Skip to main content
ENDO 2026 Main banner

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, MD: No financial relationships to disclose
Kai Yu, MD, PhD: No financial relationships to disclose
Irina Bancos, MD: 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.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*