Goiter is a frequent clinical finding in patients with acromegaly, an effect mediated by chronically elevated insulin-like growth factor I (IGF-I) levels. It is unclear, however, whether the presence of TSH is a prerequisite for the growth-promoting actions of IGF-I on the human thyroid. We, therefore, studied a group of subjects with hypopituitarism, who were deficient in both TSH and GH, examining the effects of GH replacement therapy on thyroid size and function. GH replacement was initiated in 14 subjects with hypopituitarism. After 6 months of recombinant human GH therapy at 0.25 IU/ kg week, IGF-I levels increased from 11.5 +/- 6.0 to 32.4 +/- 15.4 nmol/L (P = 0.002). Thyroid volume, as determined by ultrasound, did not change significantly over this period. Similarly, there was no change in thyroglobulin levels after treatment with GH, but there was a decrease in the free T4/free T3 ratio (P = 0.043). Pretreatment thyroid size in subjects with hypopituitarism was also compared to that in a group of age- and sex-matched controls. The size of thyroid glands in the hypopituitarism group was smaller than that in controls (P = 0.015). We found that GH therapy did not increase thyroid size in patients with hypopituitarism. From these data we conclude that in vivo, IGF-I does not independently stimulate thyroid growth, but promotes thyroid cell proliferation by potentiating the mitogenic action of TSH.