Overnight metyrapone therapy looks good for mild autonomous cortisol secretion

In patients with mild autonomous cortisol secretion (MACS), overnight metyrapone therapy helps to partially retore hypothalamic-pituitary-adrenal (HPA) axis balance and improve sleep and mood, with a favourable tolerability profile, according to a phase II trial.

The trial was conducted in a single centre and included 28 adult patients (median age 64 years, 64 percent female) with MACS (post–1 mg dexamethasone cortisol >1.8 μg/dL) and an adrenal mass. All patients received metyrapone at 250 mg, with the dose titrated up to 1,000 mg based on tolerance each evening. Treatment was administered for 6 months.

The primary endpoint was safety, assessed by adverse events and adrenal insufficiency. HPA axis biomarkers, urine steroid profiling, cardiometabolic measures, and patient-reported outcomes (Short Form-36 [SF-36], Beck Depression Inventory [BDI], Pittsburgh Sleep Quality Index) were the secondary endpoints.

A total of 26 patients completed the 6-month trial. None of the patients developed adrenal insufficiency or experienced serious adverse events (AEs). All AEs were grade 1–2, with the most common being dizziness (17 percent), fatigue (13 percent), and nausea (9 percent).

Plasma adrenocorticotrophic hormone increased by a median of 4 pg/mL at 3 months (p=0.009). Furthermore, glucocorticoid-to-androgen ratio decreased by a median of 60 percent at 6 months (p<0.001).

Depressive symptoms significantly improved (BDI, 8.5 to 5.5; p=0.03), and the proportion of patients with poor sleep substantially decreased (from 57 percent to 24 percent; p=0.007) at 6 months. No significant changes were observed in overall health-related quality of life as measured by SF-36 scores, blood pressure, HbA1c, BMI, and non-HDL cholesterol.

These findings support further evaluation of metyrapone in MACS.