Dr. Ron’s Research Review – June 6, 2012

This week’s research review focuses on Metformin's effect on hormones.

Metformin has been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism. Metformin caused suppression of TSH to subnormal levels without clinical symptoms of hyperthyroidism in any patients.  (Vigersky, Filmore-Nassar et al. 2006) (Isidro, Penin et al. 2007) (Cappelli, Rotondi et al. 2009)

Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males. (Shegem, Nasir et al. 2002)

Dr. Ron


Abstracts

TSH-lowering effect of metformin in type 2 diabetic patients

         (Cappelli, Rotondi et al. 2009) Download

OBJECTIVE: To assess the interplay between metformin treatment and thyroid function in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: The acute and long-term effects of metformin on thyroid axis hormones were assessed in diabetic patients with primary hypothyroidism who were either untreated or treated with levothyroxine (L-T4), as well as in diabetic patients with normal thyroid function. RESULTS: No acute changes were found in 11 patients with treated hypothyroidism. After 1 year of metformin administration, a significant thyrotropin (TSH) decrease (P < 0.001) was observed in diabetic subjects with hypothyroidism who were either treated (n = 29; from 2.37 +/- 1.17 to 1.41 +/- 1.21 mIU/l) or untreated (n = 18; 4.5 +/- 0.37 vs. 2.93 +/- 1.48) with L-T4, but not in 54 euthyroid subjects. No significant change in free T4 (FT4) was observed in any group. CONCLUSIONS: Metformin administration influences TSH without change of FT4 in patients with type 2 diabetes and concomitant hypothyroidism. The need for reevaluation of thyroid function in these patients within 6-12 months after starting metformin is indicated.

Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy

          (Isidro, Penin et al. 2007) Download

Context It has been reported that metformin might modify thyroid hormone economy. In two retrospective studies, initiation of treatment with metformin caused suppression of TSH to subnormal levels. Objective To prospectively evaluate if administration of metformin to obese, diabetic patients with primary hypothyroidism on stable thyroxine replacement doses modifies TSH levels. Patients and methods Eight obese, diabetic postmenopausal women with primary hypothyroidism participated in the study. They received 1,700 mg of metformin daily for 3 months. Weight, TSH, free T4, and free T3 levels were measured at baseline, 3 months after metformin initiation and 3 months after its withdrawal. Results After 3 months of on metformin, mean TSH was significantly lower than basal TSH (3.11 +/- 0.50 microUI/ml vs. 1.18 +/- 0.36 microUI/ml; P = 0.01). Mean TSH 3 months after metformin withdrawal was 2.21 +/- 0.37 microUI/ml, significantly higher than TSH after metformin (P = 0.05), but not different from basal TSH. Mean fT4 level increased during metformin administration (basal fT4: 1.23 +/- 0.06 ng/dl, fT4 after metformin: 1.32 +/- 0.04 ng/dl; P = ns), and decreased after its withdrawal (fT4 3 months after metformin withdrawal: 1.15 +/- 0.05 ng/dl; vs. 3 months after metformin, P = 0.04; vs. basal; P = ns). Conclusions In obese, diabetic patients with primary hypothyroidism on thyroxine replacement treatment, short-term metformin administration is associated with a significant fall in TSH.

Effects of short term metformin administration on androgens in normal men

         (Shegem, Nasir et al. 2002) Download

OBJECTIVE: To study the effect of metformin on androgens in normal men. METHODS: A total of 12 healthy males volunteered to participate in the study. A blood sample was obtained from each of them and analyzed for the following: Testosterone (total and free), sex hormone binding globulin dehydroepiandrosterone sulphate, 17-hydroxyprogesterone, luteinizing hormone, and follicle stimulating hormone. In addition, each participant was subjected to a glucose tolerance test and his insulin level was measured. Metformin 850 mg twice daily for 2-weeks was given to each subject after which the above tests were repeated. A paired t-test was used to assess the statistical significance of any observed differences before and after metformin. RESULTS: After metformin administration, there was a significant reduction in serum level of total testosterone (p=0.0001), free testosterone (P=0.002), and 17 hydroxyprogesterone (p=0.0001). There was also a significant increase in serum level of sex hormone binding globulin (p=0.009) and dehydroepiandrosterone sulphate (P=0.0008). Serum levels of luteinizing hormone and follicle stimulating hormone showed no significant changes. Similarly, there were no changes in fasting plasma glucose, fasting serum insulin, weight, or blood pressure. CONCLUSION: Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males. The clinical significance of these findings needs further investigation.

Thyrotropin suppression by metformin

         (Vigersky, Filmore-Nassar et al. 2006) Download

CONTEXT: Drug-drug interactions are common but often are discovered only long after initial drug release. Metformin has been available in the United States for 9 yr and elsewhere for many years, but as of yet there are no reports that the drug modifies thyroid hormone economy. OBJECTIVE: The objective of the study was to describe the clinical and biochemical findings of four patients with chronic hypothyroidism, previously euthyroid on fixed doses of L-T4 for several years, in whom the metformin was initiated. DESIGN: This was a retrospective review. SETTING: The study was conducted at a tertiary care military hospital providing care to active-duty soldiers, sailors, and marines, retirees of the armed forces, and their eligible dependents. PARTICIPANTS: Four patients with chronic hypothyroidism who were placed on metformin participated in the study. INTERVENTION, MAIN OUTCOME MEASURE: Serum TSH, free T4, and free T3 levels were measured during metformin treatment. RESULTS: Initiation of treatment with metformin (three for diabetes mellitus and one for nonalcoholic steatohepatitis) caused suppression of TSH to subnormal levels without clinical symptoms of hyperthyroidism in any patients. There was no change in free T4 or free T3 in patient 1. CONCLUSIONS: No other potential causes of TSH suppression, including medication changes or interference in the TSH assay, could be identified. The mechanism of the fall in serum TSH in these four patients is unclear at this time. Should these findings be confirmed in larger prospective studies, 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.


References

Cappelli, C., M. Rotondi, et al. (2009). "TSH-lowering effect of metformin in type 2 diabetic patients: differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients." Diabetes Care 32(9): 1589-90.

Isidro, M. L., M. A. Penin, et al. (2007). "Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy." Endocrine 32(1): 79-82.

Shegem, N. S., A. M. Nasir, et al. (2002). "Effects of short term metformin administration on androgens in normal men." Saudi Med J 23(8): 934-7.

Vigersky, R. A., A. Filmore-Nassar, et al. (2006). "Thyrotropin suppression by metformin." J Clin Endocrinol Metab 91(1): 225-7.