolism (decreased levels of ACTH in plasma, non suppressible cortisol level after dexamethasone administration), and bilateral adrenal nodular enlargement on radiological imaging. The exact etiology is unknown but the adrenal overgrowth seen in CSMAH may be due to the expression of aberrant membrane receptors found in the adrenal cortex that regulate cortisol secretion and which are stimulated by gastric inhibitory polypeptide (GIP), vasopressin, serotonin, catecholamines and luteinizing hormone (LH). The adrenal glands can be massively enlarged bilaterally with the presence of numerous macronodules however diffuse adrenal enlargement without nodules has been described. However, in some patients the adrenal lesions are found incidentally, in the process of radiological investigation of another disease. CSMAH most frequently presents as clinical or subclinical CS and signs usually become apparent only after several decades of life. Most patients present in their 5th or 6th decade and the disease might be more prevalent in females. The disease presents a bimodal age distribution with a rare subset presenting in the first years of life, particularly associated to McCune-Albright syndrome (MAS see this term). Prevalence of endogenous CS is estimated at 1/26,000 and Cushing syndrome due to macronodular adrenal hyperplasia (CSMAH) represents less than 1% of the cases.

Nodular adrenal gland