Recombinant human TSH (rhTSH), usually given as 0.9-mg doses im on 2 successive days, increases serum thyroglobulin (Tg) and radioactive iodine uptake (RAIU) in residual thyroid tissue in patients with thyroid cancer. We previously reported that a single, relatively low dose of rhTSH (0.1 mg im) is a potent stimulator of T(4), T(3), and Tg secretion in normal subjects. The present study describes the effects of higher doses of rhTSH on thyroid hormone and Tg secretion. Six normal subjects for each dose group, having no evidence of thyroid disease, received either 0.3 or 0.9 mg rhTSH by im injection. Serum TSH, T(4), T(3), and Tg concentrations were measured at 2, 4, and 8 h and 1, 2, 3, 4, and 7 days after rhTSH administration. The peak serum TSH concentrations were 82 +/- 18 and 277 +/- 89 mU/L, respectively, for the 0.3- and 0.9-mg doses of rhTSH. Serum T(4), T(3), and Tg concentrations increased significantly in subjects receiving 0.3 and 0.9 mg rhTSH, with significant increases in T(4) and T(3) being observed before significant increases in serum TG: Peak concentrations of serum T(4), T(3), and Tg, after 0.3 mg rhTSH administration, were 100 +/- 19, 131 +/- 14, and 1035 +/- 724% above individual baselines, respectively. Similarly, peak concentrations of serum T(4), T(3), and Tg, after 0.9 mg rhTSH administration, were 102 +/- 16, 134 +/- 7, and 1890 +/- 768% above individual baselines, respectively. These data, compared with previously reported data for the responses to 0.1 mg rhTSH, indicated that 0.1, 0.3, and 0.9 mg rhTSH had similar quantitative stimulatory effects on thyroid hormone and Tg secretion, except that the T(4) response was greater in groups receiving 0.3 and 0.9 mg rhTSH than in the group receiving 0.1 mg rhTSH. We also studied the effect of rhTSH on the thyroid RAIU in the group that received 0.9 mg rhTSH. The 6- and 24-h RAIU values were significantly higher after rhTSH (pre-rhTSH, 6-h value = 12.5 +/- 1.8%; 24 h value = 23 +/- 2.7%; post-rhTSH, 6 h value = 27 +/- 4.8%; 24-h value = 41 +/- 4.2%). The stimulating effects of 0.9 mg rhTSH on the 6- and 24-h RAIUs were similar. rhTSH is a potent stimulator of T(4), T(3), and Tg secretion and the RAIU in normal subjects. Single doses greater than 0.1--0.3 mg do not seem to further enhance thyroid hormone or Tg secretion.