ACTH-independent hypercortisolism across the cardiometabolic spectrum.

BACKGROUND

Accumulating evidence suggests that the prevalence of hypercortisolism in patients with cardiometabolic risk factors is much higher than previously thought. This study aimed to evaluate the prevalence of ACTH-independent hypercortisolism across the spectrum of cardiometabolic risk.

METHODS

Participants were prospectively recruited into three cohorts to undergo protocolized assessment of adrenal physiology:1) normotensive participants; 2) participants with hypertension and obesity, but without diabetes; 3) participants with diabetes and overweight/obesity. All participants (n=216) underwent overnight 1 mg dexamethasone suppression testing followed by cosyntropin stimulation test, and 24-hour urine free cortisol (UFC) testing. ACTH-independent hypercortisolism was defined as post-dexamethasone serum cortisol >1.8 μg/dL (50 nmol/L) with a concomitant post-dexamethasone ACTH ≤10 pg/mL (2.2 pmol/L).

RESULT: 16 of 216 (7.4%) participants were found to have ACTH-independent hypercortisolism, including 5.6% (4/71) in the normotensive cohort, 6.2% (5/81) in the hypertension-obesity cohort and 10.9% (7/64) in the diabetes-obesity cohort. Age, body mass index, hemoglobin A1c, blood pressure, renal function, morning ACTH, and 24-hour UFC were similar among those with and without ACTH-independent hypercortisolism. Following cosyntropin stimulation, those with ACTH-independent hypercortisolism had higher stimulated cortisol levels (greater ACTH- dependent responses) when compared to those without ACTH-independent hypercortisolism: 25.8±4.5 versus 20.6±4.1 μg/dL (711±124 v. 568±113 nmol/L) ( P <0.001).

CONCLUSIONS

In this prospective study, the prevalence of ACTH-independent hypercortisolism paralleled the burden of cardiometabolic risk features. ACTH-independent hypercortisolism was associated with greater ACTH-stimulable cortisol production, identifying a unique biochemical phenotype. These findings reveal new insights into cortisol pathophysiology as a function of ACTH and cardiometabolic risk profiles.