The effects of TSH on iodothyronine 5- and 5'-deiodinations were investigated using cultured thyroid tissues from patients with Graves' disease. The addition of TSH to the culture medium stimulated all of the iodothyronine-deiodinating activities of thyroid tissues cultured for more than 4 days. Peak TSH-induced activities were found on the fifth day of culture, and increased activities were found up to 9 days. On the fifth day of culture, TSH enhanced both outer and inner ring monodeiodinations in a dose-responsive manner between 62.5 and 250 microU/ml. This stimulation by TSH was blocked by the addition of actinomycin D or propylthiouracil. Incubation of thyroid tissues with (Bu)2cAMP mimicked the action of TSH, and theophylline potentiated the action of TSH. These results suggest that TSH, in an action probably mediated by cAMP, induces synthesis of iodothyronine deiodinases in the thyroid gland.

To evaluate the effects of aging on T4 metabolism, serum 3,3'diiodothyronine (3,3'-T2), 3',5'-diiodothyronine (3',5'-T2), and 3,5-diiodothyronine (3,5-T2) as well as T4, T3, and rT3 concentrations were determined by RIAs in 81 normal subjects, aged 24-81 yr. 3,3'-T2, 3',5'-T2, and 3,5-T2 antisera were prepared by immunizing rabbits with the protein conjugate of each diiodothyronine. Since the 3',5'-T2 antiserum cross-reacted with rT3 to the extent of 1.8%, correction was made by subtracting 1.8% of the rT3 value from the measured 3',5'-T2 value. The other 2 antisera had no noticeable cross-reactivity with various thyroid hormone derivatives. Although no significant relation existed between T4 levels and age (r = -0.14; P greater than 0.1) serum T3 showed a significant correlation with age (r = -0.28; P less than 0.05). In contrast, no significant correlation was observed between rT3 and age (r = 0.12; P greater than 0.1). Serum 3,3'-T2, 3',5'-Tw, and 3,5-T2 values (nanograms per dl) all had significant inverse correlations with age, the coefficients of correlation being -0.38 for 3,3'-T2 (P less than 0.01), -0.58 for 3',5'-Tw (P less than 0.01), and -0.47 for 3,5-T2 (P less than 0.01). These findings suggest that sequential monodeiodinating activities in T4 metabolism decrease with increasing age.

Abstract.A prospective long-term follow-up study was performed with conventional divided doses (group C:10 mg 3 times daily, N=58) and a small single daily dose (group S:15 mg once daily, N=54) of methimazole (MMI) for the treatment of Graves' hyperthyroidism. Within 8 weeks, almost 80% of the patients in both groups became euthyroid. The mean time required to achieve a euthyroid state was 5.6 ± 2.7 weeks in group C and 5.8 ± 3.1 in group S. TSH binding inhibitor immunoglobulin (TBII) levels before therapy were 44.2 ± 22.7% and 47.1 ± 23.9% in group C and group S, respectively. A similar gradual fall in TBII levels was observed in both groups over a two-year period of treatment. MMI doses were gradually reduced to a maintenance dose (5 mg daily) after the patients became euthyroid. The patients were treated for 28 ± 9 months and were followed up after therapy was stopped (observation period in patients who remained in remission was 12-130 (75 ± 34) months and the interval to relapse in reccured cases was 1-98 (20 ± 27) months).The rates of recurrence in group C were 41% at 1 yr, 54% at 2 yrs, 56% at 4 yrs and 61% at 6 yrs. In group S, these were 44%, 53%, 56% and 63%, respectively. No differences between relapse rates were observed with the two different dosage regimens. Adverse effects occurred more frequently in group C patients (24%) than in group S patients (13%). These results show that there is no difference in the clinical and immunological course or in the long-term remission rate of Graves' hyperthyroidism when the treatment is initiated with either a small single daily dose (15 mg) or the conventional regimen (10 mg 3 times daily).

Conversion of T4 to T3 was studied in normal, Graves', and neoplastic thyroid tissues obtained at surgery. Homogenates of human thyroid follicular adenoma and carcinomas were incubated with [125I]T4 and dithiothreitol (DTT) at 37 C for 60 min under N2 gas. T3 formation was assessed by measuring [125I]T3 formed, using paper chromatography. In the second series of experiments, the suspensions of the 100,000 X g pellet of normal thyroid tissues adjacent to the tumor and Graves' thyroid tissues were incubated with unlabeled T4 and DTT at 37 C for 60 min under N2 gas. T3 generated was measured by RIA. T3 generation in the thyroid tissue was dependent on incubation time, amount of the tissue used, concentration of DTT, temperature, and pH. Propylthioracil inhibited T3 formation, while methimazole had no effect. A kinetic study with the homogenate of a thyroid adenoma and 100,000 X g pellet suspensions of two normal and three Graves' thyroids gave apparent Km values of 2.7, 4.9, and 4.1 microM for T4, respectively, and Vmax values of 0.8, 3.0, and 10.9 pmol T3/mg protein.min, respectively. Conversion of T4 to T3 was observed in two of three tumor tissues studied and was markedly enhanced in Graves' thyroid tissues (mean +/- SE, 11.9 +/- 2.0 pmol/mg protein.min) compared to that of normal thyroid tissues (3.2 +/- 0.6 pmol/mg protein.min; P less than 0.01). It is concluded that T4 is enzymatically converted to T3 in normal and Graves' thyroids and differentiated thyroid neoplasms. Moreover, enhanced conversion of T4 to T3 was found in Graves' thyroid tissue.