Thyroidal Effect of Metformin Treatment in Patients With Polycystic Ovary Syndrome

Mario Rotondi; Carlo Cappelli; Flavia Magri; Roberta Botta; Rosa Dionisio; Carmelo Iacobello; Pasquale De Cata; Rossella E. Nappi; Maurizio Castellano; Luca Chiovato

Disclosures

Clin Endocrinol. 2011;75(3):378–381 

In This Article

Discussion

Treatment with metformin in euthyroid patients with PCOS is not associated with significant changes in the serum levels of TSH and FT4. On the other hand, metformin treatment results in a significant reduction in serum TSH concentrations in hypothyroid patients with PCOS, independently from the concomitant substitution therapy with l-thyroxine.

Previous studies reported a significant fall in serum TSH concentrations and a slight, even if not significant, increase in serum FT4 values following initiation of metformin therapy in patients with diabetes and hypothyroidism either treated with l-thyroxine or untreated.[11–13] The mechanisms by which metformin would lead to a lowering of serum TSH levels are still debated. Several mechanisms have hypothesized for explaining this phenomenon: i) a change in the affinity or in the number of TSH receptors; ii) an increase in the central dopaminergic tone; or iii) a direct effect of metformin on TSH regulation. The design of the current study does not allow conclusions to be drawn in this regard, nevertheless the observation that metformin has a TSH-lowering effect also in patients with PCOS and hypothyroidism seems relevant. In particular, the observation that this TSH-lowering effect of metformin also occurs in untreated hypothyroid patients excludes that the effect is because of increased absorption of L-T4 in the gastrointestinal tract. Neither can the TSH-lowering effect be ascribed to the dose of metformin, which was similar in euthyroid as compared with hypothyroid patients with PCOS. Moreover, our findings in euthyroid patients with diabetes[13] and PCOS, and those reported by Oleandri et al.,[15] showing no change of serum thyroid hormones and TSH levels in euthyroid patients with abdominal obesity after 3 months of metformin therapy, would not be in line with the previously hypothesized direct effect of metformin on TSH regulation. Taken together, our results have not disclosed the precise mechanism by which metformin exerts its "thyroid effect", but provide further insights for future investigations.

The amelioration of thyroid function in PCOS patients with subclinical hypothyroidism following initiation of metformin treatment might also be viewed as an adjunctive mechanism by which metformin has beneficial effects in this condition. It is known that hypothyroidism may worsen PCOS by further decreasing the levels of sex hormone–binding globulin and by increasing the conversion of androstenedione to testosterone and its aromatization to oestradiol.[16,17] Thus, correction of hypothyroidism might be helpful for the management of PCOS. If future studies enrolling larger series of patients with PCOS will confirm our observation, a further step in our understanding of the beneficial effect of metformin in these patients might be performed.

In conclusion, the results of this study show that treatment with metformin in hypothyroid patients with PCOS leads to a significant decrease in the serum levels of TSH. No such effect is observed in euthyroid patients with PCOS. This observation seems of clinical relevance. Indeed, as stated by Haugen in his recent review, metformin may affect thyroid function tests and TSH levels in hypothyroid patients.[18] Thus, monitoring serum TSH and free T4 levels is recommended in patients taking both metformin and l-thyroxine. Our results extend the observations of the TSH-lowering effect of metformin, previously described only in hypothyroid patients with diabetes, also to hypothyroid patients with PCOS.

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