Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion
Open accessAbstract
Context: Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. Objective: We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. Design, Setting, and Participants: In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Results: Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. Conclusions: In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6.
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Evidence suggests that restoring cortisol circadian rhythm may improve disease control and alleviate symptoms.
“However, evidence suggests that restoring cortisol circadian rhythm may improve disease control and alleviate symptoms (39-43).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [40]
Normalization of the cortisol circadian rhythm after most medical therapies has rarely been investigated and is not routinely measured to assess treatment response.
“Although this can be achieved after successful surgery selectively removing the source of excess ACTH or cortisol, normalization of the cortisol circadian rhythm after most medical therapies has rarely been investigated and is not routinely measured to assess treatment response (39-44).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [40]
Salivary cortisol generally correlates well with total and free serum cortisol, while salivary cortisone shows an even stronger correlation.
“Salivary cortisol generally correlates well with total and free serum cortisol, while salivary cortisone shows an even stronger correlation (40).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [40]
Salivary cortisone had the strongest correlation to serum cortisol in patients with MACS before and after timed evening metyrapone.
“Salivary cortisone had the strongest correlation to serum cortisol and the authors concluded that salivary cortisone may be useful for monitoring medical therapy in the community setting.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [40]
Timed metyrapone treatment was associated with reduction in interleukin-6, a cardiovascular risk marker.
“This study also displayed an association between timed metyrapone treatment and reduction in interleukin-6, a cardiovascular risk marker, highlighting the need for future investigations into whether correction of the cortisol circadian rhythm can reduce morbidity and mortality.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [40]
Abnormal 24-hour cortisol circadian rhythm, measured by hourly serum and salivary cortisol levels, was successfully corrected after metyrapone treatment.
“Abnormal 24-hour cortisol circadian rhythm, measured by hourly serum and salivary cortisol levels, was successfully corrected after metyrapone treatment.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [40]
Cites
The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.
Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0125 · Cited by 2,718 · cited 3× · see citing works
“Although an ONDST cut-off of serum cortisol of 50 nmol/L is recommended by both the Endocrine Society and European Society of Endocrinology to identify hypercortisolemia in AI (5, 12), other data suggest that a lower level of serum cortisol may be associated with true normality.”
BackgroundSelf-citationInflammatory Markers and Risk of Type 2 Diabetes
Wang, X., Bao, W., Liu, J., OuYang, Y.-Y., Wang, D., Rong, S., Xiao, X., Shan, Z.-L., Zhang, Y., Yao, P., et al. (2013) · Diabetes Care · doi:10.2337/dc12-0702 · Cited by 820 · see citing works
Circadian misalignment increases cardiovascular disease risk factors in humans
Morris, C. J., Purvis, T. E., Hu, K., & Scheer, F. A. J. L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1516953113 · Cited by 691 · see citing works
Diagnosis and Treatment of Subclinical Hypercortisolism
Chiodini, I. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2722 · Cited by 279 · cited 1× · see citing works
“Between 30% and 50% of AI exhibit low-grade cortisol secretion variously termed “subclinical Cushing,” “subclinical hypercortisolism,” or, more recently, “autonomous cortisol secretion (ACS)” (4, 5), because patients lack the classical clinical features of Cushing syndrome (6, 7).”
BackgroundCortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas
Debono, M., Bradburn, M., Bull, M., Harrison, B., Ross, R. J., & Newell-Price, J. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3007 · Cited by 269 · cited 3× · see citing works
“Patients with adrenal incidentalomas (AIs) and lowgrade excess cortisol secretion have higher mortality due to cardiovascular events and infections (1, 2).”
BackgroundMethodSelf-citationMorris, C. J., Purvis, T. E., Mistretta, J., & Scheer, F. A. J. L. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3924 · Cited by 262 · see citing works
Plat, L., Leproult, R., L’Hermite-Baleriaux, M., Fery, F., Mockel, J., Polonsky, K. S., & Van Cauter, E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.5978 · Cited by 225 · cited 1× · see citing works
“Moreover, disturbances in the quiescent phase of cortisol secretion in the evening have been associated with impaired glucose tolerance (24) and predict future new-onset type 2 diabetes (25).”
BackgroundLong-term follow-up in adrenal incidentalomas: an Italian multicenter study
Morelli, V., Reimondo, G., Giordano, R., Della Casa, S., Policola, C., Palmieri, S., Salcuni, A. S., Dolci, A., Mendola, M., Arosio, M., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3527 · Cited by 223 · see citing works
Salivary cortisone is a potential biomarker for serum free cortisol
Perogamvros, I., Keevil, B. G., Ray, D. W., & Trainer, P. J. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1215 · Cited by 222 · see citing works
Plat, L. (1999) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.84.9.3082 · Cited by 177 · see citing works
Nunes, M.-L., Vattaut, S., Corcuff, J.-B., Rault, A., Loiseau, H., Gatta, B., Valli, N., Letenneur, L., & Tabarin, A. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1542 · Cited by 129 · see citing works
Debono, M., Harrison, R. F., Whitaker, M. J., Eckland, D., Arlt, W., Keevil, B. G., & Ross, R. J. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3694 · Cited by 128 · see citing works
Self-citationMasserini, B., Morelli, V., Bergamaschi, S., Ermetici, F., Eller-Vainicher, C., Barbieri, A. M., Maffini, M. A., Scillitani, A., Ambrosi, B., Beck-Peccoz, P., et al. (2009) · European Journal of Endocrinology · doi:10.1530/eje-08-0485 · Cited by 106 · see citing works
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Galik, E., Fukudo, S., Tanaka, Y., Gidron, Y., Campbell, T. S., Johnson, J. A., Zernicke, K., Pellowski, J. A., García, L. I., Mitchell, J., et al. (2020) · Definitions · doi:10.1007/978-3-211-89836-9_624 · Cited by 987
Approach to the Patient With Adrenal Incidentaloma
Bancos, I., & Prete, A. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab512 · Cited by 201 · see citing works
Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches
Prete, A., & Bancos, I. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-024-00984-y · Cited by 130 · see citing works
Human studies on hypothalamo-pituitary-adrenal (HPA) axis
Liyanarachchi, K., Ross, R. J. M., & Debono, M. (2017) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2017.10.011 · Cited by 78 · see citing works
Self-citationDiagnosis and management of primary bilateral macronodular adrenal hyperplasia
Vassiliadi, D. A., & Tsagarakis, S. (2019) · Endocrine Related Cancer · doi:10.1530/erc-19-0240 · Cited by 83 · see citing works
“…approach is to use steroidogenesis inhibitors in a manner that aims to restore normal cortisol rhythm, that is to lower evening and night cortisol levels without affecting morning levels, by administering timed evening doses of a short-acting compound, such as metyrapone (Debono et al. 2017).”
Approach to the Patient Treated with Steroidogenesis Inhibitors
Castinetti, F., Nieman, L. K., Reincke, M., & Newell-Price, J. D. C. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab122 · Cited by 75 · see citing works
Self-citationFixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy
Minnetti, M., Hasenmajer, V., Pofi, R., Venneri, M. A., Alexandraki, K., & Isidori, A. M. (2020) · Journal of Endocrinology · doi:10.1530/joe-20-0066 · Cited by 70 · see citing works
Burgermeister, E., Battaglin, F., Eladly, F., Wu, W., Herweck, F., Schulte, N., Betge, J., Härtel, N., Kather, J. N., Weis, C., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.07.004 · Cited by 69 · see citing works
“by seliciclib in mice [63] or cortisol in patients [64].”
BackgroundRaff, H., & Phillips, J. M. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00186 · Cited by 53 · see citing works
“Using LC-MS/MS does not mitigate the lack of usefulness of late-night salivary cortisol measurements for the evaluation of patients with adrenal incidentalomas, although salivary cortisone clearly has potential in this regard [23, 44].”
BackgroundModern management of mild autonomous cortisol secretion
Delivanis, D. A., Athimulam, S., & Bancos, I. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1551 · Cited by 46 · see citing works
“Metyrapone was studied in a proofof-concept study that demonstrated that when administered in the evening to patients with MACS, a correction of the abnormal circadian rhythm of cortisol secretion was noted.(57) Metyrapone use is approved only in the European Union but not in the United States.”
BackgroundCardiovascular complications of mild autonomous cortisol secretion
Aresta, C., Favero, V., Morelli, V., Giovanelli, L., Parazzoli, C., Falchetti, A., Pugliese, F., Gennari, L., Vescini, F., Salcuni, A. S., et al. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101494 · Cited by 53 · see citing works
Update on primary bilateral macronodular adrenal hyperplasia (PBMAH)
Bouys, L., Chiodini, I., Arlt, W., Reincke, M., & Bertherat, J. Y. (2021) · Endocrine · doi:10.1007/s12020-021-02645-w · Cited by 61 · see citing works
Nieman, L. K., Castinetti, F., Newell-Price, J. D. C., Valassi, E., Drouin, J., Takahashi, Y., & Lacroix, A. (2025) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00588-w · Cited by 73 · see citing works
Self-citationFleseriu, M., & Biller, B. M. K. (2022) · Pituitary · doi:10.1007/s11102-022-01268-2 · Cited by 53 · see citing works
“Further, in patients with adrenal incidentalomas and mild autonomous cortisol secretion who were given metyrapone specifically in the evening, the cortisol rhythm was “reset,” with reduced cortisol levels at night and normalized levels comparable to those of healthy controls [56].”
BackgroundManagement and Medical Therapy of Mild Hypercortisolism
Favero, V., Cremaschi, A., Falchetti, A., Gaudio, A., Gennari, L., Scillitani, A., Vescini, F., Morelli, V., Aresta, C., & Chiodini, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111521 · Cited by 38 · see citing works
“This administration schedule led to a correction of the abnormal circadian rhythm of cortisol secretion, thus suggesting the possible use of low doses of metyrapone in patients with mHC with the aim to restore the physiological rhythm of cortisol [71].”
BackgroundAssessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses
Yozamp, N., & Vaidya, A. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101491 · Cited by 33 · see citing works
Cardiovascular mortality in patients with subclinical Cushing
Morelli, V., Arosio, M., & Chiodini, I. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2018.03.005 · Cited by 31 · see citing works
Ferrari, D., Bonaventura, I., Simeoli, C., Tomaselli, A., Vincenzi, L., De Alcubierre, D., Sciarra, F., Rizzo, F., Cerroni, L., Di Paola, N., et al. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf206 · Cited by 28 · see citing works
Harrison, R. F., Debono, M., Whitaker, M. J., Keevil, B. G., Newell-Price, J., & Ross, R. J. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01172 · Cited by 27 · see citing works
“• Cohort 3: Twenty-eight healthy (nine female) volunteers, mean age 28 years (range, 18 to 56 years), who had undergone 24-hour hourly serum cortisol profiling measured by LC-MS/MS (22).”
BackgroundMethodInfluentialSelf-citationMifepristone Treatment for Mild Autonomous Cortisol Secretion Due to Adrenal Adenomas: A Pilot Study
Belokovskaya, R., Ravikumar, A., Arumugam, D., Izadmehr, S., Goddard, G. M., Geer, E. B., & Levine, A. C. (2019) · Endocrine Practice · doi:10.4158/ep-2019-0047 · Cited by 30 · see citing works
Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment
Chevalier, B., Vantyghem, M., & Espiard, S. (2021) · Biomedicines · doi:10.3390/biomedicines9101397 · Cited by 30 · see citing works
“Treatment with metyrapone administered at the end of the afternoon and at bedtime has been proposed in patients with adrenal incidentalomas and subclinical CS to try to restore the normal circadian rhythm [143].”
Medical management of Cushing's disease: When and how?
Castinetti, F. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13120 · Cited by 27 · see citing works
What is the role of medical therapy in adrenal-dependent Cushing’s syndrome?
Braun, L. T., & Reincke, M. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101376 · Cited by 21 · see citing works
Castro, M. A., Reincke, M., & Lamas, C. (2023) · Biomedicines · doi:10.3390/biomedicines11123115 · Cited by 24 · see citing works
“However, data on the efficacy and safety of the medical treatment for MACS are still lacking since few studies have described their use in that setting [36].”
BackgroundInfluentialPharmacological Treatment of Cushing's Syndrome
Castinetti, F. (2023) · Archives of Medical Research · doi:10.1016/j.arcmed.2023.102908 · Cited by 27 · see citing works
Castro, M. A., & Marazuela, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.913253 · Cited by 23 · see citing works
“In other study, metyrapone restore the physiological rhythm of cortisol in patients with ACS (64).”
BackgroundSaini, J., Singh, S., Ebbehoj, A., Zhang, C. D., Nathani, R., Fell, V., Atkinson, E., Achenbach, S., Rivard, A., Singh, R., et al. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae468 · Cited by 20 · see citing works
MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing’s disease? A personal view
BERTAGNA, X. Y. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0062 · Cited by 22 · see citing works
Management of adrenal incidentalomas: Working through uncertainty
Cambos, S., & Tabarin, A. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101427 · Cited by 22 · see citing works
Do the diagnostic criteria for subclinical hypercortisolism exist?
Tabarin, A. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2018.03.013 · Cited by 18 · see citing works
Recent Advances on Subclinical Hypercortisolism
Zavatta, G., & Dalmazi, G. D. (2018) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2018.01.003 · Cited by 17 · see citing works
Fleseriu, M., Auchus, R. J., Bancos, I., & Biller, B. M. K. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf027 · Cited by 17 · see citing works
“Circadian cortisol rhythm is abnormal in these patients [118] and has been shown to normalize following 2 evening doses of metyrapone [119].”
Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations
Tang, P., Zhang, J., Peng, S., Yan, X., Wang, Y., Wang, S., Zhang, Y., Liu, G., Xu, J., Huang, Y., et al. (2023) · BMC Endocrine Disorders · doi:10.1186/s12902-023-01324-3 · Cited by 14 · see citing works
“Steroid synthesis inhibitors including metyrapone and ketoconazole [23], mifepristone and glucocorticoid receptor antagonist [24], and mitotane [25] were the suggested medical treatment.”
BackgroundAdrenal incidentaloma: cardiovascular and metabolic effects of mild cortisol excess
Kelsall, A., Iqbal, A., & Newell-Price, J. D. C. (2020) · Gland Surgery · doi:10.21037/gs.2019.11.19 · Cited by 15 · see citing works
“Metyrapone administered in the evening led to a reduction in AUC cortisol and IL-6 levels resetting the abnormal circadian rhythm to “normal” (65).”
BackgroundSelf-citationBabińska, A., Kaszubowski, M. F., Kmieć, P., & Sworczak, K. (2018) · Steroids · doi:10.1016/j.steroids.2018.08.011 · Cited by 14 · see citing works
“searchers, overt glucocorticoid excess was associated with increased concentration of pro-inflammatory cytokines, including IL6 [2,14,15].”
Adrenal Incidentaloma: Picking out the High-Risk Patients
Dalmazi, G. D. (2018) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0713-0598 · Cited by 14 · see citing works
“Moreover, the reduction in IL6 levels after restoration of cortisol rhythm by Metyrapone pointed toward a possible link between altered circa dian rhythmicity and infectious complications [23].”
Primary bilateral macronodular adrenal hyperplasia: A series of 32 cases and literature review
Castro, M. A., & Reincke, M. (2023) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2022.12.010 · Cited by 4 · see citing works
Giorgi, R. B., Correa, M. V., Costa‐Barbosa, F. A., & Kater, C. E. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2018-00385 · Cited by 12 · see citing works
“, the difference between the highest and the lowest post-DST serum cortisol value in the same patient) [20].”
BackgroundApproach to patients with bilateral adrenal incidentalomas
Vassiliadi, D. A., Partsalaki, E., & Tsagarakis, S. (2020) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000536 · Cited by 10 · see citing works
“A compelling approach is to attempt to restore normal cortisol rhythm, that is to lower evening and night cortisol levels without affecting morning levels, by administering timed evening doses of a short acting compound, such as metyrapone [38].”
BackgroundDiurnal salivary cortisol profiles in patients with Cushing's syndrome
Braun, L. T., Vogel, F., Zopp, S., Rubinstein, G., Schilbach, K., Künzel, H., Beuschlein, F., & Reincke, M. (2022) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1719-5381 · Cited by 8 · see citing works
“Our data might confirm the approach to treat these patients with chronotherapy using medical therapy in the evening to lower cortisol levels [25] taking into account the importance of a circadian rhythm [26, 27].”
MethodParagliola, R. M., Marchetti, M., Montagna, C., Corsello, S. M., & Peluso, G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211230 · Cited by 5 · see citing works
“Furthermore, this specific treatment is associated with a reduction in the cardiovascular risk marker IL-6 [133].”
Update on Medical Treatment of Cushing’s Syndrome
Dillon, B. R., Agrawal, N., Schwarz, Y., Dancel-Manning, K., Tabarin, A., Lacroix, A., Hofland, L. J., & Feelders, R. A. (2025) · Drugs · doi:10.1007/s40265-025-02223-8 · Cited by 9 · see citing works
“In a limited, proof-of-concept study, therapy was adjusted with higher doses in the evening than during daytime to reset the cortisol nycthemeral rhythm and reduce the cardiovascular risk marker interleukin-6 [143].”
Samson, S. L., Donegan, D. M., Geer, E. B., Gordon, M. B., Hamidi, O., Huang, W., Ioachimescu, A. G., Silverstein, J. M., Spencer-Segal, J. L., Tritos, N. A., et al. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf103 · Cited by 9 · see citing works
“…nighttime (6 PM to 2 AM ) cortisol levels that normalized when metyrapone was administered at 6 PM (500 mg) and 10 PM (250 mg); although there was speculation that this could alleviate some symptoms and comorbidities of MACS, such outcomes were not reported and sleep quality was not measured [55].”
The impact of mild autonomous cortisol secretion and proposed interventions
Iriarte-Durán, M. B., Donato, S., Herrera-Martínez, A. D., Vega, A., Casinello, J. M. J., Marazuela, M., & Castro, M. A. (2025) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2025.2480704 · Cited by 9 · see citing works
“Unfortunately, hypertension control was not assessed in this study [82].”
Chen, A., & Burt, M. G. (2022) · Clinical Endocrinology · doi:10.1111/cen.14850 · Cited by 10 · see citing works
“Recent estimates indicate that possible autonomous cortisol F IGURE 1 Twenty‐four‐hour serum cortisol profile in patients with adrenal adenoma and mild autonomous cortisol secretion, nonfunctioning adrenal adenoma and healthy controls (From reference Debono et al.(17) with permission).”
BackgroundMethodInfluentialMetyrapone in Cushing’s syndrome: a profile of its use
Al-Salama, Z. T. (2021) · Drugs & therapy perspectives · doi:10.1007/s40267-021-00853-y · Cited by 7 · see citing works
Albuja-Cruz, M. B., Raeburn, C. D., & McIntyre, R. C. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-47873-1.00064-4
“in vestigated the potential implications of the restoration of a normal circadian cortisol rhythm in patients with incidentalomas, by using a steroidogenesis inhibitor [23].”
Niziolek, H., Just, I., Tosin, A., Baumgartner, C., Körmöczi, K., Bellach, L., Fellinger, P., Beiglböck, H., Skuciova, H., Gericke, G., et al. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.103775 · Cited by 7 · see citing works
“In a previous study Debono and colleagues 8 showed that short-acting cortisol synthesis blockade with evening doses of metyrapone, a selective inhibitor of 11 β -hydroxylase, is able to restore the physiological circadian cortisol rhythm by lowering nocturnal cortisol levels without the risk of…”
Berry, S. A., Iqbal, A., Newell-Price, J. D. C., & Debono, M. (2025) · Clinical Endocrinology · doi:10.1111/cen.70056 · Cited by 5 · see citing works
“Previously we showed that metyrapone can acutely reset the nocturnal cortisol rhythm without affecting morning cortisol levels [3].”
Self-citationNowak, E., Zhang, Q., Zhang, S., Yao, Z., Ye, H., Machado, M. C., Moises, C., Tóth, M., Stark, J., Yuen, K. C. J., et al. (2025) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(25)00249-9 · Cited by 12 · see citing works
Self-citationAdrenal incidentaloma: differential diagnosis and management strategies
Morelli, V., & Palmieri, S. (2018) · Minerva Endocrinology · doi:10.23736/s0391-1977.18.02868-7 · Cited by 12 · see citing works
Trandafir, A.-I., Ghemigian, A. M., Ciobica, M.-L., Nistor, C., Gurzun, M., Nistor, T. V. I., Petrova, E. N., & Carşote, M. (2024) · Biomedicines · doi:10.3390/biomedicines12071606 · Cited by 4 · see citing works
“Medical therapy such as mifepristone, a glucocorticoid receptor blocker, may improve the insulin resistance and even provide a bridge to surgery [179].”
BackgroundRethinking hypercortisolism screening in obesity and diabetes: A systematic review and meta-analysis
Ferrari, D., Bonaventura, I., Tenuta, M., Pofi, R., Awadi, F. A., Jamal, H. F., Pivonello, R., Corona, G., & Isidori, A. M. (2026) · Metabolism · doi:10.1016/j.metabol.2026.156675 · Cited by 4 · see citing works
Beyond the Classical Axis: Metabolic “Pressure” on the Adrenal Gland?
Isidori, A. M., Pofi, R., & Fleseriu, M. (2025) · Diabetes · doi:10.2337/dbi25-0035 · Cited by 4 · see citing works
Cardiometabolic risk and therapeutic outcomes in mild autonomous cortisol secretion
Athimulam, S. (2025) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000922 · Cited by 4 · see citing works
Osilodrostat oral tablets for adults with Cushing’s disease
Martino, M., Aboud, N., Lucchetti, B., Salvio, G., & Arnaldi, G. (2022) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2022.2044789 · Cited by 4 · see citing works
“Several studies suggest a beneficial effect of adrenalectomy on cardiovascular risk factors in these patients as compared to conservative management [42], but this issue is controversial and the medical treatment with osilodrostat or other adrenal steroidogenesis inhibitors [43] could be another valid therapeutic opti…”
BackgroundCurrent approach of primary bilateral adrenal hyperplasia
Delivanis, D. A., Vassiliadi, D. A., & Tsagarakis, S. (2022) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000725 · Cited by 5 · see citing works
Hamidi, O., St-Jean, M., Lacroix, A., & Bancos, I. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag095 · Cited by 5 · see citing works
A Circadian Trough in Glucocorticoid Signaling Is Essential for Bone Health in Mice
Smit, A. E., Yue, K., Kooijman, S., Afkir, S., Schilperoort, M., Koedam, M., van der Eerden, B. C. J., Kroon, J., Meijer, O. C., & Winter, E. M. (2026) · Aging Cell · doi:10.1111/acel.70479 · Cited by 2 · see citing works
“This could be achieved with, for example, 11b-hydroxylase inhibitors, which have been shown to restore normal cortisol rhythm in patients with adrenal incidentalomas (Debono et al. 2017).”
Bilateral Adrenal Nodules Presenting With Mild Autonomous Cortisol Secretion
Sandooja, R., Hamidi, O., Zhang, C. D., Dogra, P., Athimulam, S., Rahimi, L., Villavicencio, C. A., Chacko, S. R., Young, W. F., & Bancos, I. (2025) · Endocrine Practice · doi:10.1016/j.eprac.2025.06.019 · Cited by 2 · see citing works
Medical Treatment of Cushing’s Syndrome
Guignat, L., & Bertherat, J. Y. (2025) · Endocrinology and Metabolism · doi:10.3803/enm.2024.501 · Cited by 5 · see citing works
“Timed evening doses have been successfully used to reset the cortisol rhythm to normal in a small prospective, open-label, controlled study of patients with adrenal adenomas causing mild autonomous cortisol secretion [38].”
Advances in the study of corticoid and melatonin in circadian rhythm disorders of oncology patients
Liang, J., Luo, L., & Wang, X. (2023) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v36i.5675 · Cited by 2 · see citing works
Non-medicalization of medical science: Rationalization for future
Mittal, M., Jethwani, P., Naik, D., & Garg, M. (2022) · World Journal of Methodology · doi:10.5662/wjm.v12.i5.402 · Cited by 2 · see citing works
Riester, A., & Beuschlein, F. (2021) · Der Internist · doi:10.1007/s00108-021-01188-6 · Cited by 2 · see citing works
Yu, C.-G., Wu, N.-N., Cao, B., Gong, H.-L., Ma, Y., Xian, S.-Z., Zhang, B.-Y., Ke, J., & Zhao, D. (2025) · Journal of Clinical Medicine Research · doi:10.14740/jocmr6359 · Cited by 1
“Medical management options include steroidogenesis inhibitors (metyrapone, ketoconazole [18]), glucocorticoid receptor antagonists (mifepristone [19]), and adrenolytic therapy (mitotane [20]).”
Management of adrenal incidentalomas: who, why and how?
Araujo-Castro, M., Iriarte-Durán, M. B., Ramírez, P. A. P., & Donato, S. (2025) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000917 · Cited by 1 · see citing works
Milde autonome Cortisolsekretion – von der Diagnose bis zur Therapie
Tosin, A., Niziolek, H., & Wolf, P. (2026) · Journal für Endokrinologie Diabetologie und Stoffwechsel · doi:10.1007/s41969-026-00321-w
MACS: mild by definition, challenging by nature
Bluszcz, G., Roszkowska, Z., Domański, J., Sharabi, A., Rapiejko, J., Malek, J., Ambroziak, U., & Bobrowicz, M. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1957127
Chacko, S. R., Yu, K., Fell, V., Powell, C., Ndovu, B., Rosenberg, R., Ferreira, E. Y., Saini, J., Nevin, S., Larson, J. J., et al. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.104210
Ramundo, G., & Dalmazi, G. D. (2026) · L Endocrinologo · doi:10.1007/s40619-026-01847-6
Managing mild autonomous cortisol secretion (MACS): evaluating the role of medical treatment
Loh, E. W., & Debono, M. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1850728
Self-citationRossini, A., Pellegrini, S., Ippolito, S., Cassibba, S., Giovanelli, L., Zappoli, M., Trevisan, R., & Lepore, G. (2026) · Endocrine · doi:10.1007/s12020-026-04601-y
“In a 2017 study, Debono et al. [11] reported that patients with MACS exhibit significantly higher evening and nighttime serum cortisol levels compared to both patients with non-functioning Table 2 Biochemical parameters of patients before and after one week of metyrapone treatment.”
InfluentialMedical therapy in mild autonomous cortisol secretion
Kelsall, A., Agboola, M., Bryden, E., Healey, W., Tolhurst, K., Hind, D., & Newell-Price, J. (2026) · Journal of the Endocrine Society · doi:10.1210/jendso/bvag090
“Two studies had control arms, one comparing metyrapone therapy in MACS to a group with MACS and no treatment [9] and a further retrospectively comparing metyrapone in MACS to nontreatment in an age-and sex-matched MACS group [12].”
InfluentialSelf-citationMild Autonomous Cortisol Secretion
Zhang, C., & Raff, H. (2026) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2026.01.004
Primary Bilateral Macronodular Adrenal Hyperplasia
Koukoula, C., Kyriakopoulos, G., Tsagarakis, S., & Vassiliadi, D. A. (2026) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2026.01.005
Chirurgia, terapia medica o follow-up nella secrezione autonoma di cortisolo (MACS)?
Morelli, V., Ceccato, F., & Dalmazi, G. D. (2026) · L Endocrinologo · doi:10.1007/s40619-026-01754-w
“Dopo il trattamento con metirapone i livelli di cortisolo si normalizzavano e si osservava una ri-duzione dei livelli di IL-6 [14].”
Kelsall, A., Johns, C., Hills, E., Zhao, J., & Newell-Price, J. (2025) · Clinical Endocrinology · doi:10.1111/cen.70055
Self-citationIl ritmo circadiano nella Sindrome di Cushing
Hasenmajer, V., & Isidori, A. M. (2025) · L Endocrinologo · doi:10.1007/s40619-025-01680-3
“Il secondo studio [17], su sei pazienti affetti da adenoma surrenalico unilaterale o bilaterale con mild autonomous cortisol secretion naïve alla terapia medica, ha mo-strato come un adeguato timing della somministrazione del metirapone ripristinasse il profilo circadiano del cortisolo e mostrasse…”
Hipercortisolismo de origen adrenal
Corrales, E. P., Castro, M. A., Ortiz-Flores, A. E., & Escobar-Morreale, H. F. (2024) · Medicine - Programa de Formación Médica Continuada Acreditado · doi:10.1016/j.med.2024.06.010
Subclinical hypercortisolemia – a therapeutic dilemma
Tuszyńska, A., & Bednarek-Papierska, L. (2023) · Wiedza Medyczna · doi:10.36553/wm.154
“Disturbed circadian cortisol se - cretion rhythm is also related to increased cardiovascular risk (24).”
BackgroundHaissaguerre, M., & Tabarin, A. (2020) · EMC - Endocrinologie - Nutrition · doi:10.1016/s1155-1941(19)83573-4
Therapy of mild cortisol excess
Iqbal, A., & Newell-Price, J. D. C. (2019) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2019.08.019
Self-citationAdrenal Incidentaloma : Picking out the High-Risk Patients
Newell-Price, J. (2018) · doi:10.1530/endoabs.56.mte16
“in vestigated the potential implications of the restoration of a normal circadian cortisol rhythm in patients with incidentalomas, by using a steroidogenesis inhibitor [23].”
Self-citation
- Authors
- Debono, M., Harrison, R. F., Chadarevian, R., Gueroult, C., Abitbol, J.-L., & Newell-Price, J.
- Affiliations
- University of Sheffield (GB)
- HRA Pharma (France) (FR)
- Corresponding author
- Newell-Price, John
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2017-06-30
- Volume
- 102
- Issue
- 9
- Pages
- 3461-3469
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5587065
- OpenAlex
- W2731632156
- Cited by
- 100
- References
- 0
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 6 · 2023: 14 · 2022: 11 · 2021: 9 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 1
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Funders
- National Institute for Health and Care Research (CL-2013-04-001, BRF-2011-005)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- adrenal incidentaloma, autonomous cortisol secretion, diurnal cortisol rhythm, metyrapone, 11β-hydroxylase inhibition, interleukin-6, cardiovascular risk, salivary cortisone, Cushing's disease, Cushing's syndrome
- MeSH terms
- Adrenal Gland Neoplasms, Aged, Circadian Rhythm, Cortisone, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Hydrocortisone, Male, Metyrapone, Middle Aged, Prospective Studies, Interleukin-6, Body Mass Index, Case-Control Studies, Statistics, Nonparametric, Area Under Curve
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