Subclinical Cushing’s Syndrome in Patients with Adrenal Incidentaloma: Clinical and Biochemical Features

Abstract

Incidentally discovered adrenal masses are mostly benign, asymptomatic lesions, often arbitrarily considered as nonfunctioning tumors. Recent studies, however, have reported increasing evidence that subtle cortisol production and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent than previously thought. The purpose of this study was to investigate the clinical and hormonal features of patients with incidentally discovered adrenal adenomas, in relation to their clinical outcome. Fifty consecutive patients with incidentally detected adrenal adenomas, selected from a total of 65 cases of adrenal incidentalomas, were prospectively evaluated. All of them underwent abdominal computed tomography scan and hormonal assays of the HPA axis function: circadian rhythm of plasma cortisol and ACTH, urinary cortisol excretion, 17-hydroxyprogesterone, androgens, corticotropin stimulation test and low-dose (2 mg) dexamethasone test. The patients were reevaluated at regular intervals (6, 12, and 24 months) for a median period of 38 months. Subtle hypercortisolism, defined as abnormal response to at least 2 standard tests of the HPA axis function in the absence of clinical signs of Cushing's syndrome (CS), was defined as subclinical CS. Mild-to-severe hypertension was found in 24 of 50 (48%) patients, type-2 diabetes in 12 of 50 (24%), and glucose intolerance in 6 of 50 (12%) patients. Moreover, 18 of 50 patients (36%) were diffusely obese (body mass index, determined as weight/height2, > 25), and 14 patients (28%) had serum lipid concentration abnormalities (cholesterol > or = 6.21 mmol/L, low-density lipoprotein cholesterol > or = 4.14 mmol/L and/or triglycerides > or = 1.8 mmol/L). Compared with a healthy population, bone mineral density Z-score, determined by the DEXA technique, tended to be slightly (but not significantly) lower in patients with adrenal adenoma (-0.41 SD). Endocrine data were compared with 107 sex- and age-matched controls, and patients with adenomas were found to have heterogeneous hormonal abnormalities. In particular, significantly higher serum cortisol values (P < 0.001), lower ACTH concentration (P < 0.05), and impaired cortisol suppression by dexamethasone (P < 0.001) were observed. Moreover, in patients with adenomas, cortisol, 17-OH progesterone, and androstenedione responses to corticotropin were significantly increased (P < 0.001, all), whereas dehydroepiandrosterone sulfate levels were significantly lower at baseline, with blunted response to corticotropin (P < 0.001, both). However, the criteria for subclinical CS were met by 12 of 50 (24%) patients. Of these, 6 (50%) were diffusely obese, 11 (91.6%) had mild-to-severe hypertension, 5 (41.6%) had type-2 diabetes mellitus, and 6 (50%) had abnormal serum lipids. The clinical and hormonal features improved in all patients treated by adrenalectomy, but seemed unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months), except for one, who was previously found as having nonfunctioning adenoma and then rev...

Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas

“…Other authors have similarly reported the development of overt hypersecretion of the mass over time and even occasional malignant transformation of adrenal incidentalomas (Hensen et al, 1990;Jockenhovel et al, 1992). In contrast, no shift toward malignancy or functional hyperactivity was observed in several other studies (Osella et al, 1994;Barry et al, 1998;Terzolo et al, 1998;Rossi et al, 2000;Siren et al, 2000;Grossrubatscher et al, 2001). Thus, the natural course of adrenal incidentalomas still requires further clarification.…”

Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

“…There is growing evidence that both stress and glucocorticoids contribute to the etiology of cardiovascular disease; however, the role of glucocorticoids in the stress response has long been a matter of debate (1,3,5,13,15,28,30,31,35,36,38,39,42,48,49,52,58,61,65,67,68,70,71). Recent research has led to the general hypothesis that stress-induced increases in glucocorticoids act in the brain to prepare the organism for future events (12,52).…”

“…Acute stress rapidly increases blood pressure, heart rate, plasma glucocorticoid concentration, and blood glucose levels (8), while chronic or repeated stress is associated with increases in baseline blood pressure and glucocorticoids (17). Chronically elevated glucocorticoids increase morbidity and mortality from cardiovascular disease and alterations in the glucocorticoid receptor (GR), and in glucocorticoid metabolizing enzymes are associated with hypertension and cardiovascular disease in humans (28,30,35,36,39,48,49,61,65,67,70,71). Thus, chronic stress-induced elevations in glucocorticoids likely contribute to the adverse effects of stress on cardiovascular health.…”

Circulating E-selectin levels and insulin resistance are associated with early stages of atherosclerosis in nonfunctional adrenal incidentaloma

“…Some authors suggested an association between NFA and mild cortisol overproduction secondary to diseases such as subclinical hypercortisolism or subclinical Cushing syndrome (SCS) (6,7). On the other hand, hyperinsulinemia mediated pathogenesis has been considered by other authors who observed a proliferative effect of insulin on adrenal cancer cells without effect on cortisol synthesis (8).…”