Thyroid volumes and serum VEGF levels in dyslipidemic patients: effects of statin treatment

Thyroid volumes and serum VEGF levels in dyslipidemic patients: effects of statin treatment

Background/aim: Defective vascularization may be important in thyroid nodular disease. In this study, we aimed to investigate serumvascular endothelial growth factor (VEGF) levels in dyslipidemic patients with thyroid nodules, as well as the effects of statin therapy.Materials and methods: The study included 37 dyslipidemic patients with thyroid nodules and 32 dyslipidemic patients without thyroidnodules. Anthropometry, serum VEGF levels, biochemical parameters, thyroid-stimulating hormone (TSH), free triiodothyronine(fT3) and free thyroxine (fT4) levels, and thyroid sonography were determined before and after 6 months of statin therapy.Results: Patients with and without thyroid nodules had similar metabolic parameters. Serum VEGF levels did not differ between thegroups. In patients with nodules, VEGF levels remained unchanged (P = 0.931) after statin therapy. However, serum VEGF levels werelowered by statin treatment in patients without nodules (P = 0.030). Statin therapy resulted in a decrease in the dominant thyroid nodulevolume. The changes in thyroid volume and dominant thyroid nodule volume were not correlated with changes in VEGF, body massindex, total cholesterol, low-density lipoprotein cholesterol, or homeostatic model assessment of insulin resistance (HOMA-IR).Conclusion: Although statin treatment decreases serum VEGF levels in dyslipidemic patients without thyroid nodules, it has nolowering effect on serum VEGF levels in patients with thyroid nodules. The decrease in thyroid nodule volume with statin treatmentwas associated with neither metabolic parameters nor serum VEGF levels.

___

  • 1. Rezzonico J, Rezzonico M, Pusiol E, Pitoia F, Niepomniszcze H. Introducing the thyroid gland as another victim of the insulin resistance syndrome. Thyroid 2008; 18: 461-464.
  • 2. Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab 2007; 92: 491-496.
  • 3. Ayturk S, Gursoy A, Kut A, Anil C, Nar A, Tutuncu NB. Metabolic syndrome and its components are associated with increased thyroid volume and nodule prevalence in a mild-to-moderate iodine-deficient area. Eur J Endocrinol 2009; 161: 599-605.
  • 4. Wang K, Yang Y, Wu Y, Chen J, Zhang D, Mao X, Wu X, Long X, Liu C. The association between insulin resistance and vascularization of thyroid nodules. J Clin Endocrinol Metab 2015; 100: 184-192.
  • 5. Erdem H, Gundogdu C, Sipal S. Correlation of E-cadherin, VEGF, COX-2 expression to prognostic parameters in papillary thyroid carcinoma. Exp Mol Pathol 2011; 90: 312-317.
  • 6. Karaca Z, Tanriverdi F, Unluhizarci K, Ozturk F, Gokahmetoglu S, Elbuken G, Cakir I, Bayram F, Kelestimur F. VEGFR1 expression is related to lymph node metastasis and serum VEGF may be a marker of progression in the follow-up of patients with differentiated thyroid carcinoma. Eur J Endocrinol 2011; 164: 277-284.
  • 7. Lennard CM, Patel A, Wilson J, Reinhardt B, Tuman C, Fenton C, Blair E, Francis GL, Tuttle RM. Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 2001; 129: 552- 558.
  • 8. Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, Demura H, Yamaguchi S, Shibuya M. Stimulation by thyroid-stimulating hormone and Grave’s immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo. J Clin Invest 1995; 96: 1295-1302.
  • 9. Mitchell JC, Parangi S. Angiogenesis in benign and malignant thyroid disease. Thyroid 2005; 15: 494-510.
  • 10. Bunone G, Vigneri P, Mariani L, Butó S, Collini P, Pilotti S, Pierotti MA, Bongarzone I. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 1999; 155: 1967-1976.
  • 11. Tanaka K, Kurebayashi J, Sonoo H, Otsuki T, Yamamoto Y, Ohkubo S, Yamamoto S, Shimozuma K. Expression of vascular endothelial growth factor family messenger RNA in diseased thyroid tissues. Surg Today 2002; 32: 761-768.
  • 12. Malkomes P, Oppermann E, Bechstein WO, Holzer K. Vascular endothelial growth factor marker for proliferation in thyroid diseases? Exp Clin Endocrinol Diabetes 2013; 121: 6-13.
  • 13. Itoh A, Iwase K, Jimbo S, Yamamoto H, Yamamoto N, Kokubo M, Senda T, Nakai A, Nagagasaka A, Nagasaka T et al. Expression of vascular endothelial growth factor and presence of angiovascular cells in tissues from different thyroid disorders. World J Sur 2010; 34: 242-248.
  • 14. Bifulco M. Therapeutic potential of statins in thyroid proliferative disease. Nat Clin Pract Endocrinol Metab 2008; 4: 242-243.
  • 15. Forrester JS, Libby P. The inflammation hypothesis and its potential relevance to statin therapy. Am J Cardiol 2007; 99: 732- 738.
  • 16. Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol 2007; 28: 88-98.
  • 17. Dworacka M, Krzyzagorska E, Wesolowska A, Borowska M, Iskakova S, Dworacki G. Statins in low doses reduce VEGF and bFGF serum levels in patients with type 2 diabetes mellitus. Pharmacology 2014; 93: 32-38.
  • 18. Takahashi Y, Satoh M, Tabuchi T, Nakamura M. Prospective, randomized, single-blind comparison of effects of 6 months’ treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in patients with coronary artery disease. Heart Vessels 2012; 27: 337-343.
  • 19. Chen J, Liu B, Yuan J, Yang J, Zhang J, An Y, Tie L, Pan Y, Li X. Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non-small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production. Mol Oncol 2012; 6: 62-72.
  • 20. Bifulco M, Laezza C, Aloj SM. Inhibition of farnesylation blocks growth but not differentiation in FRTL-5 thyroid cells. Biochimie 1999; 81: 287-290.
  • 21. Vitale M, Di Matola T, Rossi G, Laezza C, Fenzi G, Bifulco M. Prenyltransferase inhibitors induce apoptosis in proliferating thyroid cells through a p53-independent CrmA-sensitive, and caspase-3-like protease-dependent mechanism. Endocrinology 1999; 140: 698-704.
  • 22. Laezza C, Mazziotti G, Fiorentino L, Gazzerro P, Portella G, Gerbasio D, Carella C, Matarese G, Bifulco M. HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway. J Mol Med (Berl) 2006; 84: 967-973.
  • 23. Zeybek ND, Gulcelik NE, Kaymaz FF, Sarisozen C, Vural I, Bodur E, Canpinar H, Usman A, Asan E. Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells. J Endocrinol 2011; 210: 105-115.
  • 24. Cappelli C, Castellano M, Pirola I, De Martino E, Gandossi E, Delbarba A, Salvi A, Rosei EA. Reduced thyroid volume and nodularity in dyslipidaemic patients on statin treatment. Clin Endocrinol (Oxf) 2008; 68: 16-21.
  • 25. Sari R, Balci MK, Altunbas H, Karayalcin U. The effect of body weight and weight loss on thyroid volume and function in obese women. Clin Endocrinol (Oxf) 2003; 59: 258-262.
  • 26. Michalaki MA, Vagenakis AG, Leonardou AS, Argentou MN, Habeos IG, Makri MG, Psyrogiannis AI, Kalfarentzos FE, Kyriazopoulou VE. Thyroid function in humans with morbid obesity. Thyroid 2006; 16: 73-78.
  • 27. De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. Clin Endocrinol (Oxf) 2007; 67: 265-269.
  • 28. Chon MG, Suk JH, Oh KH, Kim KI, Kim YJ, Lee HG, Kim SM, Cho KI, Kim MK, Kim TI. Influence of long-term statin use in type 2 diabetic patients on thyroid nodularity in iodine-sufficient area. Exp Clin Endocrinol Diabetes 2011; 119: 497-501.
  • 29. Jebreel A, England J, Bedford K, Murphy J, Karsai L, Atkin S. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathol 2007; 88: 271-277.
  • 30. Deshpande H, Roman S, Thumar J, Sosa JA. Vandetanib (ZD6474) in the treatment of medullary thyroid cancer. Clin Med Insights Oncol 2011; 5: 213-221.
  • 31. Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 2007; 92: 3531-3534.
  • 32. Araujo FA, Rocha MA, Mendes JB, Andrade SP. Atorvastatin inhibits inflammatory angiogenesis in mice through down regulation of VEGF, TNF-α and TGF-β1. Biomed Pharmacother 2010; 64: 29-34.
  • 33. Giurgea AG, Margeta C, Maca T, Rezaie-Majd A, Bucek RA, Manavi M, Afarideh R, Minar E, Baghestanian M. Simvastatin reduces serum level of vascular endothelial growth factor in hypercholesterolemic patients. J Cardiovasc Pharmacol 2006; 47: 30-36.
  • 34. Trapé J, Morales C, Molina R, Filella X, Marcos JM, Salinas R, Franquesa J. Vascular endothelial growth factor serum concentrations in hypercholesterolemic patients. Scand J Clin Lab Invest 2006; 66: 261-267.
  • 35. Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res 2002; 90: 737- 744.