Plasma fibronectin, serum procollagen-III-peptide and sex-hormone-binding globulin as non-specific markers of thyroid hormone effect at peripheral tissue level were determined and their values were related with serum levels of TSH, free-thyroxine and triiodothyronine during levothyroxine sodium replacement therapy for hypothyroidism. Low levels of biologic markers characteristic of hypothyroidism were normalized in consequence of hormone replacement and a negative correlation between their serum levels, and TSH concentration was demonstrated in most subjects. However, in some patients a discrepancy in the response to levothyroxine between the pituitary and other target organs was revealed. Additional evidence was disclosed that the pituitary thyrotroph sensitizes a minor decrease in serum thyroxine level, which would not be recognized by other target organs. Furthermore, it was revealed that during L-T4 replacement therapy in a large fraction of patients with subnormal serum TSH concentration blood levels of the measured markers often exceeded the upper limit of the normal range indicating a possibility of "tissue" thyrotoxicosis, besides the pituitary, in other target organs, too. According to the present study, which takes into consideration markers reflecting end-organ responsiveness to thyroid hormones, it is recommended to adjust the dose of levothyroxine to maintain serum TSH in the normal range. For patients with subnormal TSH concentration a close follow-up is obligatory and in case of concomitantly raised free-thyroxine level the reduction of the levothyroxine dosage is proposed.