Hypercortisolism in Obesity-Associated Hypertension

  • Amy G. Varughese
  • Oksana Nimkevych
  • Gabriel I. Uwaifo
Hypertension and Obesity (E Reisin, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and Obesity

Abstract

Obesity is prevalent worldwide and associated with co-morbidities that result in increased cardiovascular risk. Hypertension is the most prevalent obesity comorbidity associated with increased cardiovascular risk. Obesity hypertension is a distinct subtype of essential hypertension. While endogenous Cushing’s syndrome is an uncommon cause of both obesity and hypertension, the recent recognition of other hypercortisolemic states has raised the profile of hypercortisolism as an important contributor in obesity hypertension. The high prevalence of exogenous, iatrogenic, pseudo, and subclinical Cushing’s syndromes makes hypercortisolism an important diagnostic consideration in the evaluation and management of patients with obesity hypertension who are resistant to conventional management. Available data suggest that the renin-angiotensin-aldosterone system modulating antihypertensives have the best efficacy in hypercortisolism-mediated obesity hypertension. Strategies aimed at reducing cortisol production and action also have utility. This review provides a comprehensive overview of the epidemiology, etiopathogenesis and management options available for glucocorticoid-mediated obesity hypertension.

Keywords

Obesity hypertension Hypercortisolism Subclinical Cushing’s syndrome Cortisol Glucocorticoids Hydrocortisone Dexamethasone Cortisone Aldosterone Elevated blood pressure Cortisol-associated hypertension Glucocorticoid-induced hypertension Pseudo Cushing’s syndrome Exogenous Cushing’s syndrome Glucocorticoid excess Dysmetabolic syndrome Insulin resistance Mineralocorticoid activation Adiposity Visceral fat excess 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Dwyer-Lindgren L, Freedman G, Engell RE, Fleming TD, Lim SS, Murray CJ, et al. Prevalence of physical activity and obesity in US counties, 2001–2011: a road map for action. Popul Health Metrics. 2013;11(1):7. doi:10.1186/1478-7954-11-7.CrossRefGoogle Scholar
  2. 2.
    Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA: J Am Med Assoc. 2010;303(3):235–41. doi:10.1001/jama.2009.2014.CrossRefGoogle Scholar
  3. 3.
    Ford ES, Mokdad AH. Epidemiology of obesity in the Western Hemisphere. J Clin Endocrinol Metab. 2008;93(11 Suppl 1):S1–8. doi:10.1210/jc.2008-1356.PubMedCrossRefGoogle Scholar
  4. 4.
    Maynard LM, Serdula MK, Galuska DA, Gillespie C, Mokdad AH. Secular trends in desired weight of adults. Int J Obes. 2006;30(9):1375–81. doi:10.1038/sj.ijo.0803297.CrossRefGoogle Scholar
  5. 5.•
    Uwaifo GI. Obesity-associated hypertension. In: Koch CA, Chrousos GP, editors. Endocrine hypertension; Underlying mechansims and therapy. New York: Humana Press; 2013. p. 251–88. A comprehensive discussion of the entity of obesity-associated hypertension, including its recognition, underlying pathophysiology, contributory factors and clinical associations, as well as an exhaustive discussion of the therapeutic options and how they fare in this condition as compared to typical essential hypertension. CrossRefGoogle Scholar
  6. 6.
    Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol/Eur Fed Endocr Soc. 2007;157(5):545–59. doi:10.1530/EJE-07-0455.CrossRefGoogle Scholar
  7. 7.
    Kurukulasuriya LR, Stas S, Lastra G, Manrique C, Sowers JR. Hypertension in obesity. Med Clin N Am. 2011;95(5):903–17. doi:10.1016/j.mcna.2011.06.004.PubMedCrossRefGoogle Scholar
  8. 8.
    Landsberg L. Obesity related hypertension as a metabolic disorder. In: Oparil S, Weber MA, editors. Hypertension; A companion to Brenner and Rector’s the Kidney. Philadelphia: WB Saunders Company; 2000. p. 118–24.Google Scholar
  9. 9.
    Reisin E, Hutchison HG. Obesity-Hypertension; Effetcs on cardiovascular and renal systems; The therapeutic approach. In: Oparil S, Weber MA, editors. Hypertension; acompanion to Brenner and Rector’s the kidney. Philadelphia: WB Saunders Company; 2000. p. 206–11.Google Scholar
  10. 10.
    Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, Smith West D, et al. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med. 2001;134(1):1–11.PubMedCrossRefGoogle Scholar
  11. 11.
    Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001;358(9294):1682–6. doi:10.1016/S0140-6736(01)06710-1.PubMedCrossRefGoogle Scholar
  12. 12.
    Kil DY, Swanson KS. Endocrinology of obesity. Vet Clin N Am Small Anim Pract. 2010;40(2):205–19. doi:10.1016/j.cvsm.2009.10.004.CrossRefGoogle Scholar
  13. 13.•
    Abraham SB, Rubino D, Sinaii N, Ramsey S, Nieman LK. Cortisol, obesity, and the metabolic syndrome: a cross-sectional study of obese subjects and review of the literature. Obesity. 2013;21(1):E105–17. doi:10.1002/oby.20083. An important clinical study that details the problems with interpreting findings from HPA-axis investigation in obese subjects without overt Cushing’s syndrome and reviews the conflicting literature on the findings in this regard. Also highlights the important distinction between findings regarding systemic cortisol dynamics as opposed to local tissue dynamics.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Baid S, Nieman LK. Glucocorticoid excess and hypertension. Curr Hypertens Rep. 2004;6(6):493–9.PubMedCrossRefGoogle Scholar
  15. 15.•
    Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol. 2010;316(2):154–64. doi:10.1016/j.mce.2009.09.024. A comprehensive discussion of the role and place of 11 beta HSD-type 1 in the normal physiology of cortisol metabolism, its role and place in obesity, hypercortisolemic states and a detailed discussion of relevant animal models, relevnace to clinical therapeutics and potential future directions in innovation and research.PubMedCrossRefGoogle Scholar
  16. 16.•
    De Leo M, Cozzolino A, Colao A, Pivonello R. Subclinical Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab. 2012;26(4):497–505. doi:10.1016/j.beem.2012.02.001. A topical discussion of the controversial topic of subclinical Cushing’s syndrome including its prevalence, clinical presentation, diagnostic evaluation protocols with the controversies therein, as well as discussion of its association with increased cardiovascular risk, associated comorbidites including hypertension and the current available management strategies.PubMedCrossRefGoogle Scholar
  17. 17.
    Magiakou MA, Smyrnaki P, Chrousos GP. Hypertension in Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab. 2006;20(3):467–82. doi:10.1016/j.beem.2006.07.006.PubMedCrossRefGoogle Scholar
  18. 18.•
    Sharma ST, Nieman LK. Cushing’s syndrome: all variants, detection, and treatment. Endocrinology and metabolism clinics of North America. 2011;40(2):379-91, viii-ix. doi:10.1016/j.ecl.2011.01.006. A thorough review of the various etiolic considerations in the differential diagnosis of Cushing’s syndrome and other hypercortisolemic states, their association with hypertension, and a discussion of the available therapeutic options.
  19. 19.
    Whitworth JA, Brown MA, Kelly JJ, Williamson PM. Mechanisms of cortisol-induced hypertension in humans. Steroids. 1995;60(1):76–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Kelly JJ, Martin A, Whitworth JA. Role of erythropoietin in cortisol-induced hypertension. J Hum Hypertens. 2000;14(3):195–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Mantero F, Boscaro M. Glucocorticoid-dependent hypertension. J Steroid Biochem Mol Biol. 1992;43(5):409–13.PubMedCrossRefGoogle Scholar
  22. 22.•
    Ong SL, Whitworth JA. How do glucocorticoids cause hypertension: role of nitric oxide deficiency, oxidative stress, and eicosanoids. Endocrinology and metabolism clinics of North America. 2011;40(2):393-407, ix. doi:10.1016/j.ecl.2011.01.010. A comprehensive discussion of the basic and animal model-based data that detail the role of glucocorticoids in influencing vascular tone, compliance and endothelial reactivity, as well as the relevance of this to the development of glucocorticoid-induced hypertension in both animal models and human patients.
  23. 23.
    Chandran DS, Jaryal AK, Jyotsna VP, Deepak KK. Impaired endothelium mediated vascular reactivity in endogenous Cushing’s syndrome. Endocr J. 2011;58(9):789–99.PubMedCrossRefGoogle Scholar
  24. 24.
    Whitworth JA, Williamson PM, Mangos G, Kelly JJ. Cardiovascular consequences of cortisol excess. Vasc Health Risk Manag. 2005;1(4):291–9.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol. 2004;2(1):1–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Yiu KH, Marsan NA, Delgado V, Biermasz NR, Holman ER, Smit JW, et al. Increased myocardial fibrosis and left ventricular dysfunction in Cushing’s syndrome. Eur J Endocrinol/Eur Fed Endocr Soc. 2012;166(1):27–34. doi:10.1530/EJE-11-0601.CrossRefGoogle Scholar
  27. 27.
    Hattori T, Murase T, Sugiura Y, Nagasawa K, Takahashi K, Ohtake M, et al. Effects of salt status and blockade of mineralocorticoid receptors on aldosterone-induced cardiac injury. Hypertens Res: Off J Jpn Soc Hypertens. 2014;37(2):125–33. doi:10.1038/hr.2013.124.CrossRefGoogle Scholar
  28. 28.
    Ermetici F, Malavazos AE, Corbetta S, Eller-Vainicher C, Cannavo S, Corsi MM, et al. Soluble adhesion molecules levels in patients with Cushing’s syndrome before and after cure. J Endocrinol Investig. 2008;31(5):389–92.CrossRefGoogle Scholar
  29. 29.
    Kristo C, Ueland T, Godang K, Aukrust P, Bollerslev J. Biochemical markers for cardiovascular risk following treatment in endogenous Cushing’s syndrome. J Endocrinol Investig. 2008;31(5):400–5.CrossRefGoogle Scholar
  30. 30.
    Terzolo M, Allasino B, Bosio S, Brusa E, Daffara F, Ventura M, et al. Hyperhomocysteinemia in patients with Cushing’s syndrome. J Clin Endocrinol Metabol. 2004;89(8):3745–51. doi:10.1210/jc.2004-0079.CrossRefGoogle Scholar
  31. 31.
    Oki K, Gomez-Sanchez EP, Gomez-Sanchez CE. Role of mineralocorticoid action in the brain in salt-sensitive hypertension. Clin Exp Pharmacol Physiol. 2012;39(1):90–5. doi:10.1111/j.1440-1681.2011.05538.x.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Duclos M, Corcuff JB, Etcheverry N, Rashedi M, Tabarin A, Roger P. Abdominal obesity increases overnight cortisol excretion. J Endocrinol Investig. 1999;22(6):465–71.CrossRefGoogle Scholar
  33. 33.
    Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19(5):647–72. doi:10.1210/edrv.19.5.0346.PubMedGoogle Scholar
  34. 34.
    Salehi M, Ferenczi A, Zumoff B. Obesity and cortisol status. Horm Metab Res Horm Stoffwechselforschung Horm Metabol. 2005;37(4):193–7. doi:10.1055/s-2005-861374.CrossRefGoogle Scholar
  35. 35.
    Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009;94(8):2692–701. doi:10.1210/jc.2009-0370.PubMedCrossRefGoogle Scholar
  36. 36.
    Ahluwalia IB, Mack KA, Murphy W, Mokdad AH, Bales VS. State-specific prevalence of selected chronic disease-related characteristics–Behavioral Risk Factor Surveillance System, 2001. Morbid Mortal Wkly Rep Surveill Summ. 2003;52(8):1–80.Google Scholar
  37. 37.
    Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect “Cushing’s disease of the omentum”? Lancet. 1997;349(9060):1210–3. doi:10.1016/S0140-6736(96)11222-8.PubMedCrossRefGoogle Scholar
  38. 38.
    Pasquali R. The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects. Ann N Y Acad Sci. 2012;1264:20–35. doi:10.1111/j.1749-6632.2012.06569.x.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Pasquali R, Cantobelli S, Casimirri F, Capelli M, Bortoluzzi L, Flamia R, et al. The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab. 1993;77(2):341–6. doi:10.1210/jcem.77.2.8393881.PubMedGoogle Scholar
  40. 40.
    Acelajado MC, Calhoun DA. Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment. Cardiol Clin. 2010;28(4):639–54. doi:10.1016/j.ccl.2010.07.002.PubMedCrossRefGoogle Scholar
  41. 41.
    Aldhahi W, Mun E, Goldfine AB. Portal and peripheral cortisol levels in obese humans. Diabetologia. 2004;47(5):833–6. doi:10.1007/s00125-004-1389-4.PubMedCrossRefGoogle Scholar
  42. 42.
    Stimson RH, Andersson J, Andrew R, Redhead DN, Karpe F, Hayes PC, et al. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans. Diabetes. 2009;58(1):46–53. doi:10.2337/db08-0969.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Alfonso B, Araki T, Zumoff B. Is there visceral adipose tissue (VAT) intracellular hypercortisolism in human obesity? Horm Metab Res Horm Stoffwechselforschung Horm Metab. 2013;45(5):329–31. doi:10.1055/s-0033-1337986.CrossRefGoogle Scholar
  44. 44.
    Prodam F, Ricotti R, Agarla V, Parlamento S, Genoni G, Balossini C, et al. High-end normal adrenocorticotropic hormone and cortisol levels are associated with specific cardiovascular risk factors in pediatric obesity: a cross-sectional study. BMC Med. 2013;11:44. doi:10.1186/1741-7015-11-44.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Bravo EL. The adrenal cortex. In: Oparil S, Weber MA, editors. Hypertension; a companion to Brenner and Rector’s the kidney. Philadelphia: WB Saunders Company; 2000. p. 682–5.Google Scholar
  46. 46.
    Nieman LK, Biller BM, 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(5):1526–40. doi:10.1210/jc.2008-0125.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.•
    Kantorovich V, Koch CA, Chrousos GP. Hypertension in patients with Cushing’s syndrome. In: Koch CA, Chrousos GP, editors. Endocrine hypertension; Underlying mechansims and therapy. New York: Humana press; 2013. p. 51–68. A comprehensive review of the etiopathogenesis of hypertension in Cushing’s syndrome, the treatment options, and its relevance to hypertension in obesity in general. CrossRefGoogle Scholar
  48. 48.
    Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science. 1988;242(4878):583–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Funder JW. Mineralocorticoid receptors: distribution and activation. Heart Fail Rev. 2005;10(1):15–22. doi:10.1007/s10741-005-2344-2.PubMedCrossRefGoogle Scholar
  50. 50.
    Pearce D, Verrey F, Chen SY, Mastroberardino L, Meijer OC, Wang J, et al. Role of SGK in mineralocorticoid-regulated sodium transport. Kidney Int. 2000;57(4):1283–9. doi:10.1046/j.1523-1755.2000.00963.x.PubMedCrossRefGoogle Scholar
  51. 51.
    Staub O, Abriel H, Plant P, Ishikawa T, Kanelis V, Saleki R, et al. Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination. Kidney Int. 2000;57(3):809–15. doi:10.1046/j.1523-1755.2000.00919.x.PubMedCrossRefGoogle Scholar
  52. 52.
    Stewart PM, Krozowski ZS, Gupta A, Milford DV, Howie AJ, Sheppard MC, et al. Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene. Lancet. 1996;347(8994):88–91.PubMedCrossRefGoogle Scholar
  53. 53.
    White PC. 11beta-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess. Am J Med Sci. 2001;322(6):308–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Whorwood CB, Stewart PM. Human hypertension caused by mutations in the 11 beta-hydroxysteroid dehydrogenase gene: a molecular analysis of apparent mineralocorticoid excess. J Hypertens Suppl: Off J Int Soc Hypertens. 1996;14(5):S19–24.Google Scholar
  55. 55.
    Frey FJ, Odermatt A, Frey BM. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens. 2004;13(4):451–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Stewart PM, Edwards CR. The cortisol-cortisone shuttle and hypertension. J Steroid Biochem Mol Biol. 1991;40(4–6):501–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Strohmayer EA, Krakoff LR. Glucocorticoids and cardiovascular risk factors. Endocrinology and metabolism clinics of North America. 2011;40(2):409-17, ix. doi:10.1016/j.ecl.2011.01.011.
  58. 58.
    Minami I, Tateno T, Yoshimoto T, Doi M, Izumiyama H, Akashi T, et al. Subclinical Cushings disease with amelioration of metabolic comorbidities after removal of pituitary tumor. Intern Med. 2006;45(21):1231–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Fallo F, Paoletta A, Tona F, Boscaro M, Sonino N. Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing’s syndrome. J Intern Med. 1993;234(6):595–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Fallo F, Sonino N, Barzon L, Pistorello M, Pagotto U, Paoletta A, et al. Effect of surgical treatment on hypertension in Cushing’s syndrome. Am J Hypertens. 1996;9(1):77–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Amy G. Varughese
    • 1
  • Oksana Nimkevych
    • 2
  • Gabriel I. Uwaifo
    • 1
  1. 1.Section of Endocrinology, Diabetes and Metabolism, Department of MedicineLouisiana State University Health Sciences Center (LSUHSC)New OrleansUSA
  2. 2.Section of Nephrology, Department of MedicineLouisiana State University Health Sciences Center (LSUHSC)New OrleansUSA

Personalised recommendations