Endocrine Abstracts

Introduction: Patients with adrenal incidentalomas and sub-clinical Cushing’s (SCH) have increased cardiovascular events and mortality. We hypothesised that these patients have a disturbed cortisol rhythm amenable to being restored to normal by using timed short-acting cortisol synthesis blockade, and that this may have a positive effect on IL6 levels.

Methods: In a phase 1, prospective study (Eudract No. 2012-002586-35) we recruited eight patients with adrenal incidentalomas and SCH and two control groups of six sex, age and BMI-matched individuals: i) patients with adrenal incidentalomas and no SCH ii) healthy volunteers with no adrenal incidentaloma. 24-h circadian cortisol analysis was performed using LC-MS/MS to measure serum cortisol hourly and salivary cortisol/cortisone when awake, before and after metyrapone. IL6 was measured.

Results: Patients with SCH had significantly higher nocturnal mean (S.D.) serum cortisol exposure than both control groups:lnAUC_{18:00–22:00}(6.6(0.4)vs(i)6.1(0.6) and (ii)6.0(0.3)nmol/l.hr; P=0.035) and lnAUC_{22:00–02:00}(6.3(0.5)vs(i)5.8(0.4) and (ii)5.7(0.5)nmol/l.hr; P=0.040). Similarly, SCH had significantly higher nocturnal mean (S.D.) salivary cortisone exposure than both control groups:lnAUC_{20:00–23:00} (3.6(0.5)vs(i)3.0(0.7) and (ii)2.8(0.3)nmol/L.hr; P=0.02). In light of these findings six patients with SCH were administered metyrapone 500 mg at 18:00 and 250 mg at 22:00 with a significant reduction in nocturnal serum cortisol and salivary cortisone, achieving analogous cortisol exposure to both control groups. IL6 levels were higher in these six patients with SCH compared to both other groups combined (lnAUC_{18:00–22:00} 3.2(0.6) vs 2.3(0.7) and lnAUC_{22:00–02:00} 3.3(0.5) vs 2.4(0.8) pg/ml.hr). This intervention was associated with a significant reduction in IL6 AUC.

Conclusion: We have shown for the first time that patients with SCH have an abnormal cortisol rhythm with higher cortisol exposure starting from the early evening period and which was associated with increased circulating IL6 levels. After metyrapone 500 mg at 18:00 and 250 mg at 22:00 nocturnal cortisol levels were ‘re-set’ to normal; this was associated with a significant reduction in IL6. We hypothesise that this intervention is likely associated with patient benefit.