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Prevalence and cardiometabolic impact of mild autonomous cortisol secretion in primary aldosteronism: a systematic review and meta-analysis.

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Title: Prevalence and cardiometabolic impact of mild autonomous cortisol secretion in primary aldosteronism: a systematic review and meta-analysis.
Authors: Eisa N; Community Health Partners, Fresno, California, USA., Khoury M; Faculty of Medicine, Damascus University, Damascus, Syria.
Source: Journal of hypertension [J Hypertens] 2026 Oct 01; Vol. 44 (10), pp. 1667-1676. Date of Electronic Publication: 2026 Jul 16.
Publication Type: Journal Article; Systematic Review; Meta-Analysis
Language: English
Journal Info: Publisher: Wolters Kluwer Health, Inc Country of Publication: Netherlands NLM ID: 8306882 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1473-5598 (Electronic) Linking ISSN: 02636352 NLM ISO Abbreviation: J Hypertens Subsets: MEDLINE
Imprint Name(s): Publication: [Alphen aan den Rijn, the Netherlands] : Wolters Kluwer Health, Inc.
Original Publication: London ; New York : Gower Academic Pub., [1983-
MeSH Terms: Hyperaldosteronism*/epidemiology , Hyperaldosteronism*/blood , Hyperaldosteronism*/complications , Hyperaldosteronism*/metabolism , Hydrocortisone*/metabolism , Hydrocortisone*/blood , Cardiovascular Diseases*/epidemiology, Diabetes Mellitus, Type 2/epidemiology ; Humans ; Prevalence
Abstract: Many primary aldosteronism (PA) patients harbor concomitant mild autonomous cortisol secretion (MACS), termed "Connshing syndrome." The prevalence and cardiometabolic impact of this co-secretion have not been quantitatively synthesized. To determine the pooled prevalence of MACS in PA and evaluate its association with cardiovascular (CV) events, type 2 diabetes mellitus (T2DM), and obesity. PubMed, Embase, Cochrane, Web of Science, and Scopus through January 2026. Following PRISMA 2020 and MOOSE guidelines (PROSPERO: CRD420261334965), studies reporting MACS prevalence [post-1 mg dexamethasone suppression test (DST) cortisol ≥1.8 μg/dl] in PA were included. Prevalence was pooled using random-effects models. Odds ratios (ORs) were calculated for cardiometabolic outcomes. Certainty was evaluated using GRADE. Fourteen studies (2356 patients) were included. Pooled MACS prevalence was 26.2% [95% confidence interval (CI): 24.1-28.4; I2 = 24.2%; prediction interval: 21.6-31.4%], consistent across European (27.0%) and East Asian (25.2%) cohorts ( P = 0.62). MACS + PA patients had higher odds of CV events (OR 1.60; 95% CI: 1.07-2.38; P = 0.021) and T2DM (OR 1.37; 95% CI: 1.00-1.86; P = 0.048), but not obesity (OR 1.10; P = 0.411). Sensitivity analyses confirmed robustness. GRADE certainty was moderate for prevalence and low for CV events. Approximately one in four PA patients has MACS, associated with a 60% higher CV event risk. These findings support routine DST screening in PA and have implications for perioperative management and cardiometabolic risk stratification.
(Copyright © 2026 Wolters Kluwer Health, LLC. All rights reserved.)
References: Funder JW, Carey RM, Mantero F, Baid SK, Fardella C, Florence JM, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101:1889–1916.
Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol 2017; 69:1811–1820.
Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45:1243–1248.
Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension 2013; 62:331–336.
Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev P, 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; 189:G1–G42.
Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, et al. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome. Eur J Endocrinol 2014; 170:1–11.
Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J, et al. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab 2014; 99:4462–4470.
Hiraishi K, Yoshimoto T, Tsuchiya K, Minami I, Doi M, Izumiyama H, et al. Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome. Endocr J 2011; 58:543–551.
Nishimoto K, Nakagawa K, Li D, Kosaka T, Oya M, Mikami S, et al. Adrenocortical zonation in humans under normal and pathological conditions. J Clin Endocrinol Metab 2010; 95:2296–2305.
Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA 2015; 112:E4591–E4599.
Araujo-Castro M, Paja Fano M, Pla Peris B, Fraile Gomez J, Garcia Cano AM, Pascual-Corrales E, et al. Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications. Endocr Connect 2023; 12:e230043.
Katabami T, Matsuba R, Kobayashi H, Nakagawa T, Kurihara I, Ichijo T, et al. Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk. Eur J Endocrinol 2022; 186:645–655.
Handgriff L, Adolf C, Heinrich DA, Schilbach K, Fazel J, Sturm L, et al. The impact of autonomous cortisol secretion on outcomes in patients with primary aldosteronism. J Clin Endocrinol Metab 2024; 109:e1234–e1243.
Arlt W, Lang K, Sitch AJ, Dietz AS, Rhayem Y, Bancos I, et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2017; 2:e93136.
Inoue K, Nishikawa T. Cortisol co-secretion and clinical usefulness of MACS evaluation in primary aldosteronism. Front Endocrinol 2021; 12:645488.
Huang WC, Wu VC, Chueh JS, Chen L, Lin YH, Ho YL, et al. Exploring the high prevalence, comorbidities, and indicators of MACS in primary aldosteronism: a cohort study and systematic review. Hypertens Res 2025; 48:1234–1245.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372:n71.
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283:2008–2012.
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2014; Ottawa Hospital Research Institute,.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177–188.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557–560.
Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ 2011; 342:d549.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315:629–634.
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56:455–463.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336:924–926.
Piaditis G, Markou A, Papanastasiou L, Androulakis II, Kaltsas G, Chrousos G, et al. Progress in aldosteronism: a review of the prevalence, underlying genetics, and clinical significance of autonomous cortisol secretion in primary aldosteronism. Eur J Endocrinol 2015; 172:R153–R165.
Araujo-Castro M, Paja FM, Pla PB, González BM, Pascual-Corrales E, García-Cano A, et al. Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes. Endocr Connect 2023; 12:e230043.
Burrello J, Monticone S, Buffolo F, Lucchiari M, Tizzani D, Mengozzi G, et al. Cortisol cosecretion in primary aldosteronism: a multicenter prospective study. J Clin Endocrinol Metab 2020; 105:e3716–e3726.
Fallo F, Pilon C, Urbanet R, Pezzi V, Boscaro M, Sonino N, et al. Primary aldosteronism and metabolic syndrome. Horm Metab Res 2020; 52:435–441.
Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, et al. Long-term follow-up in adrenal incidentalomas. Best Pract Res Clin Endocrinol Metab 2020; 34:101381.
Akehi Y, Yanase T, Motonaga R, Umakoshi H, Tsuiki M, Takeda Y, et al. High prevalence of diabetes in patients with primary aldosteronism associated with autonomous cortisol secretion. J Clin Endocrinol Metab 2022; 107:e2017–e2025.
Gerards J, Heinrich DA, Adolf C, Meisinger C, Rathmann W, Sturm L, et al. Impaired glucose metabolism in primary aldosteronism is associated with cortisol cosecretion. J Clin Endocrinol Metab 2019; 104:3192–3202.
Peng KY, Liao HW, Chan CK, Lin YH, Ho YL, Chen L, et al. Presence of subclinical hypercortisolism in clinical aldosterone-producing adenomas predicts lower clinical success. Hypertension 2023; 80:1453–1462.
Umakoshi H. Mild autonomous cortisol secretion in primary aldosteronism: the origin of cortisol. Hypertens Res 2025; 48:2272–2273.
Carsote M. The Entity of Connshing Syndrome: Primary Aldosteronism with Autonomous Cortisol Secretion. Diagnostics 2022; 12:2772.
Dekkers T, Deinum J, Schultzekool LJ, Schultze Kool LJ, Lenders JW, Hermus AR, et al. Plasma metanephrines for assessing the selectivity of adrenal venous sampling. Hypertension 2013; 62:1152–1157.
Wu W, Peng K, Lu J, Chan C, Wang C, Tseng F, et al. Cortisol-producing adenoma-related somatic mutations in unilateral primary aldosteronism with concurrent autonomous cortisol secretion: their prevalence and clinical characteristics. Eur J Endocrinol 2022; 187:519–530.
Hung LY, Sheu JY, Huang YT, Chen JY, Lai CF, Wu VC, et al. Exploring the high prevalence, comorbidities, and indicators of mild autonomous cortisol secretion in primary aldosteronism: a cohort study and systematic review. Hypertens Res 2025; 48:1716–1729.
Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol 2007; 157:545–559.
Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A, et al. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol 2016; 4:611–629.
Adolf C, Köhler A, Franke A, Lang K, Heinrich DA, Sturm L, et al. Cortisol excess in patients with primary aldosteronism impacts left ventricular hypertrophy. J Clin Endocrinol Metab 2018; 103:4543–4552.
Mazziotti G, Gazzaruso C, Giustina A. Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol Metab 2011; 22:499–506.
Briet M, Schiffrin EL. Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol 2010; 6:261–273.
Contributed Indexing: Keywords: Connshing syndrome; cardiovascular risk; cortisol co-secretion; dexamethasone suppression test; meta-analysis; mild autonomous cortisol secretion; primary aldosteronism
Substance Nomenclature: WI4X0X7BPJ (Hydrocortisone)
Entry Date(s): Date Created: 20260805 Date Completed: 20260826 Latest Revision: 20260910
Update Code: 20260910
DOI: 10.1097/HJH.0000000000004367
PMID: 42554261
Database: MEDLINE
Description
ISSN:1473-5598
DOI:10.1097/HJH.0000000000004367