Reduction in Extrathyroidal Triiodothyronine Production

In eight patients receiving 0.1 mg T4 daily, administration of PTU resulted in a prompt fall in mean serum T3 concentrations from 78±6 ng/100 ml (SEM) to 61±3 ng/100 ml after 1 day. The mean serum Ts concentrations ranged from 55 to 60 ng/100 ml during the remainder of the PTU treatment period (P < 0.01): The mean control serum TSH concentration was 29.6 AU/ml and it increased to a peak of 40 /U/ml on the 5th and 6th days. In five patients receiving 0.2 mg T4 daily, the mean control serum Ta concentration was 84±7 ng/ 100 ml. It fell to 70+5 ng/100 ml after 1 day and 63±7 ng/100 ml after 2 days of PTU administration and thereafter ranged from 61 to 69 ng/100 ml (P < 0.01). Serum TSH concentrations did not increase. No changes in serum To concentrations were found in either group. In five patients who received 100 mg methimazole (MMI) daily for 7 days there were no changes in serum T4, T3, or TSH concentrations. These results indicate that PTU, but not MMI, produces a prompt and sustained, albeit modest, reduction in serum Ts concentrations in patients whose sole or major source of Ts is ingested T4. These findings most likely result from inhibition of extrathyroidal formation of T3 from T4. Received for publication 4 June 1974 and in revised form 9 September 1974. INTRODUCTION Propylthiouracil (PTU)1 has been shown to have both intraand extrathyroidal antithyroid actions. It inhibits many of the peripheral actions of thyroxine (T4) and slows the peripheral deiodination and, in some studies, the overall rate of degradation of T4 in both animals and man (1-6). In contrast, while PTU has been shown to slow the fractional deiodination and degradation rate of triiodothyronine (T3) in animals (2, 6, 7), it has not been found to inhibit the biological actions of T3 (1). It is now clear that an important pathway of extrathyroidal T4 metabolism is conversion of T4 to T8, a more potent thyroid hormone, and that a large portion of the serum T3 is produced as a result of extrathyroidal conversion from T4 (8-10). Thus, the extrathyroidal antithyroid actions of PTU might reflect reduction in serum T3 concentrations due to inhibition of peripheral T4 deiodination. It has previously been shown by Oppenheimer, Schwartz, and Surks that PTU inhibited the rate of conversion of ["I]T4 to ['I]Ts in rats (7). The present study was undertaken to determine if PTU could be shown to inhibit extrathyroidal Ts formation in man. To obviate alterations in thyroidal T4 or T3 secretion occurring as a result of PTU treatment, patients with documented hypothyroidism receiving chronic To therapy were studied. The results indicate that administration of PTU, but not methimazole (MMI), results in significant reduction in serum Ts concentrations in TA-treated hypothyroid patients. Similar results have been presented in abstract form by Geffner, Azukizawa, and Hershman (11). lAbbreviations used in this paper: MMI, methimazole; PTU, propylthiouracil; TSH, thyrotropin; T8, triiodothyronine; T4, thyroxine. The Journal of Clinical Investigation Volume 55 February 1975-218-223 218