|Year : 2012 | Volume
| Issue : 3 | Page : 75-77
Metformin and the thyroid: An unexplored therapeutic option
Sanjay Kalra1, Puneet Dhamija2, Ambika Gopalakrishnan Unnikrishnan3
1 Department of Endocrinology, Bharti Hospital and BRIDE, Karnal, Haryana, India
2 Department of Pharmacology, Post-Graduate Institute of Medical Sciences, Rohtak, Haryana, India
3 Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, India
|Date of Web Publication||11-Aug-2012|
Ambika Gopalakrishnan Unnikrishnan
Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kalra S, Dhamija P, Unnikrishnan AG. Metformin and the thyroid: An unexplored therapeutic option. Thyroid Res Pract 2012;9:75-7
|How to cite this URL:|
Kalra S, Dhamija P, Unnikrishnan AG. Metformin and the thyroid: An unexplored therapeutic option. Thyroid Res Pract [serial online] 2012 [cited 2017 Mar 25];9:75-7. Available from: http://www.thetrp.net/text.asp?2012/9/3/75/99642
| Introduction|| |
As metformin completes a century of existence as a molecule and over half a century in clinical use, we keep on discovering newer facets of its personality.  It is rightly described as a molecule with mid-life maturity, yet excluding modern charm. Newer indications, some approved, others unapproved, have been found for this drug, and while the list of contra indications seems to be shrinking.
Metformin is now used not only for the prevention and treatment of various disorders with hyperglycemia, but also for managing other metabolic, endocrine and non- endocrine diseases [Table 1]. The effect of metformin as a gero protective agent, as an anti-neoplastic drug, and as therapy for metabolic syndrome has been discussed in details earlier.  Ongoing medical research is opening up new dimensions of metformin pharmacology. Co-existence of hypothyroidism and diabetes has been documented in a number of epidemiological studies. ,, Moreover, hypothyroidism may be associated with polycystic ovarian syndrome (PCOS)  and obesity.  With metformin being a key component of management of these disorders, it is prudent to explore its actions on various aspects of thyroid physiology. While rapid advances have been made in elucidating the mechanism of anti-hyperglycemic action of metformin up to the subcellular or mitochondrial level,  we have not moved beyond speculation while discussing the mechanism of action of metformin on thyroid economy. This editorial focuses on this neglected, yet important, aspect of metformin pharmacology.
| Metformin and Hypothyroidism|| |
A retrospective review of four patients with chronic hypothyroidism, who were prescribed metformin (three for diabetes, one for nonalcoholic steatohepatitis) revealed interesting findings. Use of metformin for a duration varying from 2 to 8 months led to suppression of TSH to subnormal levels in all patients without clinical symptoms of hypothyroidism.  A prospective study  in eight obese diabetic women on stable doses of thyroxin replacement also showed significant reduction in mean TSH level 3 months after initiation of metformin which returned to baseline 3 months after cessation of therapy. Mean free T4 levels also changed in accordance with variation in TSH.
Cappelli et al, conducted a larger prospective proof of concept study in groups of euthyroid diabetics, diabetics with subclinical and overt primary hypothyroidism.  Authors concluded that TSH lowering effect of metformin was seen in only hypothyroid patients only irrespective of thyroxin replacement and was not associated with effects on thyroid functions.
Capelli et al, also reported results of a retrospective study done on 393 euthyroid diabetic patients, divided into three groups: 119 subjects never treated with metformin and L-thyroxin; 203 subjects who started only metformin at recruitment; and 71 patients on L-thyroxin who started metformin at recruitment.  Significant reduction in TSH levels was seen in all patients treated with both metformin and L-thyroxin, and in those patients on metformin who had a baseline TSH higher than 2.5 mIU/l. This finding was independent of the presence or absence of thyroid peroxidase antibodies. The results of this large study will certainly generate interest in this field, and may not be the last word in the metformin-thyroidology saga.
In an animal study, metformin has been used to induce hypothyroidism in type 2 diabetic animals. Metformin in dose of 150 mg/kg reduced circulating T4 levels and caused severe hypothyroidism. 
| Mechanism of Action|| |
The mechanisms responsible for these findings remain an enigma although a number of hypotheses have been put forward.  These include an increase in number or sensitivity of thyroid receptors, an increase in dopaminergic tone, and activation of the TSH receptor. Other authors suggest that metformin potentiates the negative feedback of thyroid hormones on TSH, or ameliorates/improves thyroid function reserve in hypothyroid patients. 
In recent years, major advances have been made in unraveling the subcellular actions of metformin. The research has focused on exploring the anti-hyperglycemic actions of metformin. Activation of AMP-activated protein kinase  or enhanced uptake of Ca 2+ by mitochondria in hepatocytes by metformin  reduces glucose output from liver. Possibly similar mechanisms are responsible in cells of hypothalamus or pituitary for reduced TSH output. Additionally, the role of co-regulators in cells producing TSH and those involved in negative feedback loop of thyroid hormones cannot be ruled out.  Co-regulators possibly modify the output of TSH from these cells following binding of thyroxin with nuclear receptors.
| Metformin and Thyroid Cancer|| |
The beneficial effects of metformin on thyroid economy are not limited to hypothyroidism. In vitro data is available to support its use in other thyroid diseases as well. A study on thyroid carcinoma cell lines showed inhibitory actions of metformin on cell cycle progression and growth-stimulatory actions of insulin. The same study also showed metformin induced induction of apoptosis and potentiation of actions of doxorubicin and cisplatin.  Other researchers have explored growth inhibitory actions of metformin mediated by mammalian Target of Rapamycin (mTOR) and cyclin D1 in cell lines. 
| Clinical Implications and Conclusion|| |
The clinical implications, and public health impact, of these findings are enormous. The rising prevalence of metabolic syndrome, type 2 diabetes mellitus and associated hypothyroidism pose a challenging clinical situation. Metformin is the first line of management in patients with type 2 diabetes mellitus and forms an indispensable part of prescription for metabolic syndrome. The effects of metformin on thyroid functions can be a boon to multiple endocrine disorders. Thyroid functions in case of co-existing diabetes and metabolic syndrome with hypothyroidism can be managed to a great extent by using a single drug. In some patients, no obvious cause for poor control is found, in spite of administering high doses of L- thyroxin. Yet other patients complain of dissatisfaction with treatment protocols and clinical outcomes, though they are biochemically euthyroid.  There is another, large, subset of patients, with subclinical hypothyroidism, whose treatment poses a clinical dilemma to the endocrinologist. Many well controlled hypothyroid patients, who are biochemically and clinically euthyroid, fit the definition of metabolic syndrome.  In these patients, too, metformin may offer additional metabolic benefits and long term advantages. In all these groups, metformin may emerge as an adjuvant therapy for selected patients. The use of metformin may hit two birds with single stone.
The flip side is increasing complexity of monitoring functional status of in diabetic patients on metformin. Low TSH levels may provide false reassurance or may prompt initiation of therapy with TSH levels may be spuriously low which may prompt the endocrinologist to increase L-throxin dose.
Patients with thyroid carcinoma need suppressive therapy with L-thyroxin after surgery and this may be associated with various adverse effects. Metformin may emerge as adjuvant therapy in patients who need TSH suppression after surgical management for thyroid cancer. Metformin may also have potential role as adjuvant therapy in patients undergoing chemotherapy for thyroid malignancy, including medullary thyroid carcinoma.
| References|| |
|1.||Kalra S, Unnikrishnan AG, Sahay R. Metformin and the promise of geroprotection. Indian J Endocr Metab 2012;16:496-8. |
|2.||Andujar-Plata P, Pi-Sunyer X, Laferrere B. Metformin effects revisited. Diabetes Res Clin Pract 2012;95:1-9. |
|3.||Tamez-Perez HE, Martinez E, Quintanilla-Flores DL, Tamez-Pena AL, Gutierrez-Hermosillo H, Diaz de Leon-Gonzalez E. The rate of primary hypothyroidism in diabetic patients is greater than in the non-diabetic population. An observational study. Med Clin (Barc) 2012;138:475-7. |
|4.||Ashrafuzzaman SM, Taib AN, Rahman R, Latif ZA. Prevalence of diabetes among hypothyroid subjects. Mymensingh Med J 2012;21:129-32. |
|5.||Diez JJ, Sanchez P, Iglesias P. Prevalence of thyroid dysfunction in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 2011;119:201-7. |
|6.||Kachuei M, Jafari F, Kachuei A, Keshteli AH. Prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Arch Gynecol Obstet 2012;285:853-6. |
|7.||Rotondi M, Magri F, Chiovato L. Thyroid and obesity: Not a one-way interaction. J Clin Endocrinol Metab 2011;96:344-6. |
|8.||Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: An overview. Clin Sci (Lond) 2012;122:253-70. |
|9.||Vigersky RA, Filmore-Nassar A, Glass AR. Thyrotropin suppression by metformin. J Clin Endocrinol Metab 2006;91:225-7. |
|10.||Isidro ML, Penin MA, Nemina R, Cordido F. Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine 2007;32:79-82. |
|11.||Cappelli C, Rotondi M, Pirola I, Agosti B, Gandossi E, Valentini U, 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;32:1589-90. |
|12.||Cappelli C, Rotondi M, Pirola I, Agosti B, Formenti AM, Zarra E, et al. Thyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol 2012;167:261-5. |
|13.||Jatwa R, Kar A. Amelioration of metformin-induced hypothyroidism by Withania somnifera and Bauhinia purpurea extracts in Type 2 diabetic mice. Phytother Res 2009;23:1140-5. |
|14.||Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-74. |
|15.||Davidoff F, Bertolini D, Haas D. Enhancement of the mitochondrial Ca2+ uptake rate by phenethylbiguanide and other organic cations with hypoglycemic activity. Diabetes 1978;27:757-65. |
|16.||Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000;14:121-41. |
|17.||Chen G, Xu S, Renko K, Derwahl M. 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:E510-20. |
|18.||Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer 2012;19:447-56. |
|19.||Kalra S, Khandelwal SK. Why are our hypothyroid patients unhappy? Is tissue hypothyroidism the answer? Indian J Endocrinol Metab 2011;15(Suppl 2):S95-8. |
|20.||Ogbera AO, Kuku S, Dada O. The metabolic syndrome in thyroid disease: A report from Nigeria. Indian J Endocrinol Metab 2012;16:417-22. |