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Adrenal (Excluding Mineralocorticoids)

MON-506 - Safety and Clinical Impact of Overnight Metyrapone in Mild Autonomous Cortisol Secretion: An Open-Label Phase 2 Trial

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Shireen R. Chacko, M.B.B.S.: No financial relationships to disclose
Kai Yu, MD, PhD: No financial relationships to disclose
Context:
While adrenalectomy improves outcomes in unilateral mild autonomous cortisol secretion (MACS), safe and effective medical therapy is needed for bilateral disease.

Objective:
To evaluate the safety of overnight metyrapone in MACS and its impact on steroid profiling, cardiometabolic outcomes, quality of life (QoL), and sleep.

Methods:
Study design: Open-Label, Phase 2 Clinical Trial (NCT06106295)
Participants: Adults with MACS (post-dexamethasone serum cortisol >1.8 µg/dL) and benign adrenal imaging, prospectively enrolled from December 2023 to January 2025. Eligibility required ≥1 MACS-related comorbidity (obesity, dysglycemia, dyslipidemia, hypertension, osteopenia/osteoporosis).
Intervention: Metyrapone was initiated at 250 mg nightly and titrated in 250-mg increments every 2-4 weeks based on tolerance (maximum 1000 mg).
Outcomes: Primary endpoint was incidence of adverse events (AE), graded by CTCAE version 5.0. Adrenal insufficiency (AI) was assessed biochemically (cortisol < 10 µg/dL and ACTH >60 pg/mL) and by AddiQoL. Secondary endpoints included changes in steroid profiling, cardiometabolic outcomes, QoL (SF-36), depression [Beck Depression Inventory (BDI)], and sleep (PSQI).

Results: 28 adults with MACS [median age 64 years, (IQR 60, 68), 64% women] initiated metyrapone. At 6 months, median dose was 1000 mg (IQR 1000-1000). All AEs were CTCAE grade 1-2, with no serious AE. Most common AEs at least possibly-related to metyrapone were dizziness (17%), fatigue (13%), nausea (9%), headache (7%), and myalgia (7%). One patient discontinued therapy at 3 months due to AEs. No patient developed AI. Morning serum cortisol was similar at baseline, 3 and 6 months. ACTH increased from baseline to 3 months [median change 4.0 pg/mL (IQR -0.7,9.6), P=0.009] and was maintained at 6 months. AddiQol improved at 3 months [82 (IQR 72, 95) vs. 88 (IQR 78, 99), P=0.021]. Diurnal salivary cortisol and cortisone amplitude (morning–bedtime difference) increased, but was not statistically significant. Urine steroid profiling showed reduction in glucocorticoid/androgen ratio at 6 months [median change from baseline -60% (IQR-70, -46), P< 0.001]. While median 24-hour blood pressure, HbA1c, BMI, or non-HDL cholesterol did not significantly change, improvement in hypertension (6%), dysglycemia (18%), obesity (19%), and elevated non-HDL cholesterol (20%) was observed. No change in SF-36 was noted. Compared to baseline, improvement in BDI [median 8.5 (IQR 4.8, 14.0) vs. 5.5 (IQR 2.2, 11.8), P=0.03] and sleep quality [bad sleep quality 57% to 23%, P=0.007] was noted at 6 months.

Conclusion: Overnight metyrapone in MACS demonstrated a favorable safety profile with no cases of AI. Treatment was associated with reduction in glucocorticoid/androgen ratio and improvement in patient-reported sleep quality and depressive symptoms. These findings support further investigation of metyrapone in MACS.

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