TSH stimulation of adenylate cyclase (AC) and iodine uptake was compared in 39 surgical specimens of primary tumours and/or lymph node metastases from 29 human differentiated thyroid carcinomas. TSH stimulation of AC was significantly lower (2.1 +/- 0.3 fold the basal level) in patients without in vivo 131I uptake than in patients with 131I uptake (4.7 +/- 0.8). A significant correlation between TSH responsiveness of AC and TSH stimulation of in vitro 125I uptake was found. There was also a relationship between 127I tissue content and AC responsiveness. Nevertheless analysis of individual data showed discrepancies in about one quarter of the cases. Thus the response of neoplastic cell membrane to TSH appears to be necessary for iodine metabolism, but it is not sufficient. Additional defects may in some cases explain the lack of either iodine uptake or organification. There is a general correlation between TSH stimulation of AC and histological type. However, data from papillary carcinomas with various degrees of uptake capacity show that TSH stimulation of AC correlates better with functional activity than with cell morphology or tissue architecture. Stimulation by GMP P(N)P was decreased in carcinomas, while NaF stimulation was not significantly different from normal. This suggests that alterations in thyroid cancer are more related to defects in the regulatory than in the catalytic subunit of AC.