Subclinical Cushing's syndrome in adrenal incidentaloma

Some patients with incidentally discovered adrenal adenomas display autonomous cortisol secretion not fully restrained by pituitary feedback, a condition that may be defined as subclinical Cushing's syndrome. We have evaluated the presence of subclinical Cushing's syndrome and its natural history in a cohort of patients with incidentally discovered adrenal adenomas.

Fifty-three consecutive patients (30 women and 23 men; median age 58 years, range 18-81 years) were studied. Diagnostic procedures were initiated for extra-adrenal complaints. Patients with known extra-adrenal malignancies or patients with hypertension of possible endocrine origin were excluded.

All patients underwent the following endocrine evaluation: (1) measurement of DHEA-S at 0800 h, (2) measurement of serum cortisol at 0800 and 2400 h, (3) measurement of the 24-h excretion of urinary free cortisol (UFC), (4) overnight low-dose dexamethasone suppression test, (5) measurement of plasma ACTH at 0800 h (mean of at least two samples on different days), (6) oCRH stimulation test. Different groups of healthy subjects recruited from the hospital medical staff and their relatives served as controls for the various tests. The same endocrine work-up was repeated after 12 months in 25 patients. All patients were followed up at regular intervals for at least 12 months with clinical examination and abdominal computed tomography. Subclinical hypercortisolism was arbitrarily defined as definitive, probable or possible, according to the degree of endocrine abnormalities.

UFC was significantly higher in patients with incidentaloma than in controls (262, 25-690 nmol/24 h versus 165, 25-772 nmol/24 h; P = 0.012). The percentage of subjects who did not suppress on dexamethasone was greater among patients than among healthy subjects (9/53 (17%) versus 5/103 (5%), P = 0.026). Plasma ACTH concentrations were lower in patients with adrenal incidentaloma than in controls (3, 1-9 pmol/l versus 5, 1-14 pmol/l; P = 0.014). These findings consistently point toward a functional autonomy of the adrenal adenomas even if the degree of cortisol excess is mild. Three patients fulfilled the criteria for definitive subclinical hypercortisolism, five for probable and two possible, but none of them experienced clinical and/or biochemical progression to overt hypercortisolism after 12 months. During follow-up, no signs of extra-adrenal malignancy became manifest and the size of the mass did not increase significantly in any patient.

This study provides a clear demonstration of the current opinion that some patients with incidentally discovered adrenal adenomas may be exposed to a subtle, silent hypercortisolism. In some patients, in whom the clustering of more abnormalities in the hypothalamo-pituitary-adrenal axis occurs, subclinical Cushing's syndrome could be assumed. This term should be preferred to that of pre-clinical Cushing's syndrome since the biochemical abnormalities do not become clinically manifest, at least in the short term.