Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2025 Nov 18;110(12):3525-3537.
doi: 10.1210/clinem/dgaf206.

Chronotherapy With Once-Daily Osilodrostat Improves Cortisol Rhythm, Quality of Life, and Sleep in Cushing's Syndrome

Davide Ferrari  1 , Ilaria Bonaventura  1 , Chiara Simeoli  2 , Alessandra Tomaselli  1 , Ludovica Vincenzi  1 , Dario De Alcubierre  1 , Francesca Sciarra  1 , Flavio Rizzo  1 , Lorenzo Cerroni  1 , Nicola Di Paola  2 , Marianna Minnetti  1 , Emilia Sbardella  1 , Mary Anna Venneri  1 , Riccardo Pofi  3 , Rosario Pivonello  2 , Daniele Gianfrilli  1 , Valeria Hasenmajer  1 , Andrea M Isidori  1   4
Affiliations
Multicenter Study

Chronotherapy With Once-Daily Osilodrostat Improves Cortisol Rhythm, Quality of Life, and Sleep in Cushing's Syndrome

Davide Ferrari et al. J Clin Endocrinol Metab. .

Abstract

Context: Medical therapy for Cushing syndrome (CS) typically aims to reduce daily cortisol output without addressing circadian rhythm restoration. No licensed drugs target this goal.

Objective: We investigated the efficacy and safety of timed, once-daily osilodrostat administration in improving circadian cortisol profiles in CS.

Methods: A prospective, multicenter study evaluated patients with well-controlled CS on a stable twice-daily osilodrostat therapy before and 60 to 90 days after transitioning to a single equivalent daily dose at 19:00 ± 1 hour. Circadian steroid analysis was performed on saliva, serum, and urine using ultra-high performance liquid chromatography-tandem mass spectrometry. Additional assessments included cardio-metabolic markers, quality of life, sleep function, and safety outcomes.

Results: Sixteen patients (4 males; 7 pituitary, mean age 53.3 ± 11.8 years) were enrolled. At baseline, CS was well-controlled with a mean osilodrostat dose of 4.2 ± 1.3 mg. After transitioning, salivary cortisol exposure decreased significantly during the afternoon to early morning period (AUC16:00-08:00: -6.1 [-0.15 to -12.1] ng/mL/h, P = .029). Quality of life and sleep improved (CushingQoL: +4.2, P = .029; Pittsburgh Sleep Quality Index: -1.7, P = .049). Serum steroid precursors, including 11-deoxycorticosterone (-3.1 ng/mL/h, P = .008) and 11-deoxycortisol (-17.8 ng/mL/h, P = .005), decreased. Eight patients advancing dosing to 16:00 ± 1 hour showed comparable reductions, with phase shifts in acrophase and nadir. No patients developed adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control.

Conclusion: Once-daily osilodrostat effectively and safely treats patients with biochemically controlled CS, improving circadian cortisol profiles, quality of life, and sleep. Findings support further exploration of chronotherapy-based approaches in CS management.

Keywords: Cushing's Disease; Cushing's syndrome; chrono-pharmacology; cortisol circadian rhythm; cortisone; hypercortisolism; medical therapy; saliva; salivary cortisol.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Salivary cortisol curves before and after shifting to once-daily osilodrostat administration. Comparison of TBID and TOD regimens. Data are mean ± SD.
Figure 2.
Figure 2.
Change in the exposure to cortisone and cortisone in afternoon through early morning (1600-0800 and 1600-0400) measured as estimated AUC of the daily cosinor-based salivary analysis. Data are mean ± SD.
Figure 3.
Figure 3.
Change in serum steroid day curves and overall exposure (AUC8-20) across TBID and TOD. Data are mean ± standard error of the mean.
See this image and copyright information in PMC

Comment in

References

    1. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611‐629. - PubMed
    1. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing's syndrome. Lancet. 2023;402(10418):2237‐2252. - PubMed
    1. Reincke M, Fleseriu M. Cushing syndrome: a review. JAMA. 2023;330(2):170‐181. - PubMed
    1. Tritos NA, Miller KK. Diagnosis and management of pituitary adenomas: a review. JAMA. 2023;329(16):1386‐1398. - PubMed
    1. Bertagna X. MANAGEMENT OF ENDOCRINE DISEASE: can we cure Cushing's disease? A personal view. Eur J Endocrinol. 2018;178(5):R183‐R200. - PubMed

Publication types