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

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.

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: https://doi.org/10.1055/s-0031-1295438

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: https://doi.org/10.3109/07853890.2013.785234

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: https://doi.org/10.1056/NEJMoa1511939

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: https://doi.org/10.1210/jc.2013-2805

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: https://doi.org/10.1210/jc.2012-3934

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: https://doi.org/10.1530/EJE-15-0450

7. Salcuni AS, Palmieri S, Carnevale V, et al. Bone involvement in aldosteronism. J Bone Miner Res. 2012;27(10):2217-2222. doi: https://doi.org/10.1002/jbmr.1660

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: https://doi.org/10.3109/15622975.2012.665480

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: https://doi.org/10.1172/jci.insight.93136

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: https://doi.org/10.1111/j.1365-2265.2009.03551.x

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: https://doi.org/10.1507/endocrj.K10E-402

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: https://doi.org/10.1155/2018/4920841

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: https://doi.org/10.1210/jc.2014-3007

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: https://doi.org/10.1530/EJE-10-1070

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: https://doi.org/10.1038/nrendo.2012.230

16. McCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol. 2012;350(2):256-265. doi: https://doi.org/10.1016/j.mce.2011.06.014

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: https://doi.org/10.1097/HJH.0b013e328330a963

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: https://doi.org/10.1161/01.HYP.0000196945.73586.0d

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: https://doi.org/10.1161/circulationaha.104.503706

20. Reil J-C, Hohl M, Selejan S, et al. Aldosterone promotes atrial fibrillation. Eur Heart J. 2012;33(16):2098-2108. doi: https://doi.org/10.1093/eurheartj/ehr266

21. Funder JW. Aldosterone, hypertension and heart failure: insights from clinical trials. Hypertens Res. 2010;33(9):872-875. doi: https://doi.org/10.1038/hr.2010.115

22. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(suppl 1):s5-s20. doi: https://doi.org/10.2337/DIACARE.26.2007.S5

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: https://doi.org/10.1097/HJH.0b013e3282861fa4

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: https://doi.org/10.7326/0003-4819-150-11-200906020-00005

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: https://doi.org/10.1210/en.2013-1115

26. Corry DB, Tuck ML. The effect of aldosterone on glucose metabolism. Curr Hypertens Rep. 2003;5(2):106-109. doi: https://doi.org/10.1007/s11906-003-0065-2

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: https://doi.org/10.1111/j.1365-2265.2009.03610.x

28. Funder JW. Is aldosterone bad for the heart? Trends Endocrinol Metab. 2004;15(4):139-142. doi: https://doi.org/10.1016/J.TEM.2004.03.006

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: https://doi.org/10.1126/science.3037703

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: https://doi.org/10.1161/CIRCHEARTFAILURE.109.868513

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: https://doi.org/10.1161/01.CIR.0000091405.00772.6E

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: https://doi.org/10.1161/hypertensionaha.109.136242

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: https://doi.org/10.1210/jc.2014-1401

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: https://doi.org/10.26442/2075-1753_19.4.75-85

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: https://doi.org/10.1210/jc.2015-4061

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: https://doi.org/10.1111/cen.12750

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: https://doi.org/10.1507/endocrj.EJ16-0433

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: https://doi.org/10.1530/EDM-15-0075

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: https://doi.org/10.3390/ijms18040848

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: https://doi.org/10.1016/j.mce.2013.11.022

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: https://doi.org/10.1530/EJE-17-0563

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: https://doi.org/10.1210/jc.2009-2010

43. Munro Neville A, O’hare MJ. Histopathology of the human adrenal cortex. Clin Endocrinol Metab. 1985;14(4):791-820. doi: https://doi.org/10.1016/S0300-595X(85)80078-5

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: https://doi.org/10.1073/PNAS.89.17.8327

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: https://doi.org/10.1016/j.mce.2015.04.022

46. Ganguly A. Cellular origin of aldosteronomas. Clin Investig. 1992; 70(5):392-395. doi: https://doi.org/10.1007/BF00235519

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: https://doi.org/10.1111/j.1440-1681.1993.tb01686.x

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: https://doi.org/10.1046/j.1365-2265.2000.01022.x

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: https://doi.org/10.1148/rg.242035092

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: https://doi.org/10.1530/eje.0.1310074

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: https://doi.org/10.1210/jcem.83.11.5237

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: https://doi.org/10.1210/jc.2008-0594

53. Ulick S, Land M, Chu MD. 18-Oxocortisol, a naturally occurring mineralocorticoid agonist Endocrinology. 1983;113(6):2320-2322. doi: https://doi.org/10.1210/endo-113-6-2320

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: https://doi.org/10.1210/endo-116-1-6

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: https://doi.org/10.1210/jc.2004-0379

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: https://doi.org/10.1093/jmp/jhv028

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: https://doi.org/10.1210/jcem-67-2-322

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: https://doi.org/10.1007/BF03349773

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: https://doi.org/10.1677/jme.0.0240321

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: https://doi.org/10.1210/jcem.76.4.8473399

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: https://doi.org/10.1161/01.HYP.38.3.688

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: https://doi.org/10.1210/jcem.85.9.6834

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: https://doi.org/10.1006/bbrc.1995.1225

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: https://doi.org/10.1126/science.1198785

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: https://doi.org/10.1210/jc.2011-2384

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: https://doi.org/10.1016/j.mce.2015.11.014

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: https://doi.org/10.1016/j.mce.2014.05.002

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: https://doi.org/10.1210/jc.2010-2785

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: https://doi.org/10.1161/hypertensionaha.114.04453

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: https://doi.org/10.1210/jc.2013-3279

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: https://doi.org/10.1038/ng.2550

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: https://doi.org/10.1038/ng.2695

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: https://doi.org/10.1056/NEJMoa1504869

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: https://doi.org/10.1161/hypertensionaha.114.03419

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: https://doi.org/10.1210/jc.2015-2149

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: https://doi.org/10.1073/pnas.1505529112

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: https://doi.org/10.1161/hypertensionaha.115.06186

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: https://doi.org/10.1210/jc.2013-4255

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: https://doi.org/10.1210/jc.2011-2965

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: https://doi.org/10.1055/s-0035-1565090

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: https://doi.org/10.1507/endocrj.EJ12-0247

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: https://doi.org/10.1210/jc.2016-1700

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: https://doi.org/10.1111/cen.13134

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: https://doi.org/10.1038/hr.2010.18