Adrenalectomy Improves Blood Pressure and Metabolic Control in Patients With Possible Autonomous Cortisol Secretion: Results of a RCT

Valentina Morelli, Sofia Frigerio, Carmen Aresta, Elena Passeri, Flavia Pugliese, Massimilano Copetti, Anna Maria Barbieri, Silvia Fustinoni, Elisa Polledri, Sabrina Corbetta, Maura Arosio, Alfredo Scillitani, Iacopo Chiodini, Valentina Morelli, Sofia Frigerio, Carmen Aresta, Elena Passeri, Flavia Pugliese, Massimilano Copetti, Anna Maria Barbieri, Silvia Fustinoni, Elisa Polledri, Sabrina Corbetta, Maura Arosio, Alfredo Scillitani, Iacopo Chiodini

Abstract

Objective: The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity.

Design: This is a multicenter randomized study (NCT number: NCT04860180).

Methods: Sixty-two AI outpatients (40-75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated.

Results: BP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively (p = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively (p = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, p = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8-108.3, p < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 p = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%).

Conclusions: AI patients with PACS benefit from surgery in terms of BP and glycometabolic control.

Keywords: adrenal incidentaloma; adrenalectomy; diabetes; hypercortisolism; hypertension.

Conflict of interest statement

IC and CA are investigators in studies on relacorilant (Corcept Therapeutics) in patients with hypercortisolism. IC received consulting fees from Corcept Therapeutics and HRA Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Morelli, Frigerio, Aresta, Passeri, Pugliese, Copetti, Barbieri, Fustinoni, Polledri, Corbetta, Arosio, Scillitani and Chiodini.

Figures

Figure 1
Figure 1
Enrollment procedure. AI, adrenal incidentaloma; PACS, possible autonomous cortisol secretion; PACS+, patients with possible autonomous cortisol secretion; PACS-, patients without possible autonomous cortisol secretion.
Figure 2
Figure 2
Amelioration and worsening of blood pressure and/or glycometabolic control in surgically treated or conservatively managed AI patients with PACS. AI, adrenal incidentaloma; PACS, possible autonomous cortisol secretion; PACS+, patients with possible autonomous cortisol secretion; PACS-, patients without possible autonomous cortisol secretion. (A) Amelioration and worsening of blood pressure control. (B) Amelioration and worsening of glycometabolic control. (C) Amelioration and worsening of blood pressure and/or glycometabolic control.

References

    1. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell–Price J, Sahdev A, et al. . Management of Adrenal Incidentalomas: European Society of Endocrinology Clinical Practice Guideline in Collaboration With the European Network for the Study of Adrenal Tumors. Eur J Endocrinol (2016) 175:G1–G34. doi: 10.1530/EJE-16-0467
    1. Morelli V, Palmieri S, Lania A, Tresoldi A, Corbetta S, Cairoli E, et al. . Cardiovascular Events in Patients With Mild Autonomous Cortisol Secretion: Analysis With Artificial Neural Networks. Eur J Endocrinol (2017) 177:73–83. doi: 10.1530/EJE-17-0047
    1. 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: A 15–Year Retrospective Study. Lancet Diabetes Endocrinol (2014) 2:396–405. doi: 10.1016/S2213-8587(13)70211-0
    1. Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell–Price J. Cortisol as a Marker for Increased Mortality in Patients With Incidental Adrenocortical Adenomas. J Clin Endocrinol Metab (2014) 99:4462–70. doi: 10.1210/jc.2014-3007
    1. Zavatta G, Di Dalmazi G. Recent Advances on Subclinical Hypercortisolism. Endocrinol Metab Clinics North America (2018) 47:375–83. doi: 10.1016/j.ecl.2018.01.003
    1. Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, et al. . Long–term Follow–Up in Adrenal Incidentalomas: An Italian Multicenter Study. J Clin Endocrinol Metab (2014) 99 827–34. doi: 10.1210/jc.2013-3527
    1. Patrova J, Kjellman M, Wahrenberg H, Falhammar H. Increased Mortality in Patients With Adrenal Incidentalomas and Autonomous Cortisol Secretion: A 13–Year Retrospective Study From One Center. Endocrine (2017) 58:267–75. doi: 10.1007/s12020-017-1400-8
    1. Chiodini I, Ramos–Rivera A, Marcus AO, Yau H. Adrenal Hypercortisolism: A Closer Look at Screening, Diagnosis, and Important Considerations of Different Testing Modalities. J Endocr Soc (2019) 3:1097–109. doi: 10.1210/js.2018-00382
    1. Eller–Vainicher C, Morelli V, Aresta C, Salcuni AS, Falchetti A, Carnevale V, et al. . Defining Nonfunctioning Adrenal Adenomas on the Basis of the Occurrence of Hypocortisolism After Adrenalectomy. J Endocr Soc (2020) 4:1–11. doi: 10.1210/jendso/bvaa079
    1. Tabarin A. Do the Diagnostic Criteria for Subclinical Hypercortisolism Exist? Ann Endocrinol (2018) 79:146–8. doi: 10.1016/j.ando.2018.03.013
    1. Olsen H, Kjellbom A, Löndahl M, Lindgren O. Suppressed ACTH Is Frequently Unrelated to Autonomous Cortisol Secretion in Patients With Adrenal Incidentalomas. J Clin Endocrinol Metab (2019) 104:506–12. doi: 10.1210/JC.2018-01029
    1. Morelli V, Masserini B, Salcuni AS, Eller–Vainicher C, Savoca C, Viti R, et al. . Subclinical Hypercortisolism: Correlation Between Biochemical Diagnostic Criteria and Clinical Aspects. Clin Endocrinol (2010) 73:161–6. doi: 10.1111/j.1365-2265.2010.03794.x
    1. Di Dalmazi G, Vicennati V, Rinaldi E, Morselli–Labate AM, Giampalma E, Mosconi C, et al. . Progressively Increased Patterns of Subclinical Cortisol Hypersecretion in Adrenal Incidentalomas Differently Predict Major Metabolic and Cardiovascular Outcomes: A Large Cross–Sectional Study. Eur J Endocrinol (2012) 166:669–77. doi: 10.1530/EJE-11-1039
    1. Palmieri S, Morelli V, Polledri E, Fustinoni S, Mercadante R, Olgiati L, et al. . The Role of Salivary Cortisol Measured by Liquid Chromatographytandem Mass Spectrometry in the Diagnosis of Subclinical Hypercortisolism. Eur J Endocrinol (2013) 168: 289–96. doi: 10.1530/EJE-12-0803
    1. Giovanelli L, Aresta C, Favero V, Bonomi M, Cangiano B, Eller–Vainicher C, et al. . Hidden Hypercortisolism: A Too Frequently Neglected Clinical Condition. J Endocrinol Invest (2021) 44:1581–96. doi: 10.1007/s40618-020-01484-2
    1. Morelli V, Aresta C, Gaudio A, Eller–Vainicher C, Zhukouskaya VV, Merlotti D, et al. . Prediction of Hypertension, Diabetes and Fractures in Eucortisolemic Women by Measuring Parameters of Cortisol Milieu. Endocrine (2020) 68 411–9. doi: 10.1007/s12020-020-02212-9
    1. Bancos I, Alahdab F, Crowley RK, Chortis V, Delivanis DA, Erickson D, et al. . Improvement of Cardiovascular Risk Factors After Adrenalectomy in Patients With Adrenal Tumors and Subclinical Cushing’s Syndrome: A Systematic Review and Meta–Analysis. Eur J Endocrinol (2016) 175:R283–95. doi: 10.1530/EJE-16-0465
    1. Toniato A, Merante–Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. Surgical Versus Conservative Management for Subclinical Cushing Syndrome in Adrenal Incidentalomas: A Prospective Randomized Study. Ann Surg (2009) 249:388–91. doi: 10.1097/SLA.0b013e31819a47d2
    1. Nieman LK, Biller BMK, Findling JW, Newell–Price J, Savage MO, Stewart PM, et al. . The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (2008) 93:1526–40. doi: 10.1210/jc.2008-0125
    1. Fustinoni S, Polledri E, Mercadante R. High–throughput Determination of Cortisol, Cortisone, and Melatonin in Oral Fluid by on–Line Turbulent Flow Liquid Chromatography Interfaced With Liquid Chromatography/Tandem Mass Spectrometry. Rapid Commun Mass Spectrom (2013) 27:1450–60. doi: 10.1002/rcm.6601
    1. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. . 2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension. Blood Pressure (2014) 23:3–16. doi: 10.3109/08037051.2014.868629
    1. Care D, Suppl SS. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetesd2019. Diabetes Care (2019) 42:S13–28. doi: 10.2337/dc19-S002
    1. Grundy SM Becker D Clark LT Cooper RS Denke MA Howard WJ et al.. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation (2002) 106:3143–421. doi: 10.1161/circ.106.25.3143
    1. Vidal J. Updated Review on the Benefits of Weight Loss. Int J Obes (2002) 26:S25–8. doi: 10.1038/sj.ijo.0802215
    1. Morelli V, Donadio F, Eller–Vainicher C, Cirello V, Olgiati L, Savoca C, et al. . Role of Glucocorticoid Receptor Polymorphism in Adrenal Incidentalomas. Eur J Clin Invest (2010) 40:803–11. doi: 10.1111/j.1365-2362.2010.02330.x
    1. Eller–Vainicher C, Morelli V, Salcuni AS, Battista C, Torlontano M, Coletti F, et al. . Accuracy of Several Parameters of Hypothalamic–Pituitary–Adrenal Axis Activity in Predicting Before Surgery the Metabolic Effects of the Removal of an Adrenal Incidentaloma. Eur J Endocrinol (2010) 163:925–35. doi: 10.1530/EJE-10-0602
    1. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, De Krijger RR, et al. . European Society of Endocrinology Clinical Practice Guidelines on the Management of Adrenocortical Carcinoma in Adults, in Collaboration With the European Network for the Study of Adrenal Tumors. Eur J Endocrinol (2018) 179:G1–G46. doi: 10.1530/EJE-18-0608
    1. Chiodini I, Albani A, Ambrogio AG, Campo M, De Martino MC, Marcelli G, et al. . Six Controversial Issues on Subclinical Cushing’s Syndrome. Endocrine (2017) 56:262–6. doi: 10.1007/s12020-016-1017-3
    1. Eller–Vainicher C, Morelli V, Salcuni AS, Battista C, Torlontano M, Coletti F, et al. . Accuracy of Several Parameters of Hypothalamic–Pituitary–Adrenal Axis Activity in Predicting Before Surgery the Metabolic Effects of the Removal of an Adrenal Incidentaloma. Eur J Endocrinol (2010) 163 925–35. doi: 10.1530/EJE-10-0602
    1. Ceccato F, Tizianel I, Voltan G, Maggetto G, Merante Boschin I, Quaia E, et al. . Attenuation Value in Adrenal Incidentalomas: A Longitudinal Study. Front Endocrinol (2021) 12:794197. doi: 10.3389/fendo.2021.794197
    1. Chiodini I, Ramos–Rivera A, Marcus AO, Yau H. Adrenal Hypercortisolism: A Closer Look at Screening, Diagnosis, and Important Considerations of Different Testing Modalities. J Endocr Soc (2019) 3:1097–109 doi: 10.1210/js.2018-00382
    1. 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) 22:11521. doi: 10.3390/ijms222111521
    1. Ferrari P, Lovati E, Frey FJ. The Role of the 11β–Hydroxysteroid Dehydrogenase Type 2 in Human Hypertension. J Hypertens (2000) 18:241–8. doi: 10.1097/00004872-200018030-00001
    1. Morelli V, Polledri E, Mercadante R, Zhukouskaya V, Palmieri S, Beck–Peccoz P, et al. . The Activity of 11β–Hydroxysteroid Dehydrogenase Type 2 Enzyme and Cortisol Secretion in Patients With Adrenal Incidentalomas. Endocrine (2016) 53:809–15 doi: 10.1007/s12020-015-0763-y
    1. Ceccato F, Artusi C, Barbot M, Lizzul L, Pinelli S, Costantini G, et al. . Dexamethasone Measurement During Low–Dose Suppression Test for Suspected Hypercortisolism: Threshold Development With and Validation. J Endocrinol Invest (2020) 43:1105–13. doi: 10.1007/s40618-020-01197-6
    1. Raverot V, Richet C, Morel Y, Raverot G, Borson–Chazot F. Establishment of Revised Diagnostic Cut–Offs for Adrenal Laboratory Investigation Using the New Roche Diagnostics Elecsys® Cortisol II Assay. Ann Endocrinol (2016) 77:620–2. doi: 10.1016/j.ando.2016.05.002

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren