The Effect of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Women with Interferon-Induced Hypothyroidism: A Pilot Study

 

 Buy Article Permissions and Reprints

Abstract

Background: One of the most frequent adverse effects of interferon-α therapy is thyroiditis. Metformin was found to improve insulin sensitivity in hepatitis C patients, as well as to reduce elevated thyrotropin levels in patients with hypothyroidism. The aim of this study was to investigate the effect of metformin on hypothalamic-pituitary-thyroid axis activity in patients with interferon-induced thyroiditis.

Methods: The study included 2 matched groups of women with type 2 diabetes and untreated subclinical hypothyroidism: patients with interferon-induced thyroiditis (n=8) and patients with Hashimoto’s thyroiditis (n=12). Fasting plasma glucose, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), glycated hemoglobin, the estimated glomerular filtration rate, as well as serum levels of thyrotropin, thyroid hormones, prolactin and insulin-like growth factor-1 (IGF-1) were assessed at baseline and after 4 months of metformin treatment.

Results: Apart from reducing plasma glucose, HOMA1-IR and glycated hemoglobin, metformin decreased serum levels of thyrotropin. Circulating levels of thyroid hormones, prolactin and IGF-1 remained at a similar level throughout the study. The effect of metformin on serum thyrotropin was stronger in patients with interferon-induced thyroiditis than in patients with Hashimoto’s thyroiditis, as well as correlated with its impact on insulin sensitivity.

Conclusions: Our results indicate that metformin may be an effective agent in patients with interferon-induced hypothyroidism.

• References

• 1 Kaddai V, Negro F. Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 2011; 5: 503-516
  CrossrefPubMedGoogle Scholar
• 2 Bose SK, Ray R. Hepatitis C virus infection and insulin resistance. World J Diabetes 2014; 5: 52-58
  CrossrefPubMedGoogle Scholar
• 3 American Diabetes Association . Standards of medical care in diabetes – 2015. Approaches to glycemic treatment. Diabetes Care 2015; 38 (Suppl. 01) S42-S48
  PubMedGoogle Scholar
• 4 Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008; 5: 157-167
  CrossrefPubMedGoogle Scholar
• 5 Hsu CS, Hsu SJ, Lin HH et al. A pilot study of add-on oral hypoglycemic agents in treatment-naïve genotype-1 chronic hepatitis C patients receiving peginterferon alfa-2b plus ribavirin. J Formos Med Assoc 2014; 113: 716-721
  CrossrefPubMedGoogle Scholar
• 6 Romero-Gómez M, Diago M, Andrade RJ et al. Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin. Hepatology 2009; 50: 1702-1708
  CrossrefPubMedGoogle Scholar
• 7 García-Ruiz I, Solís-Muñoz P, Gómez-Izquierdo E et al. Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice. J Biol Chem 2012; 287: 19564-19573
  CrossrefPubMedGoogle Scholar
• 8 Nkontchou G, Cosson E, Aout M et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011; 96: 2601-2608
  CrossrefPubMedGoogle Scholar
• 9 Menconi F, Hasham A, Tomer Y. Environmental triggers of thyroiditis: hepatitis C and interferon-α. J Endocrinol Invest 2011; 34: 78-84
  CrossrefPubMedGoogle Scholar
• 10 Tomer Y, Menconi F. Interferon induced thyroiditis. Best Pract Res Clin Endocrinol Metab 2009; 23: 703-712
  CrossrefPubMedGoogle Scholar
• 11 Tomer Y. Hepatitis C and interferon induced thyroiditis. J Autoimmun 2010; 34: J322-J326
  CrossrefPubMedGoogle Scholar
• 12 Vigersky RA, Filmore-Nassar A, Glass AR. Thyrotropin suppression by metformin. J Clin Endocrinol Metab 2006; 91: 225-227
  CrossrefPubMedGoogle Scholar
• 13 Cappelli C, Rotondi M, Pirola I et al. TSH-lowering effect of metformin in type 2 diabetic patients: differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care 2009; 32: 1589-1590
  CrossrefPubMedGoogle Scholar
• 14 Isidro ML, Penín MA, Nemiña R et al. Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine 2007; 32: 79-82
  CrossrefPubMedGoogle Scholar
• 15 Morteza Taghavi S, Rokni H, Fatemi S. Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism. Diab Vasc Dis Res 2011; 8: 47-48
  CrossrefPubMedGoogle Scholar
• 16 Lupoli R, Di Minno A, Tortora A et al. Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies. J Clin Endocrinol Metab 2014; 99: E143-E148
  CrossrefPubMedGoogle Scholar
• 17 Krysiak R, Okopien B. The effect of metformin on the hypothalamic-pituitary-thyroid axis in women with polycystic ovary syndrome and subclinical hypothyroidism. J Clin Pharmacol 2015; 55: 45-49
  CrossrefPubMedGoogle Scholar
• 18 Krysiak R, Okopien B. Thyrotropin-lowering effect of metformin in a patient with resistance to thyroid hormone. Clin Endocrinol 2011; 75: 404-406
  CrossrefPubMedGoogle Scholar
• 19 Cappelli C, Rotondi M, Pirola I et al. Metformin-induced thyrotropin suppression is not associated with cardiac effects. Hormones (Athens) 2014; 13: 252-258
  PubMedGoogle Scholar
• 20 Krysiak R, Szkrobka W, Okopien B. The effect of metformin on the hypothalamic-pituitary-thyroid axis in patients with type 2 diabetes and subclinical hyperthyroidism. Exp Clin Endocrinol Diabetes 2015;
  PubMedGoogle Scholar
• 21 Oleandri SE, Maccario M, Rossetto R et al. Three-month treatment with metformin or dexfenfluramine does not modify the effects of diet on anthropometric and endocrine-metabolic parameters in abdominal obesity. J Endocrinol Invest 1999; 22: 134-140
  CrossrefPubMedGoogle Scholar
• 22 Labbuzek K, Suchy D, Gabryel B et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2010; 62: 956-965
  CrossrefPubMedGoogle Scholar
• 23 Krysiak R, Okrzesik J, Okopien B. The effect of short-term metformin treatment on plasma prolactin levels in bromocriptine-treated patients with hyperprolactinaemia and impaired glucose tolerance: a pilot study. Endocrine 2014;
  PubMedGoogle Scholar
• 24 Oride A, Kanasaki H, Purwana IN et al. Effects of metformin administration on plasma gonadotropin levels in women with infertility, with an in vitro study of the direct effects on the pituitary gonadotrophs. Pituitary 2010; 13: 236-241
  CrossrefPubMedGoogle Scholar
• 25 Genazzani AD, Battaglia C, Malavasi B et al. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril 2004; 81: 114-119
  CrossrefPubMedGoogle Scholar
• 26 Weissenborn K, Ennen JC, Bokemeyer M et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut 2006; 55: 1624-1630
  CrossrefPubMedGoogle Scholar
• 27 Felger JC, Li L, Marvar PJ et al. Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations. Brain Behav Immun 2013; 31: 153-160
  CrossrefPubMedGoogle Scholar
• 28 Brabant G, Ocran K, Ranft U et al. Physiological regulation of thyrotropin. Biochimie 1989; 71: 293-301
  CrossrefPubMedGoogle Scholar
• 29 Cappelli C, Rotondi M, Pirola I et al. Thyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol 2012; 167: 261-265
  PubMedGoogle Scholar
• 30 Krysiak R, Gdula-Dymek A, Okopień B. Lymphocyte-suppressing, endothelial-protective and systemic anti-inflammatory effects of metformin in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep 2013; 65: 429-434
  CrossrefPubMedGoogle Scholar
• 31 Krysiak R, Gdula-Dymek A, Okopień B. Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep 2013; 65: 1311-1316
  CrossrefPubMedGoogle Scholar
• 32 Krysiak R, Gdula-Dymek A, Okopien B. Effect of simvastatin and fenofibrate on cytokine release and systemic inflammation in type 2 diabetes mellitus with mixed dyslipidemia. Am J Cardiol 2011; 107: 1010-1018
  CrossrefPubMedGoogle Scholar
• 33 Ittermann T, Markus MR, Schipf S et al. Metformin inhibits goitrogenous effects of type 2 diabetes. Eur J Endocrino 2013; 169: 9-15
  PubMedGoogle Scholar
• 34 Rezzónico J, Rezzónico M, Pusiol E et al. Metformin treatment for small benign thyroid nodules in patients with insulin resistance. Metab Syndr Relat Disord 2011; 9: 69-75
  CrossrefPubMedGoogle Scholar
• 35 Chen G, Xu S, Renko K et al. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab 2012; 97: E510-E512
  CrossrefPubMedGoogle Scholar
• 36 López M, Varela L, Vázquez MJ et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010; 16: 1001-1008
  CrossrefPubMedGoogle Scholar
• 37 Duntas LH, Orgiazzi J, Brabant G. The interface between thyroid and diabetes mellitus. Clin Endocrinol 2011; 75: 1-9
  CrossrefPubMedGoogle Scholar
• 38 Chau-Van C, Gamba M, Salvi R et al. Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology 2007; 148: 507-511
  CrossrefPubMedGoogle Scholar
• 39 Szybiński Z. Polish Council for Control of Iodine Deficiency Disorders. Work of the Polish Council for Control of Iodine Deficiency Disorders, and the model of iodine prophylaxis in Poland. Endokrynol Pol 2012; 63: 156-160
  PubMedGoogle Scholar