The Impact of Testosterone on Metformin Action on Hypothalamic-Pituitary-Thyroid Axis Activity in Men: A Pilot Study

J Clin Pharmacol. 2020 Feb;60(2):164-171. doi: 10.1002/jcph.1507. Epub 2019 Aug 6.


The effect of metformin on thyrotrope function seems to be sex dependent. The aim of this study was to determine the role of endogenous testosterone in the impact of metformin on hypothalamic-pituitary-thyroid axis activity. The study population consisted of 2 groups of men with nonautoimmune hypothyroidism matched for age, weight, insulin sensitivity, and thyrotropin levels. The first group (n = 11) included subjects with low serum testosterone levels, while the second (n = 12) men with testosterone levels within the reference range. Because of concomitant type 2 diabetes, all men were treated with metformin (2550-3000 mg daily). Circulating levels of glucose, prolactin, testosterone, gonadotropins, thyrotropin, and free thyroid hormones were measured, while the structure parameters of thyroid homeostasis and the degree of insulin sensitivity were calculated at baseline and 16 weeks later. In both study groups, metformin decreased plasma glucose levels and improved insulin sensitivity. However, only in men with low testosterone levels, the drug decreased thyrotropin levels, reduced Jostel's thyrotropin index, and increased SPINA-GT. Metformin-induced changes in thyrotropin and Jostel's index correlated with their baseline values, baseline levels of testosterone, and with the effect of treatment on insulin sensitivity. In men with neither low or normal testosterone levels, metformin affected free thyroid hormones, prolactin, testosterone, gonadotropins, and SPINA-GD. The obtained results suggest that the impact of metformin on thyrotrope function depends on the androgen status of a patient.

Keywords: hypothalamic-pituitary-thyroid axis; hypothyroidism; metformin; testosterone; thyroid function tests.

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Hypogonadism / blood
  • Hypogonadism / complications
  • Hypothalamo-Hypophyseal System / drug effects*
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothyroidism / blood
  • Hypothyroidism / complications
  • Male
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Middle Aged
  • Pilot Projects
  • Testosterone / blood*
  • Thyroid Gland / drug effects


  • Hypoglycemic Agents
  • Testosterone
  • Metformin