Semin Thromb Hemost 2009; 35(5): 478-487
DOI: 10.1055/s-0029-1234143
© Thieme Medical Publishers

Hormones and Cardiovascular Disease: A Shift in Paradigm with Clinical Consequences?

Bregje van Zaane1 , 2 , Anne Q. Reuwer1 , Harry R. Büller1 , John J. P Kastelein1 , Victor E. A Gerdes1 , 2 , Marcel Th. B Twickler1
  • 1Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
  • 2Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands
Further Information

Publication History

Publication Date:
08 September 2009 (online)

ABSTRACT

Several endocrine disorders have been associated with an increased risk of cardiovascular disease (CVD) and mortality. In addition, even subtle hormonal disturbances may modulate the function of cardiovascular organs. In this article, we discuss in detail the contribution of thyroid hormones, cortisol, the somatotropic hormones, and prolactin in the development of CVD. We do not only discuss epidemiological evidence on the association between hormones and cardiovascular disease, but we also address possible pathophysiological mechanisms underlying this association. In fact, hormones can contribute to the development of CVD both indirectly by inducing secondary metabolic changes such as hypertension, insulin resistance, or dyslipidemia, and directly by modulation of cellular pathways that are important in the process of atherosclerotic plaque formation (atherogenesis), plaque instability, and thrombosis.

To date several new therapeutic approaches that focus on the control of hormones at the tissue level, independently of their circulating levels, are being developed. These may offer new possibilities for cardiovascular risk reduction.

REFERENCES

  • 1 Wilson P W, Castelli W P, Kannel W B. Coronary risk prediction in adults (the Framingham Heart Study).  Am J Cardiol. 1987;  59(14) 91G-94G
  • 2 Faggiano A, Pivonello R, Spiezia S et al.. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission.  J Clin Endocrinol Metab. 2003;  88(6) 2527-2533
  • 3 Vanhaelst L, Neve P, Chailly P, Bastenie P A. Coronary-artery disease in hypothyroidism. Observations in clinical myxoedema.  Lancet. 1967;  2(7520) 800-802
  • 4 Flynn R W, Macdonald T M, Jung R T, Morris A D, Leese G P. Mortality and vascular outcomes in patients treated for thyroid dysfunction.  J Clin Endocrinol Metab. 2006;  91(6) 2159-2164
  • 5 Osman F, Franklyn J A, Holder R L, Sheppard M C, Gammage M D. Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study.  J Am Coll Cardiol. 2007;  49(1) 71-81
  • 6 Völzke H, Schwahn C, Wallaschofski H, Dörr M. Review: the association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship?.  J Clin Endocrinol Metab. 2007;  92(7) 2421-2429
  • 7 Etxabe J, Vazquez J A. Morbidity and mortality in Cushing’s disease: an epidemiological approach.  Clin Endocrinol (Oxf). 1994;  40(4) 479-484
  • 8 Baykan M, Erem C, Gedikli O et al.. Impairment of flow-mediated vasodilatation of brachial artery in patients with Cushing’s syndrome.  Endocrine. 2007;  31(3) 300-304
  • 9 Albiger N, Testa R M, Almoto B et al.. Patients with Cushing’s syndrome have increased intimal media thickness at different vascular levels: comparison with a population matched for similar cardiovascular risk factors.  Horm Metab Res. 2006;  38(6) 405-410
  • 10 Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison’s disease: a population-based study.  J Clin Endocrinol Metab. 2006;  91(12) 4849-4853
  • 11 van den Akker E L, Koper J W, van Rossum E F et al.. Glucocorticoid receptor gene and risk of cardiovascular disease.  Arch Intern Med. 2008;  168(1) 33-39
  • 12 Colao A. The GH-IGF-I axis and the cardiovascular system: clinical implications.  Clin Endocrinol (Oxf). 2008;  69(3) 347-358
  • 13 Boero L, Manavela M, Rosso L G et al.. Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly.  Clin Endocrinol (Oxf). 2009;  70(1) 88-95
  • 14 Cannavo S, Almoto B, Cavalli G et al.. Acromegaly and coronary disease: an integrated evaluation of conventional coronary risk factors and coronary calcifications detected by computed tomography.  J Clin Endocrinol Metab. 2006;  91(10) 3766-3772
  • 15 Colao A, Di Somma C, Savanelli M C, De Leo M, Lombardi G. Beginning to end: cardiovascular implications of growth hormone (GH) deficiency and GH therapy.  Growth Horm IGF Res. 2006;  16(Suppl A) S41-S48
  • 16 Yavuz D, Deyneli O, Akpinar I et al.. Endothelial function, insulin sensitivity and inflammatory markers in hyperprolactinemic pre-menopausal women.  Eur J Endocrinol. 2003;  149(3) 187-193
  • 17 Ochs N, Auer R, Bauer D C et al.. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality.  Ann Intern Med. 2008;  148(11) 832-845
  • 18 Parle J V, Maisonneuve P, Sheppard M C, Boyle P, Franklyn J A. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study.  Lancet. 2001;  358(9285) 861-865
  • 19 Razvi S, Shakoor A, Vanderpump M, Weaver J U, Pearce S H. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis.  J Clin Endocrinol Metab. 2008;  93(8) 2998-3007
  • 20 Kim B J, Kim T Y, Koh J M et al.. Relationship between serum free T4 (FT4) levels and metabolic syndrome (MS) and its components in healthy euthyroid subjects.  Clin Endocrinol (Oxf). 2009;  70(1) 152-160
  • 21 Tauchmanovà L, Rossi R, Biondi B et al.. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk.  J Clin Endocrinol Metab. 2002;  87(11) 4872-4878
  • 22 Dekker M J, Koper J W, van Aken M O et al.. Salivary cortisol is related to atherosclerosis of carotid arteries.  J Clin Endocrinol Metab. 2008;  93(10) 3741-3747
  • 23 Matthews K, Schwartz J, Cohen S, Seeman T. Diurnal cortisol decline is related to coronary calcification: CARDIA study.  Psychosom Med. 2006;  68(5) 657-661
  • 24 Raaz D, Wallaschofski H, Stumpf C et al.. Increased prolactin in acute coronary syndromes as putative co-activator of ADP-stimulated P-selectin expression.  Horm Metab Res. 2006;  38(11) 767-772
  • 25 Wallaschofski H, Lohmann T, Hild E et al.. Enhanced platelet activation by prolactin in patients with ischemic stroke.  Thromb Haemost. 2006;  96(1) 38-44
  • 26 Ross R. Atherosclerosis—an inflammatory disease.  N Engl J Med. 1999;  340(2) 115-126
  • 27 Brent G A. The molecular basis of thyroid hormone action.  N Engl J Med. 1994;  331(13) 847-853
  • 28 Duntas L H. Thyroid disease and lipids.  Thyroid. 2002;  12(4) 287-293
  • 29 Diekman T, Demacker P N, Kastelein J J, Stalenhoef A F, Wiersinga W M. Increased oxidizability of low-density lipoproteins in hypothyroidism.  J Clin Endocrinol Metab. 1998;  83(5) 1752-1755
  • 30 Oziol L, Faure P, Bertrand N, Chomard P. Inhibition of in vitro macrophage-induced low density lipoprotein oxidation by thyroid compounds.  J Endocrinol. 2003;  177(1) 137-146
  • 31 Hiroi Y, Kim H H, Ying H et al.. Rapid nongenomic actions of thyroid hormone.  Proc Natl Acad Sci U S A. 2006;  103(38) 14104-14109
  • 32 Squizzato A, Romualdi E, Büller H R, Gerdes V E. Clinical review: thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review.  J Clin Endocrinol Metab. 2007;  92(7) 2415-2420
  • 33 Shih C H, Chen S L, Yen C C et al.. Thyroid hormone receptor-dependent transcriptional regulation of fibrinogen and coagulation proteins.  Endocrinology. 2004;  145(6) 2804-2814
  • 34 Baumgartner-Parzer S M, Wagner L, Reining G et al.. Increase by tri-iodothyronine of endothelin-1, fibronectin and von Willebrand factor in cultured endothelial cells.  J Endocrinol. 1997;  154(2) 231-239
  • 35 Ford H C, Carter J M. Haemostasis in hypothyroidism.  Postgrad Med J. 1990;  66(774) 280-284
  • 36 Palareti G, Biagi G, Legnani C et al.. Association of reduced factor VIII with impaired platelet reactivity to adrenalin and collagen after total thyroidectomy.  Thromb Haemost. 1989;  62(4) 1053-1056
  • 37 Whitworth J A, Williamson P M, Mangos G, Kelly J J. Cardiovascular consequences of cortisol excess.  Vasc Health Risk Manag. 2005;  1(4) 291-299
  • 38 Yang S, Zhang L. Glucocorticoids and vascular reactivity.  Curr Vasc Pharmacol. 2004;  2(1) 1-12
  • 39 Almawi W Y, Melemedjian O K. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids.  J Mol Endocrinol. 2002;  28(2) 69-78
  • 40 Hafezi-Moghadam A, Simoncini T, Yang Z et al.. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase.  Nat Med. 2002;  8(5) 473-479
  • 41 Marumo T, Schini-Kerth V B, Brandes R P, Busse R. Glucocorticoids inhibit superoxide anion production and p22 phox mRNA expression in human aortic smooth muscle cells.  Hypertension. 1998;  32(6) 1083-1088
  • 42 Dover A R, Hadoke P W, Walker B R, Newby D E. Acute effects of glucocorticoids on endothelial fibrinolytic and vasodilator function in humans.  J Cardiovasc Pharmacol. 2007;  50(3) 321-326
  • 43 Mangos G J, Walker B R, Kelly J J, Lawson J A, Webb D J, Whitworth J A. Cortisol inhibits cholinergic vasodilation in the human forearm.  Am J Hypertens. 2000;  13(11) 1155-1160
  • 44 Villa A E, Guzman L A, Chen W, Golomb G, Levy R J, Topol E J. Local delivery of dexamethasone for prevention of neointimal proliferation in a rat model of balloon angioplasty.  J Clin Invest. 1994;  93(3) 1243-1249
  • 45 Wang L, Salu K, Verbeken E et al.. Stent-mediated methylprednisolone delivery reduces macrophage contents and in-stent neointimal formation.  Coron Artery Dis. 2005;  16(4) 237-243
  • 46 Perretti M, Ahluwalia A. The microcirculation and inflammation: site of action for glucocorticoids.  Microcirculation. 2000;  7(3) 147-161
  • 47 Brotman D J, Girod J P, Posch A et al.. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers.  Thromb Res. 2006;  118(2) 247-252
  • 48 Fatti L M, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci P M. Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome.  J Endocrinol Invest. 2000;  23(3) 145-150
  • 49 Darmon P, Dadoun F, Boullu-Ciocca S, Grino M, Alessi M C, Dutour A. Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity.  Am J Physiol Endocrinol Metab. 2006;  291(5) E995-E1002
  • 50 de Kruif M D, Lemaire L C, Giebelen I A et al.. Prednisolone dose-dependently influences inflammation and coagulation during human endotoxemia.  J Immunol. 2007;  178(3) 1845-1851
  • 51 Jilma B, Cvitko T, Winter-Fabry A, Petroczi K, Quehenberger P, Blann A D. High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men.  Thromb Haemost. 2005;  94(4) 797-801
  • 52 Hutton R A, Mikhailidis D P, Georgiadis E, Hyden A, Ginsburg J. The effect of tetracosactin and corticosteroids on platelet aggregation : an in vivo and in vitro study.  Thromb Res. 1980;  17(1-2) 5-11
  • 53 Náray-Fejes-Tóth A, Rosenkranz B, Frölich J C, Fejes-Tóth G. Glucocorticoid effect on arachidonic acid metabolism in vivo.  J Steroid Biochem. 1988;  30(1-6) 155-159
  • 54 Rosenkrantz B, Náray-Fejes-Tóth A, Fejes-Tóth G, Fischer C, Sawada M, Frölich J C. Dexamethasone effect on prostanoid formation in healthy man.  Clin Sci (Lond). 1985;  68(6) 681-685
  • 55 Rudling M, Parini P, Angelin B. Effects of growth hormone on hepatic cholesterol metabolism. Lessons from studies in rats and humans.  Growth Horm IGF Res. 1999;  9(Suppl A) 1-7
  • 56 Twickler T B, Cramer M J, Dallinga-Thie G M, Chapman M J, Erkelens D W, Koppeschaar H P. Adult-onset growth hormone deficiency: relation of postprandial dyslipidemia to premature atherosclerosis.  J Clin Endocrinol Metab. 2003;  88(6) 2479-2488
  • 57 Nilsson L, Binart N, Bohlooly-Y M et al.. Prolactin and growth hormone regulate adiponectin secretion and receptor expression in adipose tissue.  Biochem Biophys Res Commun. 2005;  331(4) 1120-1126
  • 58 Sesmilo G, Biller B M, Llevadot J et al.. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial.  Ann Intern Med. 2000;  133(2) 111-122
  • 59 Jia G, Cheng G, Gangahar D M, Agrawal D K. Insulin-like growth factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells.  Immunol Cell Biol. 2006;  84(5) 448-454
  • 60 Martin R M, Gunnell D, Whitley E et al.. Associations of insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein (IGFBP)-2 and IGFBP-3 with ultrasound measures of atherosclerosis and plaque stability in an older adult population.  J Clin Endocrinol Metab. 2008;  93(4) 1331-1338
  • 61 Erem C, Nuhoglu I, Kocak M et al.. Blood coagulation and fibrinolysis in patients with acromegaly: increased plasminogen activator inhibitor-1 (PAI-1), decreased tissue factor pathway inhibitor (TFPI), and an inverse correlation between growth hormone and TFPI.  Endocrine. 2008;  33(3) 270-276
  • 62 Johansson J O, Landin K, Tengborn L, Rosén T, Bengtsson B A. High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults.  Arterioscler Thromb. 1994;  14(3) 434-437
  • 63 Johansson J O, Landin K, Johannsson G, Tengborn L, Bengtsson B A. Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults.  Thromb Haemost. 1996;  76(3) 422-428
  • 64 Kvasnicka J, Marek J, Kvasnicka T et al.. Increase of adhesion molecules, fibrinogen, type-1 plasminogen activator inhibitor and orosomucoid in growth hormone (GH) deficient adults and their modulation by recombinant human GH replacement.  Clin Endocrinol (Oxf). 2000;  52(5) 543-548
  • 65 Brandebourg T, Hugo E, Ben-Jonathan N. Adipocyte prolactin: regulation of release and putative functions.  Diabetes Obes Metab. 2007;  9(4) 464-476
  • 66 Serri O, Li L, Mamputu J C, Beauchamp M C, Maingrette F, Renier G. The influences of hyperprolactinemia and obesity on cardiovascular risk markers: effects of cabergoline therapy.  Clin Endocrinol (Oxf). 2006;  64(4) 366-370
  • 67 Merkle C J, Schuler L A, Schaeffer Jr R C, Gribbon J M, Montgomery D W. Structural and functional effects of high prolactin levels on injured endothelial cells: evidence for an endothelial prolactin receptor.  Endocrine. 2000;  13(1) 37-46
  • 68 Montes de Oca P, Macotela Y, Nava G, López-Barrera F, de la Escalera G M, Clapp C. Prolactin stimulates integrin-mediated adhesion of circulating mononuclear cells to endothelial cells.  Lab Invest. 2005;  85(5) 633-642
  • 69 Sauro M D, Zorn N E. Prolactin induces proliferation of vascular smooth muscle cells through a protein kinase C-dependent mechanism.  J Cell Physiol. 1991;  148(1) 133-138
  • 70 Aziz M M, Ishihara S, Rumi M A et al.. Prolactin induces MFG-E8 production in macrophages via transcription factor C/EBPbeta-dependent pathway.  Apoptosis. 2008;  13(5) 609-620
  • 71 Corbacho A M, Martínez De La Escalera G, Clapp C. Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis.  J Endocrinol. 2002;  173(2) 219-238
  • 72 Tallet E, Rouet V, Jomain J B, Kelly P A, Bernichtein S, Goffin V. Rational design of competitive prolactin/growth hormone receptor antagonists.  J Mammary Gland Biol Neoplasia. 2008;  13(1) 105-117
  • 73 Beaudeux J L, Giral P, Bruckert E, Foglietti M J, Chapman M J. Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives.  Clin Chem Lab Med. 2004;  42(2) 121-131
  • 74 Clapp C, Aranda J, González C, Jeziorski M C, Martínez de la Escalera G. Vasoinhibins: endogenous regulators of angiogenesis and vascular function.  Trends Endocrinol Metab. 2006;  17(8) 301-307
  • 75 Gonzalez C, Corbacho A M, Eiserich J P et al.. 16K-prolactin inhibits activation of endothelial nitric oxide synthase, intracellular calcium mobilization, and endothelium-dependent vasorelaxation.  Endocrinology. 2004;  145(12) 5714-5722
  • 76 Gordon E M, Douglas J G, Ratnoff O D, Arafah B M. The influence of estrogen and prolactin on Hageman factor (factor XII) titer in ovariectomized and hypophysectomized rats.  Blood. 1985;  66(3) 602-605
  • 77 Nishino Y. Hormonal control of prothrombin synthesis in rat liver microsomes, with special reference to the role of estradiol, testosterone and prolactin.  Arch Toxicol Suppl. 1979;  (2) 397-402
  • 78 Houlihan C M, Knuppel R A, Vintzileos A M, Guo J Z, Hahn D W. The effect of specific hormones on fibrinolysis in pregnancy.  Am J Obstet Gynecol. 1996;  175(1) 168-172
  • 79 Wallaschofski H, Kobsar A, Koksch M et al.. Prolactin receptor signaling during platelet activation.  Horm Metab Res. 2003;  35(4) 228-235
  • 80 Atmaca A, Gurlek A, Dagdelen S et al.. Hyperprolactinemia of pregnancy is not associated with increased in vivo platelet activity and shortened in vitro bleeding times.  Exp Clin Endocrinol Diabetes. 2006;  114(4) 188-191
  • 81 Wallaschofski H, Donné M, Eigenthaler M et al.. PRL as a novel potent cofactor for platelet aggregation.  J Clin Endocrinol Metab. 2001;  86(12) 5912-5919
  • 82 Bryzgalova G, Effendic S, Khan A et al.. Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141.  J Steroid Biochem Mol Biol. 2008;  111(3-5) 262-267
  • 83 Johansson L, Rudling M, Scanlan T S et al.. Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice.  Proc Natl Acad Sci U S A. 2005;  102(29) 10297-10302
  • 84 Berkenstam A, Kristensen J, Mellström K et al.. The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans.  Proc Natl Acad Sci U S A. 2008;  105(2) 663-667
  • 85 Walker B R, Andrew R. Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease.  Ann N Y Acad Sci. 2006;  1083 165-184
  • 86 Sukhanov S, Higashi Y, Shai S Y et al.. IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice.  Arterioscler Thromb Vasc Biol. 2007;  27(12) 2684-2690
  • 87 Cittadini A, Grossman J D, Napoli R et al.. Growth hormone attenuates early left ventricular remodeling and improves cardiac function in rats with large myocardial infarction.  J Am Coll Cardiol. 1997;  29(5) 1109-1116
  • 88 Jayasankar V, Bish L T, Pirolli T J, Berry M F, Burdick J, Woo Y J. Local myocardial overexpression of growth hormone attenuates postinfarction remodeling and preserves cardiac function.  Ann Thorac Surg. 2004;  77(6) 2122-2129 discussion 2129

Marcel Th. B TwicklerM.D. 

Academic Medical Center of the University of Amsterdam, Department of Vascular Medicine

Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: T.B.Twickler@amc.uva.nl

    >