Subclinical hypercortisolism in refractory hypertension
Keywords:
subclinical hypercortisolism; adrenal adenoma; hypertension; adrenal incidentaloma; glucocorticoids; diabetes mellitusAbstract
Introduction: Subclinical hypercortisolism is a condition characterized by excess cortisol without the typical clinical manifestations of Cushing's syndrome, and it is a significant secondary cause of resistant hypertension.
Objective: To present recent evidence on the pathophysiology, diagnosis, and treatment of subclinical hypercortisolism in patients with refractory hypertension.
Method: A literature review that included peer-reviewed articles, clinical practice guidelines and systematic reviews published in the last five years was conducted. The search terms were: subclinical hypercortisolism, mild autonomous cortisol secretion, resistant hypertension, refractory hypertension, and adrenal incidentaloma.
Development: Subclinical hypercortisolism is observed in 5–50% of patients with adrenal incidentalomas and is more prevalent in those with resistant hypertension than in the general hypertensive population. Its pathophysiology is multifactorial and involves the activation of mineralocorticoid and glucocorticoid receptors, the renin-angiotensin-aldosterone system, and the sympathetic nervous system. Diagnosis is based primarily on the nocturnal dexamethasone suppression test, supplemented by measurement of plasma ACTH, nocturnal salivary cortisol, and 24-hour urinary free cortisol. Treatment includes adrenalectomy in selected cases and targeted medical therapy.
Conclusions: Subclinical hypercortisolism is an underdiagnosed, but clinically significant cause, of resistant hypertension. Systematic screening improves blood pressure control and reduces cardiovascular morbidity and mortality.
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References
1. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing's syndrome. Lancet. 2023 [citado 18/05/2026];402(10418):2237-2252. Disponible en: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01961-X/abstract
2. Siemińska L, Siemińska K, Marek B, Kos-Kudła B, Nowak M, Głogowska-Szeląg J, et al. Adrenal tumours and subclinical adrenal hyperfunction. Endokrynol Pol. 2024 [citado 18/05/2026];75(6):630-642. Disponible en: https://journals.viamedica.pl/endokrynologia_polska/article/view/101940
3. Pizzorno L, Pizzorno J. Subclinical Hypercortisolism: An Important, Unrecognized Dysfunction. Integr Med (Encinitas). 2022 [citado 21/05/2026];21(3):8-15.Disponible en: https://pmc.ncbi.nlm.nih.gov/articles/PMC9380834
4. Khadembashiri MM, Mohseni S, Harandi H, Pejman Sani M, Amin Khadembashiri M, Rasha Atlasi, et al. Comparison of adrenalectomy with conservative treatment on mild autonomous cortisol secretion: a systematic review and meta-analysis. Front Endocrinol. 2024 [citado 02/05/2026];15:1374711. Disponible en: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1374711/full
5. Higgs JA, Quinn AP, Seely KD, Richards Z, Mortensen SP, Cody S Crandall, et al. Pathophysiological Link between Insulin Resistance and Adrenal Incidentalomas. Int J Mol Sci. 2022 [citado 02/05/2026];23(8):4340. Disponible en: https://pmc.ncbi.nlm.nih.gov/articles/PMC9032410/
6. Farah S, Nasr L, Eid Fares J. An Overlooked Disease: Minimal Autonomous Cortisol Secretion (MACS). A Narrative Review. Endocr Metab Immune Disord Drug Targets. 2024 [citado 02/05/2026];24(13):1518-1524. Disponible en: https://www.eurekaselect.com/article/138583
7. Capalbo MS, Deligiannis N, Danilowicz K. Secreción autónoma leve de cortisol: comorbilidades y resultados del tratamiento quirúrgico. Medicina (B Aires). 2025 [citado 15/03/2026];85(6):1326-1336. Disponible en: https://www.scielo.org.ar/scielo.php?pid=S0025-76802025001001326&script=sci_arttext
8. Tabarin A, Espiard S, Deutschbein T, Amar L, Vezzossi D, Di Dalmazie G, et al. Surgery for the treatment of arterial hypertension in patients with unilateral adrenal incidentalomas and mild autonomous cortisol secretion (CHIRACIC): a multicenter, open-label, superiority randomized controlled trial. Lancet Diabetes Endocrinol. 2025 [citado 02/05/2026];13(7):580-590. Disponible en: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00062-2/abstract
9. Favero V, Cremaschi A, Falchetti A, Gaudio A, Gennari L, Scillitani A, et al. Management and Medical Therapy of Mild Hypercortisolism. Int J Mol Sci. 2021 [citado 02/05/2026];22(21):11521. Disponible en: https://pmc.ncbi.nlm.nih.gov/articles/PMC8584167/
10. Musolino A, Parazzoli C, Delle Donne E, Favero V, Aresta C, Bilo G, et al. Prevalence of Hypercortisolism in Hypertension and Its Link to Carotid Atherosclerosis Markers. Endocr Pract. 2026 [citado 02/05/2026];32(3):329-336. Disponible en: https://www.endocrinepractice.org/article/S1530-891X(25)01261-3/fulltext
11. Inoue K, Horikoshi H, Omura M, Tsurutani Y, Saito J, Nishikawa T. Association Between Aldosterone and Hypertension Among Patients With Overt and Subclinical Hypercortisolism. J Endocr Soc. 2022[citado 02/05/2026];7(1):bvac167. Disponible en: https://pmc.ncbi.nlm.nih.gov/articles/PMC9683494/
12. Araujo Castro M, Cortés Gómez A, Rosillo M, Rodríguez A, Madrid I, Pascual Corrales E, et al. Value of the Serum Dexamethasone Determination for the Diagnosis of Mild Autonomous Cortisol Secretion. Clin Endocrinol. 2026 [citado 02/06/2026]5;104(5):428-435. Disponible en: https://onlinelibrary.wiley.com/doi/10.1111/cen.70065
13. Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell Price J, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 [citado 02/05/2026];189(1):G1-G42. Disponible en: https://academic.oup.com/ejendo/article/189/1/G1/7198474
14. Mirica A, Tilici DM, Paun DL, Arnautu AM, Nimigean V, Paun S. Adrenal Incidentaloma: From Silent Diagnosis to Clinical Challenge. Biomedicines. 2025 [citado 02/05/2026];13(9):2298. Disponible en: https://www.mdpi.com/2227-9059/13/9/2298
15. Prete A, Bancos I. Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches. Nat Rev Endocrinol. 2024 [citado 02/05/2026];20(8):460-473. Disponible en: https://www.nature.com/articles/s41574-024-00984-y
16. Bancos I, Prete A. Approach to the Patient With Adrenal Incidentaloma. J Clin Endocrinol Metab. 2021 [citado 02/05/2026];106(11):3331-3353. Disponible en: https://academic.oup.com/jcem/article/106/11/3331/6321402
17. Ren X, Nan M, Zhang X. Evaluating the efficacy of surgical and conservative approaches in mild autonomous cortisol secretion: a meta-analysis. Front Endocrinol. 2024 [citado 02/05/2026];15:1399311. Disponible en: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1399311/full
18. Chacko SR, Sharma Sharma S, Ahmadian S, Saini J, Fell V, Peersen AF, et al. Cardiometabolic Outcomes after Surgical Remission of Endogenous Hypercortisolism: a Prospective Cohort Study. J Clin Endocrinol Metab. 2026 [citado 02/06/2026];111(6)1613-1627. Disponible en: https://academic.oup.com/jcem/article-abstract/111/6/1613/8407100?redirectedFrom=fulltext
19. Januszewicz A, Mulatero P, Dobrowolski P, Monticone S, Van der Niepen P, Sarafidis P, et al. Cardiac Phenotypes in Secondary Hypertension: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022 [citado 02/05/2026];80(15):1480-1497. Disponible en: https://www.jacc.org/doi/10.1016/j.jacc.2022.08.714
20. Favero V, Cremaschi A, Parazzoli C, Falchetti A, Gaudio A, et al. Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside. Int J Mol Sci. 2022 [citado 02/05/2026];23(2):673. Disponible en: https://www.mdpi.com/1422-0067/23/2/673
21. Araujo Castro M, Reincke M, Lamas C. Epidemiology and Management of Hypertension and Diabetes Mellitus in Patients with Mild Autonomous Cortisol Secretion: A Review. Biomedicines. 2023 [citado 02/05/2026];11(12):3115. Disponible en: https://www.mdpi.com/2227-9059/11/12/3115
22. Knezevic E, Nenic K, Milanovic V, Knezevic NN. The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders. Cells. 2023 [citado 02/05/2026];12(23):2726. Disponible en: https://www.mdpi.com/2073-4409/12/23/2726
23. MacLeod C, Hadoke PWF, Nixon M. Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers? Int J Mol Sci. 2021 [citado 02/05/2026];22(14):7622. Disponible en: https://www.mdpi.com/1422-0067/22/14/7622
24. Cuthbertson DJ, Alam U, Davison AS, Belfield J, Shore SL, Vinjamuri S. Investigation and assessment of adrenal incidentalomas. Clin Med. 2023 [citado 02/05/2026];23(2):135-140. Disponible en: https://pmc.ncbi.nlm.nih.gov/articles/PMC11046519/
25. Nowak E, Viëtor CL, Feelders RA, Hofland J, Castro MA, Minguéz Ojeda C, et al. Effect of surgical versus conservative management on cardiovascular outcomes in patients with bilateral adrenal tumours and cortisol excess: an international, retrospective cohort study. Lancet Diabetes Endocrinol. 2026 [citado 02/05/2026];14(3):202-215. Disponible en: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00302-X/abstract
26. Kumar AL, Dream S, Shaik T, Doffek K, Conrardy R, Findling JW, et al. The impact of adrenalectomy on metabolic outcomes of patients with mild autonomous cortisol secretion defined by low-dose dexamethasone suppression testing. Surgery. 2026 [citado 02/05/2026];189:109775. Disponible en: https://www.surgjournal.com/article/S0039-6060(25)00627-0/abstract
27. Ueland GÅ, Ragnarsson O, Heie A, Kjellbom A, Lindgren O, Muth A, et al. Randomized trial studying metabolic outcomes and quality of life after adrenalectomy versus conservative management for mild autonomous cortisol secretion. Endocr Connect. 2025 [citado 02/05/2026];14(7):e250361. Disponible en: https://journals.bioscientifica.com/ec/article/14/7/e250361/1421/Randomized-trial-studying-metabolic-outcomes-and
28. Berry S, Iqbal A, Newell-Price J, Debono M. Efficacy and Tolerability of Metyrapone in Mild Autonomous Cortisol Secretion: Real-World Findings From Clinical Practice. Clin Endocrinol. 2025 [citado 02/05/2026];104(3):215-221. Disponible en: https://onlinelibrary.wiley.com/doi/10.1111/cen.70056
29. Stone JY, Bailey TS. How Common Is Hypercortisolism in Patients With Type 2 Diabetes? Risk Factors, Epidemiology, and Making a Diagnosis Using a Dexamethasone Suppression Test. Diabetes Obes Metab. 2026 [citado 11/05/2026];28(Suppl 4):17-24. Disponible en: https://pmc.ncbi.nlm.nih.gov/articles/PMC13522864/
30. Czapla Iskrzycka A, Świątkowska Stodulska R, Sworczak K. Comorbidities in Mild Autonomous Cortisol Secretion - A Clinical Review of Literature. Exp Clin Endocrinol Diabetes. 2022[citado 02/05/2026];130(9):567-576. Disponible en: https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-1827-4113
31. Ibrahimli A, Memisoglu E, Perez Soto R, Veeramachaneni R, Bendaram SR, Berber E . Steroid replacement after adrenalectomy for mild autonomous cortisol secretion: Clinical predictors and a practical algorithm. Surgery. 2025 [citado 02/05/2026];191:109967. Disponible en: https://www.surgjournal.com/article/S0039-6060(25)00819-0/abstract
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