Statins, metformin, proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones: Immunomodulatory properties?
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Abstract
The immune system is closely intertwined with the endocrine system. Many effects of medications used for various clinical endocrine conditions such as the metabolic syndrome, hypercholesterolemia, diabetes mellitus, hypertension, Graves’ disease and others also have an impact on the immune system. Some drugs including statins, metformin, angiotensin converting enzyme and proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones are known to have immunomodulatory properties. We here review the literature on this topic and provide some clinical examples including the use of statins in Graves’ orbitopathy, rheumatoid arthritis, multiple sclerosis, and adult-onset Still’s disease. In that context, we introduce a special immunodiagnostics method developed at the Institute of Diabetes “Gerhardt Katsch” in Karlsburg, Germany, to not only measure but also monitor immune disease activity.
Keywords
Statin Flow cytometry Interleukin 2 Autoantigen Somatostatin Immune Thyroid Orbitopathy Autoimmune Multiple sclerosis Rheumatoid arthritis Metformin PCSK9 Testosterone LupusNotes
Compliance with ethical standards
All patients have provided informed consent for the off label use of statins and for permission to conduct experiments and publish the results. One case study with Graves’s orbitopathy has been published in poster format at the Endocrine Society Meeting 2018 in Chicago: Statins As Immunomodulatory Therapy In Graves’ Orbitopathy. Poster Presentation SAT-676, 100th Endocrine Society Meeting, Chicago, IL, March 17, 2018.
Conflict of interest
Prof. Koch declares no direct conflict with this article. He has served on the Advisory Board of Novartis on the topic acromegaly and has participated in educational conferences on the topics neuroendocrine tumors and acromegaly sponsored by Novartis and Ipsen. Dr. Hehmke declares no conflict of interest. Prof. Krabbe declares no direct conflict with this article. He has served on the Advisory Board of Lilly and as speaker for Berlin-Chemie, Amgen, and MSD Sharp & Dohme / Merck & Co. Inc.
Figure and Table legends are provided within the respective text sections.
Reference [16] and parts of the table from it are available as open access article and for reproduction use as long as the source is acknowledged / cited which is the case here.
References
- 1.Karalis K, Sano H, Redwine J, Listwak S, Wilder RL, Chrousos GP. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science. 1991;254(5030):421–3.Google Scholar
- 2.Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351–62.Google Scholar
- 3.Franchimont D, Bouma G, Galon J, Wolkersdörfer GW, Haidan A, Chrousos GP, Bornstein SR. Adrenal cortical activation in murine colitis. Gastroenterology 2000 119(6):1560–1568.Google Scholar
- 4.Antonelli A, Ferrari SM, Frascerra S, Di Domenicantonio A, Nicolini A, Ferrari P, Ferrannini E, Fallahi P. Increase of circulating CXCL9 and CXCL11 associated with euthyroid or subclinically hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab 2011;96(6):1859–1863.Google Scholar
- 5.Antonelli A, Ferri C, Fallahi P, Colaci M, Giuggioli D, Ferrari SM, et al. Th1 and Th2 chemokine serum levels in systemic sclerosis in the presence or absence of autoimmune thyroiditis. J Rheumatol. 2008;35(9):1809–11.Google Scholar
- 6.Ferrari SM, Fallahi P, Galetta F, Citi E, Benvenga S, Antonelli A. Thyroid disorders induced by checkpoint inhibitors. Rev Endocr Metab Disord. 2018. https://doi.org/10.1007/s11154-018-9463-2.
- 7.Gubbi S, Hannah-Shmouni F, Stratakis CA, Koch CA. Primary hypophysitis and other autoimmune disorders of the sellar and suprasellar regions. Rev Endocr Metab Disord 2018.Google Scholar
- 8.Koch CA, Robyn JA, Pacak K. How do levels of (endogenous) glucocorticoids, interleukin-10 and interleukin-12 relate to multiple sclerosis relapse before, during and after pregnancy? Clin Endocrinol. 1999;50(6):818–9.Google Scholar
- 9.Melcescu E, Kemp EH, Majithia V, Vijayakumar V, Uwaifo GI, Koch CA. Graves' disease, hypoparathyroidism, systemic lupus erythematosus, alopecia, and angioedema: autoimmune polyglandular syndrome variant or coincidence? Int J Immunopathol Pharmacol. 2013;26(1):217–22.Google Scholar
- 10.Melcescu E, Hogan RB 2nd, Brown K, Boyd SA, Abell TL, Koch CA. The various faces of autoimmune endocrinopathies: non-tumoral hypergastrinemia in a patient with lymphocytic colitis and chronic autoimmune gastritis. Exp Mol Pathol. 2012;93(3):434–40.Google Scholar
- 11.Nati M, Haddad D, Birkenfeld AL, Koch CA, Chavakis T, Chatzigeorgiou A. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Rev Endocr Metab Disord. 2016;17(1):29–39.Google Scholar
- 12.Hehmke B, Michaelis D, Gens E, Laube F, Kohnert KD. Aberrant activation of CD8+ T-cell and CD8+ T-cell subsets in patients with newly diagnosed IDDM. Diabetes. 1995;44(12):1414–9.Google Scholar
- 13.Hehmke B, Salzsieder E, Matic GB, Winkler RE, Tiess M, Ramlow W. Immunoadsorption of immunoglobulins alters intracytoplasmic type 1 and type 2 T cell cytokine production in patients with refractory autoimmune diseases. Ther Apher. 2000;4(4):296–302.Google Scholar
- 14.Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542(7640):177–85.Google Scholar
- 15.Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–8.Google Scholar
- 16.Martino M, Rocchi G, Escelsior A, Fornaro M. Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance. Curr Neuropharmacol. 2012;10(2):97–123.Google Scholar
- 17.Ameri P, Ferone D. Diffuse endocrine system, neuroendocrine tumors and immunity: what’s new ? Neuroendocrinology. 2012;95(4):267–76.Google Scholar
- 18.Blum AM, Metwali A, Mathew RC, Cook G, Elliott D, Weinstock JV. Granuloma T lymphocytes in murine schistosomiasis mansoni have somatostatin receptors and respond to somatostatin with decreased IFN-gamma secretion. J Immunol. 1992;149:3621.Google Scholar
- 19.Bhanat E, Koch CA, Parmar R, Garla V, Vijayakumar V. Somatostatin receptor expression in non-classical locations - clinical relevance? Rev Endocr Metab Disord. 2018;19(2):123–32.Google Scholar
- 20.Lincke T, Orschekowski G, Singer J, Sabri O, Paschke R. Increased gallium-68 DOTATOC uptake in normal thyroid gland. Horm Metab Res. 2011;43(4):282–6.Google Scholar
- 21.Koch CA, Petersenn S. Black swans - neuroendocrine tumors of rare locations. Rev Endocr Metab Disord. 2018;19(2):111–21.Google Scholar
- 22.Tarkin JM, Joshi FR, Evans NR, Chowdhury MM, Figg NL, Shah AV, et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to 18F FDG PET imaging. J Am Coll Cardiol. 2017;69(14):1774–91.Google Scholar
- 23.Bedi O, Dhawan V, Sharma PL, Kumar P. Pleiotropic effects of statins: new therapeutic targets in drug design. Naunyn Schmiedeberg's Arch Pharmacol. 2016;389(7):695–712.Google Scholar
- 24.Troeman DP, Postma DF, van Werkhoven CH, Oosterheert JJ. The immunomodulatory effects of statins in community-acquired pneumonia: a systematic review. J Inf Secur. 2013;67(2):93–101.Google Scholar
- 25.Xu X, Gao W, Cheng S, Yin D, Li F, Wu Y, et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation. 2017;14(1):167.Google Scholar
- 26.Moctezuma-Velázquez C, Abraldes JG, Montano-Loza AJ. The use of statins in patients with chronic liver disease and cirrhosis. Curr Treat Options Gastroenterol. 2018;16(2):226–40.Google Scholar
- 27.Mascitelli L, Goldstein MR. Statin immunomodulation and thyroid cancer. Clin Endocrinol. 2015;82(4):620.Google Scholar
- 28.Vallianou NG, Kostantinou A, Kougias M, Kazazis C. Statins and cancer. Anti Cancer Agents Med Chem. 2014;14(5):706–12.Google Scholar
- 29.Coward WR, Chow SC. Effect of atorvastatin on TH1 and TH2 cytokine secreting cells during T cell activation and differentiation. Atherosclerosis. 2006;186:302–9.Google Scholar
- 30.Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 1999;353:983–4.Google Scholar
- 31.Bruegel M, Teupser D, Haffner I, Mueller M, Thiery J. Statins reduce macrophage inflammatory protein-1alpha expression in human activated monocytes. Clin Exp Pharmacol Physiol. 2006;33(12):1144–9.Google Scholar
- 32.Ulivieri C, Baldari CT. Statins: from cholesterol-lowering drugs to novel immunomodulators for the treatment of Th17-mediated autoimmune diseases. Pharmacol Res. 2014;88:41–52.Google Scholar
- 33.Jameel A, Ooi KG, Jeffs NR, Galatowicz G, Lightman SL, Calder VL. Statin Modulation of Human T-Cell Proliferation, IL-1β and IL-17 Production, and IFN-γ T Cell Expression: Synergy with Conventional Immunosuppressive Agents. Int J Inflam. 2013;2013:434586.Google Scholar
- 34.Khattri S, Zandman-Goddard G. Statins and autoimmunity. Immunol Res. 2013 Jul;56(2–3):348–57.Google Scholar
- 35.Lozanoska-Ochser B, Barone F, Pitzalis C, et al. Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells. Diabetes. 2006;55:1004–10.Google Scholar
- 36.Kotyla PJ, Kucharz EJ. Statins Therapy for Connective Tissue Diseases: New Therapeutic Opportunities. Endocr Metab Immune Disord Drug Targets. 2018;18(2):135–47.Google Scholar
- 37.Lei A, Yang Q, Li X, Chen H, Shi M, Xiao Q, et al. Atorvastatin promotes the expansion of myeloid-derived suppressor cells and attenuates murine colitis. Immunology. 2016;149(4):432–46.Google Scholar
- 38.Côté-Daigneault J, Mehandru S, Ungaro R, Atreja A, Colombel JF. Potential Immunomodulatory Effects of Statins in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016;22(3):724–32.Google Scholar
- 39.Barsante MM, Roffe E, Yokoro CM, et al. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. Eur J Pharmacol. 2005;516:282–9.Google Scholar
- 40.Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003;170:1524–30.Google Scholar
- 41.ten Cate R, Nibbering PH, Bredius RG. Therapy-refractory systemic juvenile idiopathic arthritis successfully treated with statins. Rheumatology (Oxford). 2004;43(7):934–5.Google Scholar
- 42.Lv S, Liu Y, Zou Z, Li F, Zhao S, Shi R, et al. The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2015;33(1):69–76.Google Scholar
- 43.McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363(9426):2015–21.Google Scholar
- 44.Li XL, Dou YC, Liu Y, Shi CW, Cao LL, Zhang XQ, et al. Atorvastatin ameliorates experimental autoimmune neuritis by decreased Th1/Th17 cytokines and up-regulated T regulatory cells. Cell Immunol. 2011;271(2):455–61.Google Scholar
- 45.Aktas O, Waiczies S, Smorodchenko A, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting TH1 cells through atorvastatin. J Exp Med. 2003;197:725–33.Google Scholar
- 46.Neuhaus O, Strasser-Fuchs S, Fazekas F, et al. Statins as immunomodulators: comparison with interferon-beta 1-beta in MS. Neurology. 2002;59:990–7.Google Scholar
- 47.Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–8.Google Scholar
- 48.Li XL, Zhang ZC, Zhang B, Jiang H, Yu CM, Zhang WJ, et al. Atorvastatin calcium in combination with methylprednisolone for the treatment of multiple sclerosis relapse. Int Immunopharmacol. 2014;23(2):546–9.Google Scholar
- 49.Cuthbert JA, Lipsky PE. Sterol metabolism and lymphocyte responsiveness: inhibition of endogenous sterol synthesis prevents mitogen-induced human T cell proliferation. J Immunol. 1981;126(6):2093–9.Google Scholar
- 50.Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacology. 1996;34(1):51–61.Google Scholar
- 51.Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6(12):1399–402.Google Scholar
- 52.Albert MA, Danielson E, Rifai N, Ridker PM, Investigators PRINCE. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286(1):64–70.Google Scholar
- 53.van de Ree MA, Huisman MV, Princen HM, Meinders AE, Kluft C, DALI-Study Group. Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus. Atherosclerosis. 2003;166(1):129–35.Google Scholar
- 54.van Halm VP, Nielen MM, Nurmohamed MT, van Schaardenburg D, Reesink HW, Voskuyl AE, et al. van der Horst-Bruinsma IE, Dijkmans BA.Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann Rheum Dis. 2007;66(2):184–8.Google Scholar
- 55.Gruaz L, Delucinge-Vivier C, Descombes P, Dayer JM, Burger D. Blockade of T cell contact-activation of human monocytes by high-density lipoproteins reveals a new pattern of cytokine and inflammatory genes. PLoS One. 2010;5(2):e9418.Google Scholar
- 56.Kahaly G, et al. Mycophenolate plus methylprednisolone vs. methylprednisolone alone in active, moderate to severe graves orbitopathy (MINGO): a randomized, observer-masked, multicentre trial. Lancet Diabetes Endocrinol. 2018;6(4):287–98.Google Scholar
- 57.Bartalena L, et al. The 2016 European thyroid association/European group on graves Orbitopathy guidelines for the Management of Graves Orbitopathy. Eur Thyroid J. 2016;5(1):9–26.Google Scholar
- 58.Melcescu E, Horton WB, Kim D, Vijayakumar V, Corbett JJ, Crowder KW, et al. Graves orbitopathy: update on diagnosis and therapy. South Med J. 2014;107(1):34–43.Google Scholar
- 59.Bifulco M, Ciaglia E. Statin reduces orbitopathy risk in patients with graves’ disease by modulating apoptosis and autophagy activities. Endocrine. 2016;53:649–50.Google Scholar
- 60.Liao KL, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005:89–118.Google Scholar
- 61.Markovic-Plese S, Singh AK, Singh I. Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future Neurol. 2008;3:1–21.Google Scholar
- 62.Soliman M, et al. T-cells recognise multiple epitopes in the human thyrotropin receptor extracellular domain. J Clin Endocrinol Metab. 1995;80:905–14.Google Scholar
- 63.Fisfalen EL, et al. Proliferative responses of T-cells to thyroid antigens and synthetic thyroid peroxidase peptides in autoimmune thyroid disease. J Clin Endocrinol Metab. 1995;80:1597–604.Google Scholar
- 64.Björkhem-Bergman L, Lindh JD, Bergman P. What is a relevant statin concentration in cell experiments claiming pleiotropic effects? Br J Clin Pharmacol. 2011;72(1):164–5.Google Scholar
- 65.Jain MK, Ridker PM. Antiinflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4:977–87.Google Scholar
- 66.Yousseff S, Stuve O, Patarryo JC, Ruiz P, Radosevich JL, Hur EM, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84.Google Scholar
- 67.Gleicher N, Kushnir VA, Darmon SK, Wang Q, Zhang L, Albertini DF, et al. New PCOS-like phenotype in older infertile women of likely autoimmune adrenal etiology with high AMH but low androgens. J Steroid Biochem Mol Biol. 2017;167:144–52.Google Scholar
- 68.Banaszewska B, Pawelczyk L, Spaczynski RZ, Dziura J, Duleba AJ. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab. 2007;92(2):456–61.Google Scholar
- 69.Sun J, Yuan Y, Cai R, Sun H, Zhou Y, Wang P, et al. An investigation into the therapeutic effects of statins with metformin on polycystic ovary syndrome: a meta-analysis of randomised controlled trials. BMJ Open. 2015;5(3):e007280.Google Scholar
- 70.Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112(6):1809–14.Google Scholar
- 71.Prattichizzo F, Giuliani A, Mensà E, Sabbatinelli J, De Nigris V, Rippo MR, et al. Pleiotropic effects of metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing. Ageing Res Rev. 2018;48:87–98.Google Scholar
- 72.Chae YK, Arya A, Malecek MK, Shin DS, Carneiro B, Chandra S, et al. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget. 2016;7(26):40767–80.Google Scholar
- 73.Negrotto L, Farez MF, Correale J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016;73(5):520–8.Google Scholar
- 74.Sun Y, Tian T, Gao J, Liu X, Hou H, Cao R, et al. Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice. J Neuroimmunol. 2016;292:58–67.Google Scholar
- 75.Kang KY, Kim YK, Kim J, Jung HR, Kim IJ, Cho JH, et al. Ju JH. Metformin downregulates Th17 differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol. 2013;16:85–92.Google Scholar
- 76.Lee SY, Lee SH, Yang EJ, Kim EK, Kim JK, Shin DY, et al. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. Plos One. 2015;10(9):e0135858.Google Scholar
- 77.Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015 Dec 10;528(7581):262–6.Google Scholar
- 78.Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016;7:10410.Google Scholar
- 79.Csongrádi É, Káplár M, Nagy B Jr, Koch CA, Juhász A, Bajnok L, et al. Adipokines as atherothrombotic risk factors in obese subjects: Associations with haemostatic markers and common carotid wall thickness. Nutr Metab Cardiovasc Dis. 2017;27(6):571–80.Google Scholar
- 80.Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res. 2011;43(3):153–64.Google Scholar
- 81.Karimi K, Lindgren TH, Koch CA, Brodell RT. Obesity as a risk factor for malignant melanoma and non-melanoma skin cancer. Rev Endocr Metab Disord. 2016;17(3):389–403.Google Scholar
- 82.Turner JB, Kumar A, Koch CA. The effects of indoor and outdoor temperature on metabolic rate and adipose tissue - the Mississippi perspective on the obesity epidemic. Rev Endocr Metab Disord. 2016;17(1):61–71.Google Scholar
- 83.Koch CA. EDITORIAL: "The Koch's" view on the sense of taste in endocrinology. Rev Endocr Metab Disord. 2016;17(2):143–7.Google Scholar
- 84.Isoda K, Akita K, Kitamura K, Sato-Okabayashi Y, Kadoguchi T, Isobe S, et al. Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. Int J Cardiol. 2018;270:221–7.Google Scholar
- 85.Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz TV, et al. Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc Natl Acad Sci U S A. 2009;106(35):14948–53.Google Scholar
- 86.Sagawa K, Nagatani K, Komagata Y, Yamamoto K. Angiotensin receptor blockers suppress antigen-specific T cell responses and ameliorate collagen-induced arthritis in mice. Arthritis Rheum. 2005;52(6):1920–8.Google Scholar
- 87.Martin MF, Surrall KE, McKenna F, Dixon JS, Bird HA, Wright V. Captopril: a new treatment for rheumatoid arthritis? Lancet. 1984;1(8390):1325–8.Google Scholar
- 88.Andersson P, Bratt J, Heimbürger M, Cederholm T, Palmblad J. Inhibition of neutrophil-dependent cytotoxicity for human endothelial cells by ACE inhibitors. Scand J Immunol. 2014;80(5):339–45.Google Scholar
- 89.Abadir P, Hosseini S, Faghih M, Ansari A, Lay F, Smith B, et al. Topical reformulation of valsartan for treatment of chronic diabetic wounds. J Invest Dermatol. 2018;138(2):434–43.Google Scholar
- 90.Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314–29.Google Scholar
- 91.Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American association of clinical endocrinologists and American College of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(Suppl 2):1–87.Google Scholar
- 92.Shapiro MD, Fazio S. PCSK9 and atherosclerosis - lipids and beyond. J Atheroscler Thromb. 2017;24(5):462–72.Google Scholar
- 93.Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, et al. Boyd JH. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014;6(258):258ra143.Google Scholar
- 94.Liu A, Frostegård J. PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque. J Intern Med. 2018. https://doi.org/10.1111/joim.12758.
- 95.Theocharidou E, Papademetriou M, Reklou A, Sachinidis A, Boutari C, Giouleme O. The role of PCSK9 in the pathogenesis of non-alcoholic fatty liver disease and the effect of PCSK9 inhibitors. Curr Pharm Des 2018.Google Scholar
- 96.Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A. Clinical review: Klinefelter syndrome--a clinical update. J Clin Endocrinol Metab. 2013;98(1):20–30.Google Scholar
- 97.Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009;5(12):673–81.Google Scholar
- 98.Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675–85.Google Scholar
- 99.Hussain R, Ghoumari AM, Bielecki B, Steibel J, Boehm N, Liere P, et al. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain. 2013;136(Pt 1):132–46.Google Scholar
- 100.Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80(6):548–52.Google Scholar
- 101.Elenkov IJ, Chrousos GP, Wilder RL. Neuroendocrine regulation of IL-12 and TNF-alpha/IL-10 balance. Clinical implications. Ann N Y Acad Sci. 2000;917:94–105.Google Scholar
- 102.Crispín JC, Tsokos GC. IL-17 in Systemic Lupus Erythematosus. J Biomed Biotechnol. 2010:1–4.Google Scholar
- 103.Nalbandian A, Crispín JC, Tsokos GC. Interleukin-17 and systemic lupus erythematosus: current concepts. Clin Exp Immunol. 2009;157(2):209–215.Google Scholar
- 104.Dey ID, Isenberg DA, Lahita RG. How hormones affect lupus treatment. Endocrine news, 2012.Google Scholar
- 105.Gomez FP, Steelman AJ, Young CR, Welsh CJ. Hormone and immune system interactions in demyelinating disease. Horm Behav. 2013;63(2):315–21.Google Scholar