Aldosterone- and cortisol-co-secreting adrenal tumors: an uneasy sum of well-known parts (review)

Cover Page
Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access


Primary aldosteronism (PA) is the most common form of secondary arterial hypertension. In patients with PA, more so than in the general population, there is a prevalence of insulin resistance, diabetes mellitus, metabolic syndrome, osteoporosis, and symptoms of depression; these conditions are more likely to manifest a gluco- rather than mineralocorticoid excess. This fact is of particular importance in light of recent studies that have shown that PA is often associated with glucocorticoid excess. Since the first reports of cases of combined secretion of aldosterone and cortisol in 1979, the number of cases of so-called Connshing syndrome has increased. An analysis of data from recent studies suggests that hypercortisolism in PA is closely associated with an increased risk of cardiovascular complications, metabolic disorders and post-surgical adrenal insufficiency. The most important diagnostic problem in adenomas with combined secretion is the risk of false interpretation of the results of adrenal venous sampling (AVS). The indications that suggest aldosterone-and-cortisol-co-producing adenoma are the lack of suppression of cortisol levels following a night test with 1mg of dexamethasone, and an adrenal tumo of over 2.5cm. As an alternative test capable of differentiating this type of tumor, a number of researchers have proposed measuring the level of so-called hybrid steroids in the peripheral plasma and urine. Taking into account the high prevalence and potential risks, ruling out of excess corisol secretion is obligatory in all cases of PA before AVS and when planning surgery.

Full Text

Restricted Access

About the authors

Boris M. Shifman

Endocrinology Research Centre

Author for correspondence.
ORCID iD: 0000-0002-1848-8978
SPIN-code: 5898-2088

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD student

Nadezhda M. Platonova

Endocrinology Research Centre

ORCID iD: 0000-0001-6388-1544
SPIN-code: 4053-3033
Scopus Author ID: 9537089700

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036


Natalya V. Molashenko

Endocrinology Research Centre

ORCID iD: 0000-0001-6265-1210
SPIN-code: 5679-2808
Scopus Author ID: 9536569400

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036


Ekaterina A. Troshina

Endocrinology Research Centre

ORCID iD: 0000-0002-8520-8702
SPIN-code: 8821-8990
Scopus Author ID: 24081800800

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD, professor

Natalia Yu. Romanova

Endocrinology Research Centre

ORCID iD: 0000-0002-9117-4908
SPIN-code: 5288-2968

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036


Galina S. Kolesnikova

Endocrinology Research Centre

ORCID iD: 0000-0002-8698-0681
SPIN-code: 7716-9680
Scopus Author ID: 7005268891

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036



  1. Hannemann A, Wallaschofski H. Prevalence of Primary Aldosteronism in Patient’s Cohorts and in Population-based Studies – A Review of the Current Literature. Horm Metab Res. 2012; 44(03):157-162. doi:
  2. Chao C-T, Wu V-C, Kuo C-C, et al. Diagnosis and management of primary aldosteronism: An updated review. Ann Med. 2013; 45(4):375-383. doi:
  3. SPRINT Research Group TSR, Wright JT, Williamson JD, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103-2116. doi:
  4. Mulatero P, Monticone S, Bertello C, et al. Long-Term Cardio- and Cerebrovascular Events in Patients With Primary Aldosteronism. J Clin Endocrinol Metab. 2013;98(12):4826-4833. doi:
  5. Fischer E, Adolf C, Pallauf A, et al. Aldosterone Excess Impairs First Phase Insulin Secretion in Primary Aldosteronism. J Clin Endocrinol Metab. 2013;98(6):2513-2520. doi:
  6. Hanslik G, Wallaschofski H, Dietz A, et al. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn’s Registry. Eur J Endocrinol. 2015;173(5):665-675. doi:
  7. Salcuni AS, Palmieri S, Carnevale V, et al. Bone involvement in aldosteronism. J Bone Miner Res. 2012;27(10):2217-2222. doi:
  8. Apostolopoulou K, Künzel HE, Gerum S, et al. Gender differences in anxiety and depressive symptoms in patients with primary hyperaldosteronism: A cross-sectional study. World J Biol Psychiatry. 2014;15(1):26-35. doi:
  9. Arlt W, Lang K, Sitch AJ, et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI insight. 2017;2(8). doi:
  10. Piaditis GP, Kaltsas GA, Androulakis II, et al. High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas. Clin Endocrinol (Oxf). 2009;71(6):772-778. doi:
  11. Hiraishi K, Yoshimoto T, Tsuchiya K, et al. Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome. Endocr J. 2011;58(7):543-551. doi:
  12. Tang L, Li X, Wang B, et al. Clinical Characteristics of Aldosterone- and Cortisol-Coproducing Adrenal Adenoma in Primary Aldosteronism. Int J Endocr. 2018 (2018): 1-9. doi:
  13. 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(12):4462-4470. doi:
  14. Späth M, Korovkin S, Antke C, Anlauf M, Willenberg HS. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. Eur J Endocrinol. 2011;164(4):447-455. doi:
  15. Mulatero P, Monticone S, Rainey WE, Veglio F, Williams TA. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol. 2013;9(2):104-112. doi:
  16. McCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol. 2012;350(2):256-265. doi:
  17. Leibovitz E, Ebrahimian T, Paradis P, Schiffrin EL. Aldosterone induces arterial stiffness in absence of oxidative stress and endothelial dysfunction. J Hypertens. 2009;27(11):2192-2200. doi:
  18. Dorrance AM, Rupp NC, Nogueira EF. Mineralocorticoid Receptor Activation Causes Cerebral Vessel Remodeling and Exacerbates the Damage Caused by Cerebral Ischemia. Hypertension. 2006;47(3):590-595. doi:
  19. Ouvrard-Pascaud A, Sainte-Marie Y, Bénitah J-P, et al. Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias. Circulation. 2005;111(23):3025-3033. doi:
  20. Reil J-C, Hohl M, Selejan S, et al. Aldosterone promotes atrial fibrillation. Eur Heart J. 2012;33(16):2098-2108. doi:
  21. Funder JW. Aldosterone, hypertension and heart failure: insights from clinical trials. Hypertens Res. 2010;33(9):872-875. doi:
  22. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(suppl 1):s5-s20. doi:
  23. Mosso LM, Carvajal CA, Maiz A, et al. A possible association between primary aldosteronism and a lower β-cell function. J Hypertens. 2007;25(10):2125-2130. doi:
  24. Sowers JR, Whaley-Connell A, Epstein M. Narrative Review: The Emerging Clinical Implications of the Role of Aldosterone in the Metabolic Syndrome and Resistant Hypertension. Ann Intern Med. 2009;150(11):776. doi:
  25. Jin HM, Zhou DC, Gu HF, et al. Antioxidant N-Acetylcysteine Protects Pancreatic β-Cells Against Aldosterone-Induced Oxidative Stress and Apoptosis in Female db/db Mice and Insulin-Producing MIN6 Cells. Endocrinology. 2013;154(11):4068-4077. doi:
  26. Corry DB, Tuck ML. The effect of aldosterone on glucose metabolism. Curr Hypertens Rep. 2003;5(2):106-109. doi:
  27. Fallo F, Sonino N. Should we evaluate for cardiovascular disease in patients with Cushing’s syndrome? Clin Endocrinol (Oxf). 2009;71(6):768-771. doi:
  28. Funder JW. Is aldosterone bad for the heart? Trends Endocrinol Metab. 2004;15(4):139-142. doi:
  29. Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987; 237(4812):268-275. doi:
  30. Yamaji M, Tsutamoto T, Kawahara C, et al. Serum Cortisol as a Useful Predictor of Cardiac Events in Patients With Chronic Heart Failure: The Impact of Oxidative Stress. Circ Hear Fail. 2009;2(6):608-615. doi:
  31. Pitt B, Reichek N, Willenbrock R, et al. Effects of Eplerenone, Enalapril, and Eplerenone/Enalapril in Patients With Essential Hypertension and Left Ventricular Hypertrophy: The 4E-Left Ventricular Hypertrophy Study. Circulation. 2003;108(15):1831-1838. doi:
  32. Mihailidou AS, Loan Le TY, Mardini M, Funder JW. Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction. Hypertension. 2009;54(6):1306-1312. doi:
  33. Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M. Adrenal Function After Adrenalectomy for Subclinical Hypercortisolism and Cushing’s Syndrome: A Systematic Review of the Literature. J Clin Endocrinol Metab. 2014;99(8):2637-2645. doi:
  34. Мельниченко Г.А., Платонова Н.М., Бельцевич Д.Г., и др. Первичный гиперальдостеронизм: диагностика и лечение. Новый взгляд на проблему. По материалам Проекта клинических рекомендаций Российской ассоциации эндокринологов по диагностике и лечению первичного гиперальдостеронизма. // Consilium Medicum. – 2017. – Т. 19. – №4. – С. 75–85. [Melnichenko GA, Platonova NM, Beltsevich DG, et al. Primary Hyperaldosteronism: Diagnosis and Treatment. A New Look at the Problem. According to the Materials of the Russian Association of Endocrinologists Clinical Guidelines for Primary Hyperaldosteronism Diagnosis and Treatment. Consilium Medicum. 2017;19(4):75–85. (In Russ.).] doi:
  35. Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. doi:
  36. Goupil R, Wolley M, Ahmed AH, Gordon RD, Stowasser M. Does concomitant autonomous adrenal cortisol overproduction have the potential to confound the interpretation of adrenal venous sampling in primary aldosteronism? Clin Endocrinol (Oxf). 2015;83(4):456-461. doi:
  37. Kishino M, Yoshimoto T, Nakadate M, et al. Optimization of left adrenal vein sampling in primary aldosteronism: Coping with asymmetrical cortisol secretion. Endocr J. 2017;64(3):347-355. doi:
  38. Goupil R, Wolley M, Ungerer J, et al. Use of plasma metanephrine to aid adrenal venous sampling in combined aldosterone and cortisol over-secretion. Endocrinol diabetes Metab case reports. 2015; 2015:150075. doi:
  39. Buffolo F, Monticone S, Williams TA, et al. Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary? Int J Mol Sci. 2017;18(4). doi:
  40. Gomez-Sanchez CE, Qi X, Velarde-Miranda C, et al. Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol. 2014;383(1-2):111-117. doi:
  41. Lenders JWM, Williams TA, Reincke M, Gomez-Sanchez CE. DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? Eur J Endocrinol. 2018;178(1):R1-R9. doi:
  42. Nishimoto K, Nakagawa K, Li D, et al. Adrenocortical Zonation in Humans under Normal and Pathological Conditions. J Clin Endocrinol Metab. 2010;95(5):2296-2305. doi:
  43. Munro Neville A, O’hare MJ. Histopathology of the human adrenal cortex. Clin Endocrinol Metab. 1985;14(4):791-820. doi:
  44. Pascoe L, Curnow KM, Slutsker L, et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA. 1992;89(17):8327-8331. doi:
  45. Monticone S, Castellano I, Versace K, et al. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol. 2015;411:146-154. doi:
  46. Ganguly A. Cellular origin of aldosteronomas. Clin Investig. 1992; 70(5):392-395. doi:
  47. Stowasser M, Tunny TJ, Klemm SA, Gordon RD. Cortisol production by aldosterone-producing adenomas in vitro. Clin Exp Pharmacol Physiol. 1993;20(5):292-295. doi:
  48. Allan CA, Kaltsas G, Perry L, et al. Concurrent secretion of aldosterone and cortisol from an adrenal adenoma – Value of MRI in diagnosis. Clin Endocrinol (Oxf). 2000. doi:
  49. Rockall AG, Babar SA, Sohaib SAA, et al. CT and MR Imaging of the Adrenal Glands in ACTH-independent Cushing Syndrome. RadioGraphics. 2004;24(2):435-452. doi:
  50. Yamakita N, Gomez-Sanchez CE, Mune T, et al. Simultaneous measurement of plasma 18-oxocortisol and 18-hydroxycortisol levels in normal man. Eur J Endocrinol. 1994. doi:
  51. Mulatero P, Curnow KM, Aupetit-Faisant B, et al. Recombinant CYP11B Genes Encode Enzymes that Can Catalyze Conversion of 11-Deoxycortisol to Cortisol, 18-Hydroxycortisol, and 18-Oxocortisol 1. J Clin Endocrinol Metab. 1998;83(11):3996-4001. doi:
  52. Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008;93(8):3117-3123. doi:
  53. Ulick S, Land M, Chu MD. 18-Oxocortisol, a naturally occurring mineralocorticoid agonist Endocrinology. 1983;113(6):2320-2322. doi:
  54. Gomez-Sanchez CE, Gomez-Sanchez EP, Smith JS, Ferris MW, Foecking MF. Receptor Binding and Biological Activity of 18 Oxocortisol. Endocrinology. 1985;116(1):6-10. doi:
  55. Russell DW, White PC. Four is not more than two. Am J Hum Genet. 1995;57(5):1002-1005. PMID: 7485148
  56. Freel EM, Shakerdi LA, Friel EC, et al. Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects. J Clin Endocrinol Metab. 2004;89(9):4628-4633. doi:
  57. Fraser R, Connell JMC, Budd PS, Corrie JET, Kenyon CJ. The origin and significance of 18-hydroxycortisol: Studies in hyperaldosteronism and in bovine adrenocortical cells in vitro. J Steroid Biochem Mol Biol. 1991. doi:
  58. Gomez-Sanchez CE, Clore JN, Estep HL, Watlington CO. Effect of Chronic Adrenocorticotropin Stimulation on the Excretion of 18-Hydroxycortisol and 18-Oxocortisol. J Clin Endocrinol Metab. 1988. doi:
  59. Hatakeyama H, Miyamori I, Fujita T, Takeda Y, Takeda R, Yamamoto H. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem. 1994. doi:
  60. MacKenzie SM, Clark CJ, Fraser R, Gómez-Sánchez CE, Connell JMC, Davies E. Expression of 11β-hydroxylase and aldosterone synthase genes in the rat brain. J Mol Endocrinol. 2000;(24):321–328. doi:
  61. Ulick S, Blumenfeld JD, Atlas SA, Wang JZ, Vaughan ED. The unique steroidogenesis of the aldosteronoma in the differential diagnosis of primary aldosteronism. J Clin Endocrinol Metab. 1993; 76(4):873-878. doi:
  62. Mosso L, Gómez-Sánchez CE, Foecking MF, Fardella C, Gomez-Sanchez CE. Serum 18-Hydroxycortisol in Primary Aldosteronism, Hypertension, and Normotensives. Hypertension. 2001;(38):688–691. doi:
  63. Stowasser M, Bachmann AW, Huggard PR, Rossetti TR, Gordon RD. Treatment of Familial Hyperaldosteronism Type I: Only Partial Suppression of Adrenocorticotropin Required to Correct Hypertension. J Clin Endocrinol Metab. 2000;85(9):3313-3318. doi:
  64. Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD. A New Genetic Test for Familial Hyperaldosteronism Type I Aids in the Detection of Curable Hypertension. Biochem Biophys Res Commun. 1995;207(2):565-571. doi:
  65. Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768-772. doi:
  66. Mulatero P, di Cella SM, Monticone S, et al. 18-Hydroxycorticosterone, 18-Hydroxycortisol, and 18-Oxocortisol in the Diagnosis of Primary Aldosteronism and Its Subtypes. J Clin Endocrinol Metab. 2012;97(3):881-889. doi:
  67. Nakamura Y, Kitada M, Satoh F, et al. Intratumoral heterogeneity of steroidogenesis in aldosterone-producing adenoma revealed by intensive double- and triple-immunostaining for CYP11B2/B1 and CYP17. Mol Cell Endocrinol. 2016;422:57-63. doi:
  68. Nakamura Y, Maekawa T, Felizola SJA, et al. Adrenal CYP11B1/2 expression in primary aldosteronism: immunohistochemical analysis using novel monoclonal antibodies. Mol Cell Endocrinol. 2014;392(1-2):73-79. doi:
  69. Nakamura Y, Satoh F, Morimoto R, et al. 18-oxocortisol measurement in adrenal vein sampling as a biomarker for subclassifying primary aldosteronism. J Clin Endocrinol Metab. 2011;96(8):E1272-8. doi:
  70. Satoh F, Morimoto R, Ono Y, et al. Peripheral Plasma 18-Oxocortisol Can Discriminate Unilateral Adenoma from Bilateral Diseases in Primary Aldosteronism Patients. Hypertension. 2015;65(5):1096-1102. doi:
  71. Doi M, Satoh F, Maekawa T, et al. Isoform-Specific Monoclonal Antibodies Against 3β-Hydroxysteroid Dehydrogenase/Isomerase Family Provide Markers for Subclassification of Human Primary Aldosteronism. J Clin Endocrinol Metab. 2014;99(2):E257-E262. doi:
  72. Beuschlein F, Boulkroun S, Osswald A, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45(4):440-444. doi:
  73. Scholl UI, Goh G, Stölting G, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013;45(9):1050-1054. doi:
  74. Teo AED, Garg S, Shaikh LH, et al. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations. N Engl J Med. 2015; 373(15):1429-1436. doi:
  75. Fernandes-Rosa FL, Williams TA, Riester A, et al. Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma. Hypertension. 2014;64(2):354-361. doi:
  76. Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP. A Meta-Analysis of Somatic KCNJ5 K + Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma. J Clin Endocrinol Metab. 2015;100(8):E1089-E1095. doi:
  77. Nishimoto K, Tomlins SA, Kuick R, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA. 2015;112(33):E4591-9. doi:
  78. Williams TA, Peitzsch M, Dietz AS, et al. Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing AdenomasNovelty and Significance. Hypertension. 2016;67(1):139-145. doi:
  79. Dekkers T, ter Meer M, Lenders JWM, et al. Adrenal Nodularity and Somatic Mutations in Primary Aldosteronism: One Node Is the Culprit? J Clin Endocrinol Metab. 2014;99(7):E1341-E1351. doi:
  80. Azizan EAB, Lam BYH, Newhouse SJ, et al. Microarray, qPCR, and KCNJ5 Sequencing of Aldosterone-Producing Adenomas Reveal Differences in Genotype and Phenotype between Zona Glomerulosa- and Zona Fasciculata-Like Tumors. J Clin Endocrinol Metab. 2012;97(5):E819-E829. doi:
  81. Williams T, Lenders J, Burrello J, Beuschlein F, Reincke M. KCNJ5 Mutations: Sex, Salt and Selection. Horm Metab Res. 2015; 47(13):953-958. doi:
  82. Yamada M, Nakajima Y, Taguchi R, et al. KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas [Rapid Communication]. Endocr J. 2012;59(8):735-741. doi:
  83. Rhayem Y, Perez-Rivas LG, Dietz A, et al. PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab. 2016;101(8):3010-3017. doi:
  84. Li X, Wang B, Tang L, et al. Clinical characteristics of PRKACA mutations in Chinese patients with adrenal lesions: a single-centre study. Clin Endocrinol (Oxf). 2016;85(6):954-961. doi:
  85. Willenberg HS, Späth M, Maser-Gluth C, et al. Sporadic solitary aldosterone- and cortisol-co-secreting adenomas: endocrine, histological and genetic findings in a subtype of primary aldosteronism. Hypertens Res. 2010;33(5):467-472. doi:

Supplementary files

Supplementary Files Action
Fig. 1. Pathways of steroidogenesis leading to the synthesis of aldosterone, cortisol, and also hybrid steroids: 18-oxo-cortex tizol and 18-hydroxycortisol. CYP11A1 - 20,22-desmolase ("Enzyme that cleaves cholesterol side chain"), HSD3B2 - 3-beta-hydroxysteroid dehydrogenase, type 2, CYP17A1 - 17α-hydroxylase, CYP21A2 - 21-hydroxylase, CYP11B1 - 11β-hydroxylase, CYP11B2 - aldosterone synthase.

Download (384KB) Indexing metadata



Abstract - 1188

PDF (Russian) - 26

Remote (Russian) - 93




Copyright (c) 2019 Shifman B.M., Platonova N.M., Molashenko N.V., Troshina E.A., Romanova N.Y., Kolesnikova G.S.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies