Abstract
BackgroundIncidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible.Methodology/Principal FindingsIn a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC >7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study).ConclusionsShort-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk.Trial RegistrationClinicalTrials.gov NCT00721201
Highlights
Adrenal masses incidentally disclosed on computed tomography (CT) scans, ‘adrenal incidentalomas’ are common
An important complication of cortisol excess is insulin resistance (IR) [9], a major independent marker of cardiovascular risk [10], and this is reflected by the fact that over 60% of individuals with adrenal incidentalomas and low grade cortisol secretion have IR, impaired glucose tolerance or diabetes mellitus compared to age, sex and BMI-matched controls [11]
As IR is common in the general population it is unknown whether the IR in patients with adrenal incidentalomas is secondary to the low level cortisol secretion or other factors
Summary
Adrenal masses incidentally disclosed on computed tomography (CT) scans, ‘adrenal incidentalomas’ are common. An important complication of cortisol excess is insulin resistance (IR) [9], a major independent marker of cardiovascular risk [10], and this is reflected by the fact that over 60% of individuals with adrenal incidentalomas and low grade cortisol secretion have IR, impaired glucose tolerance or diabetes mellitus compared to age, sex and BMI-matched controls [11]. As IR is common in the general population it is unknown whether the IR in patients with adrenal incidentalomas is secondary to the low level cortisol secretion or other factors. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible
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