Metformin and L-Carnitine in Thyroid Hormone Suppression Therapy

by Jacob Schor, ND, FABNO

There is a decent chance that the prescription drug metformin, commonly used to treat diabetes, may prove useful in the long-term treatment of thyroid cancer. Several papers report that metformin suppresses the production of thyroid stimulating hormone (TSH). By doing so, metformin may be a useful addition to the TSH suppression therapy aimed at preventing thyroid cancer recurrence. The amino acid L-carnitine may also have utility by reducing the discomforts that these patients experience resulting from treatment. TSH suppression, typically achieved by taking excessive doses of thyroid hormone, has for many years been a common, though debated, treatment for thyroid cancer.

Approximately 56,460 new cases of thyroid cancer will be (or were) diagnosed in the US in 2012 and about 1780 deaths (will) result(ed) from thyroid cancer.¹

Most of those people diagnosed will undergo thyroidectomy, a surgery to remove their thyroid gland. Many of these patients will then have any remaining thyroid tissue destroyed with oral doses of radioactive iodine. All of these people will end up taking supplemental thyroid hormone for life. Many of these people, particularly those with more aggressive cancers, will be prescribed thyroid hormone at doses high enough to suppress nearly all TSH production.

TSH suppressive doses of thyroid hormone are also used in treating of benign thyroid nodules. Although this treatment has not been proven effective for this condition and is becoming increasingly controversial, “ … approximately half of endocrinologists recently surveyed in Europe and North America indicated that they would use TSH-suppressive therapy in the management of typical cases of benign nodular thyroid.”²

There are also some practitioners who suggest TSH suppression in the treatment of malignant melanoma. This idea is in response to two reports from researchers at MD Anderson. In August 2004, a paper by Ellerhost et al reported that melanoma cells were sensitive to thyrotopin-releasing hormone, the hormone that stimulates TSH production.³ In a 2006 paper, Ellerhost focused on TSH instead and concluded, “Taken together, these data support the hypothesis that TSH is a growth factor for human melanoma.” ⁴

In a certain instances, specific cancers respond to the same stimuli that regulate the tissue from which they originated. Breast cancer responds to estrogen. Prostate cancer responds to testosterone. These hormones stimulate these cancers to grow faster. Thyroid cancer is one of these cancers that respond to specific regulating hormones made in the body. Thyroid cancer, to no one’s great surprise, is stimulated by TSH, just as healthy thyroid tissue is.

Many thyroid cancers contain membrane receptors for TSH. When stimulated by TSH, these tumors take-up radioactive iodine faster, secrete more thyroglobulin, grow in size, and show signs of progression. Thus it has become common therapy to give patients with thyroid cancer enough thyroid hormone to lower their TSH into a range typically seen with hyperthyroid disease. The rationale for doing this is simple enough. The cost is minimal, the side effects are not overly serious, and logically it should reduce disease recurrence. ⁵

That was the rationale at least in 1991. This practice it turns out is not totally without side effects. In a June 2012 report, slightly over 10% of patients receiving suppressive doses of thyroid developed atrial fibrillation.⁶

TSH suppression may also negatively affect bone density. Studies have varied but the consensus is that TSH suppression will lead to decreased bone density in postmenopausal women.^7,8 Still this may not be that big a deal. A 2011 paper that reviewed the long-term consequences concluded:

There are many studies on the potential harmful effects of suppressive therapy on various organs and systems with discrepant results. However, there is no scientific evidence that the clinical impact of these effects is significant.⁹

Perhaps a greater concern than side effects is that the actual benefit of being on TSH suppression therapy for many patients is not clear, at least for those at low risk of recurrence. A 2005 paper reported no improvement in those with low-risk cancer, and suggested, “Only selected patients with high-risk papillary and follicular thyroid cancer require long-term TSH-suppressive doses. … In these patients, careful monitoring is necessary to avoid undesirable effects on bone and heart.”¹⁰

A 2010 paper found negligible benefit as well when measuring impact. Disease free survival (DFS) “ … for patients without TSH suppression was not inferior by more than 10% to DFS for patients with TSH suppression. Thyroid-conserving surgery without TSH suppression should be considered for patients with low-risk PTC [papillary thyroid carcinoma] to avoid potential adverse effects of TSH suppression.”¹¹

These days there is a fair bit of talk in the journals about risk versus benefit in deciding whether a patient should be put on long-term TSH suppression.

More aggressive TSH suppression is now suggested for patients with high-risk disease or recurrent tumor, whereas less aggressive TSH suppression is reasonable in low-risk patients. Cancer risk should be individualized and balanced against the potential for adverse effects. In patients with an intermediate risk for thyroid cancer recurrence and a high risk of adverse effects of therapy, the degree of TSH suppression should be reevaluated during the follow-up period. Normalization of serum TSH is advisable for long-term treatment of disease-free elderly patients with [differentiated thyroid cancer]  … and significant comorbidities. …¹²

In this same 2012 paper, Bernadette Biondi et al. go so far as to define nine potential patient categories varying with disease risk and side-effect potential, each with differing TSH targets for both initial and long-term L-T4 therapy. The higher the risk or recurrence of an aggressive tumor, the lower target TSH is suggested.

Whether or not this is a useful treatment in all situations, there are still a great many patients being treated with TSH-suppressive doses of thyroid. Though this treatment may not be as dangerous as once thought, few patients like it. To achieve TSH suppression necessitates doses of thyroid hormone that make the patient feel subjectively as if they were hyperthyroid. They come in to the office and “ … complain of symptoms such as anxiety, heat intolerance, tremors, sweaty skin, insomnia, forgetfulness, or mood disorders.”¹³

It is in this clinical situation, that a number of recent papers on metformin are so interesting. Metformin, it turns out, appears to lower TSH without changing thyroid hormone levels.

In 2006, Vigersky et al. from the Walter Reed Army Hospital reported this effect on TSH and were the first to suggest that “ … metformin’s ability to suppress TSH without causing clinical or chemical hyperthyroidism might render this drug a useful adjunct to the treatment of patients with thyroid cancer.”¹⁴

Isidro et al confirmed this TSH lowering effect in August 2007 “ … in obese, diabetic patients with primary hypothyroidism.”¹⁵ Capelli et al. reported similar findings in 2009 this time in hypothyroid diabetics.¹⁶ Rotundi found a similar TSH-lowering effect in women treated for polycystic ovarian syndrome (PCOS) and reported it in 2011. The only thyroid parameter that changes with addition of metformin is TSH decreasing. There are no changes in free T4 level.¹⁷

Two large retrospective studies on metformin and TSH were published in August 2012. Oddly, in contrast to all these other papers, a study by Díez and Iglesias from Madrid found no association between TSH and metformin.¹⁸ A second retrospective study by Cappelli et al. did find a significant reduction in TSH in euthyroid patients associated with metformin use.¹⁹

The potential of using metformin in patients on TSH suppression therapy is obvious. To quote another August 2012 paper, “To find a drug with few if any side effects that inhibited TSH appeared a very attractive option, as such drugs might become useful in the treatment of thyroid cancer patients where sometimes the desired TSH suppression is achieved at the expense of unwanted iatrogenic hyperthyroidism, resulting from excess dose of thyroxine” ²⁰

Although metformin is sold as a prescription drug, it may be considered a modern cousin of the plant goat’s rue (Galega officinalis). This plant has a long history of use in treating diabetes, its use dating back to ancient Egypt.²¹

While metformin has been prescribed in Britain since 1958 and in Canada since 1972, it has only been used in the US since 1995. Metformin is widely used; 120 million prescriptions are written for it each year.²²

In recent years there has been considerable interest in using metformin to treat cancer. “Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer.”²³ Thus it is possible that metformin could also have a direct anti-thyroid-cancer impact on its own.

An April 2012 paper that examined impact of metformin on various thyroid cancer cell lines concluded, “Our results suggest this drug as adjuvant treatment for thyroid cancer in type 2 diabetic patients.”²⁴ Another paper, this one published in May 2012, reported on the mechanics of how “metformin inhibits growth  … in medullary thyroid cancer cells.”²⁵

While discussing the care of patients undergoing TSH suppression, some mention must be made of L-carnitine, as it may also play a role in helping this patient population. While this amino acid in itself does not suppress TSH, it does seem to reduce the impact of thyroid hormone, making high dose thyroid hormone treatment more tolerable.

This idea is an extrapolation of Salvatore Benvenga’s work on L-carnitine and hyperthyroidism. Since 2000, Benvenga has been suggesting that L-carnitine can block thyroid hormone action on the cells. It actually appears to prevent both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei.²⁶ Moreover, “L-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a beneficial effect on bone mineralization.”²⁷

From Benvenga’s 2004 paper: “We showed that 2 and 4 grams per day of oral L-carnitine are capable of reversing hyperthyroid symptoms (and biochemical changes in the hyperthyroid direction.”²⁸

Thus, it has been common for us to use L-carnitine to ameliorate some of the side effects of the TSH suppression therapy thyroid cancer patients are often subjected to.

Thus we have two relatively safe tools to offer thyroid cancer patients (and possibly others) that may make their treatment more tolerable and possibly more successful. Obviously using metformin to treat cancer is still considered an off-label use. These new publications should, at the least, certainly encourage us to thoroughly rule out diabetes in all patients treated with TSH-suppressive doses of thyroid hormone.

Notes

1. Thyroid cancer [Web page]. National Cancer Institute. http://www.cancer.gov/cancertopics/types/thyroid.

2. Pearce E, Braverman L. Clinical use of TSH suppression: why, when, and how?

Hot Thyroidol. January 2005;1. Available at www.hotthyroidology.com.

3. Ellerhorst JA, Naderi AA, Johnson MK, et al. Expression of thyrotropin-releasing hormone by human melanoma and nevi. Clin Cancer Res. 2004 Aug 15;10(16):5531–5536.

4. Ellerhorst JA, Sendi-Naderi A, Johnson MK, Cooke CP, Dang SM, Diwan AH. Human melanoma cells express functional receptors for thyroid-stimulating hormone. Endocr Relat Cancer. 2006 Dec;13(4):1269–1277.

5. Thomas CG Jr. Role of thyroid stimulating hormone suppression in the management of thyroid cancer. Semin Surg Oncol. 1991 Mar–Apr;7(2):115–119.

6. Abonowara A, Quraishi A, Sapp JL, et al. Prevalence of atrial fibrillation in patients taking TSH suppression therapy for management of thyroid cancer. Clin Invest Med. 2012 Jun 1;35(3):E152–E156.

7. Chen CH, Chen JF, Yang BY, et al. Bone mineral density in women receiving thyroxine suppressive therapy for differentiated thyroid carcinoma. J Formos Med Assoc. 2004 Jun;103(6):442–447.

8. Sugitani I, Fujimoto Y. Effect of postoperative thyrotropin suppressive therapy on bone mineral density in patients with papillary thyroid carcinoma: a prospective controlled study. Surgery. 2011 Dec;150(6):1250–1257.

9. Reverter JL, Colomé E. Potential risks of the adverse effects of thyrotropin suppression in differentiated thyroid carcinoma. [In Spanish.] Endocrinol Nutr. 2011 Feb;58(2):75–83.

10. Biondi B, Filetti S, Schlumberger M. Thyroid-hormone therapy and thyroid cancer: a reassessment. Nat Clin Pract Endocrinol Metab. 2005 Nov;1(1):32–40.

11. Sugitani I, Fujimoto Y. Does postoperative thyrotropin suppression therapy truly decrease recurrence in papillary thyroid carcinoma? A randomized controlled trial. J Clin Endocrinol Metab. 2010 Oct;95(10):4576–8453. Epub 2010 Jul 21.

12. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid. 2010 Feb;20(2):135–146.

13. Pearce and Braverman. Op. cit.

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16. 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 Sep;32(9):1589–1590.

17. Rotondi M, Cappelli C, Magri F, Botta R, Dionisio R, Iacobello C, et al. Thyroidal effect of metformin treatment in patients with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2011 Sep;75(3):378–381.

18. Díez JJ, Iglesias P. Relationship between serum thyrotropin concentrations and metformintherapy in euthyroid patients with type 2 diabetes. Clin Endocrinol (Oxf). 2012 Jun 12.

19. Cappelli C, Rotondi M, Pirola I, et al. Thyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol. 2012 Aug;167(2):261–5. Epub 2012 May 29.

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24. 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 Apr;97(4):E510–E520. Epub 2012 Jan 25.

25. Klubo-Gwiezdzinska J, Jensen K, Costello J, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer. 2012 May 24;19(3):447–456. Print 2012 Jun.

26. Benvenga S, Lakshmanan M, Trimarchi F. Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. Thyroid. 2000 Dec;10(12):1043–1050.

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