Orlo H. Clark

TSH suppression in the management of thyroid nodules and thyroid cancer

Clinical and experimental data concerning TSH suppression, by giving exogenous thyroid hormone, in patients with goiter and in patients with thyroid cancer show a beneficial effect. In the goiter patients, TSH suppressive therapy seems most effective in young patients with diffuse or newly discovered goiters, in hypothyroid patients, and in patients with chronic lymphocytic thyroiditis or compensatory thyroid hypertrophy after partial thyroidectomy. With TSH suppressive therapy about 2/3 of thyroid nodules become smaller, but only about 5% to 10% disappear. In patients with differentiated thyroid cancer (papillary, mixed papillary-follicular, and follicular), tumor recurrence, tumor progression, and long-term survival all seem to be influenced favorably by TSH suppressive therapy. Experimental investigations demonstrate that both benign thyroid adenomas and differentiated thyroid carcinomas have TSH receptors situated on the plasma membranes. These TSH receptors appear to be coupled to the activation of adenylate cyclase in a one-to-one relationship. Experimental and clinical studies strongly support the use of thyroid hormone both for the treatment of patients after thyroidectomy for thyroid cancer and as prophylaxis to prevent the development of thyroid cancer in high-risk irradiated patients. The dose of thyroxine recommended for adequate TSH suppression is the lowest dose of thyroxine that will completely block the TSH response to TRH (usually 0.2 to 0.25 mg).

Inhibition of Endogenous Lactate Turnover With Lactate Infusion in Humans

The extent to which lactate infusion may inhibit endogenous lactate production, though previously considered, has never been critically assessed. To examine this proposition, single injection tracer methodology (U-14C Lactate) has been used for the estimation of lactate kinetics in 12 human subjects under basal conditions and with the infusion of sodium lactate. The basal rate of lactate turnover was measured on a day before the study with lactate infusion, and averaged 63.7 + 5.5 mg/kg/h. Six of these individuals received a stable lactate infusion at an approximate rate of 160 mg/kg/h, while the remaining six individuals were infused at the approximate rate of 100 mg/kg/h. It has been found that stable lactate infused at rates approximating 160 mg/kg/h consistently produced a complete inhibition of endogenous lactate production. Infusion of lactate at 100 mg/kg/h caused a lesser and more variable inhibition of endogenous lactate production (12% to 64%). In conclusion, lactate infusion significantly inhibits endogenous lactate production.

Alterations in thyrotropin (TSH) binding in iodine-deficient rats.

Thyrotropin (TSH) is thought to stimulate thyroid activity and growth by binding to TSH receptors on thyroid plasma membranes. Iodine depletion has been shown to increase the sensitivity of the thyroid to the goitrogenic effects of TSH. The present investigation was performed to determine if chronic iodine depletion altered either the number or the affinity of TSH receptor sites in the thyroid. Six paired experiments were performed comparing the binding of 125I-labeled bovine TSH to a particulate fraction of thyroid from male Sprague-Dawley rats that had received regular (C) or low iodine diet (LID) for 3 to 7 months. The number of TSH receptors and the association constants of these receptors were calculated from Scatchard plots and binding was compared with glandular concentrations of DNA, RNA, protein, plasma membrane markers (5′-nucleotidase, Mg2+ ATPase, Na+, K+ ATPase), and per thyroid gland. (1) The weights of all animals were initially similar but after 3 to 7 months the LID group (638 ± 139 g (mean ± 1 SD)) was heavier than the C group (544 ± 45 g (P < .01)). (2) Serum TSH concentrations in the LID group (5231 ± 547 ng/ml) were higher than those in the C group (850 ± 221 ng/ml) (P < .005). (3) Thyroid weight, thyroid weight per animal weight, DNA, RNA, total protein, Mg2+ ATPase, Na+, K+ ATPase, and 5′-nucleotidase were all increased in the LID group (P < .005). Histological examination demonstrated that the thyroid enlargement was primarily due to an increase in number of follicle cells, or hyperplasia. (4) The concentration of TSH receptors (maximum binding capacity) per DNA content was similar in the C and LID groups. (5) The concentration of TSH receptors per plasma membrane marker decreased in the LID group (P < .01) primarily because of the large increase in amount of plasma membrane. (6) The total number of TSH receptors per thyroid gland or TSH receptor content increased from 0.52 ± 0.16 × 1014 in the C group to 2.27 ± 0.79 × 1014 in the iodine-deficient animals (P < .001), and the association constant in these animals (1.28 ± .27 × 108M−1) was also higher than that in the C group (0.68 ± 0.16 × 108M−1) (P < .001). Thus, chronically iodine-deficient rats developed increased serum TSH concentrations and enlarged hyperplastic thyroid glands. Although the number of TSH receptors per DNA or cell did not change in the respective groups, the TSH receptor content and the association constant of these receptors for TSH in the thyroid gland of the iodine-deficient animals increased. It therefore appears that increased serum TSH concentrations in iodine-deficient rats exerts a positive regulatory effect on its own receptors and that alterations in serum TSH level modulate the TSH receptor. Whether this effect is due to a direct effect of TSH on the TSH receptor or an indirect effect secondary to thyroid growth is unknown.

Thyroid function and lipid concentration after thyroidectomy in rats

The purpose of this study was to determine whether subjects with high serum thyrotropin (TSH) levels and low-normal serum thyroxine (T4) levels are euthyroid, as a result of the increased TSH stimulation of the thyroid, or hypothyroid. As a model to study this clinically important problem we analyzed serum cholesterol (Chol), triglyceride (Tg), TSH, T4, and triiodothyroxine (T3) before and 7, 10, and 12 weeks after sham operation (SO), hemithyroidectomy (Htx), and total thyroidectomy (Ttx) in 33 male Sprague—Dawley rats. By 7 weeks after Ttx serum TSH levels increased from 861 ± 84 to 9657 ± 644 ng/ml, T4 decreased from 3.7 ± 0.18 to 0.84 ± 14 ng/ml, and T3 decreased from 0.317 ± 0.026 to 0.217 ± 0.007 ng/ml (P < 0.001). Serum Chol increased from 69.6 to 112.5 mg/dl, whereas Tg decreased from 70.93 ± 3.56 to 50.54 ± 4.18 mg/dl (P < 0.01). After Htx serum TSH levels were higher than before operation and were higher than in the SO group (P < 0.05); serum T4 and T3 levels tended to be lower than before Htx and lower than in the SO group, but this decrease was only significant for both T4 and T3 10 weeks after operation (P < 0.05); serum Chol and Tg levels were the same in Htx and SO animals. Thus, after Ttx (1) serum T3 and T4 levels decrease, (2) serum TSH levels increase, (3) serum Chol levels increase, and (4) serum Tg levels decrease. After Htx (1) serum TSH levels increase, (2) serum T3 and T4 levels are low-normal or slightly low, (3) serum Chol and Tg levels are normal. It appears that increased TSH stimulation of the thyroid gland can maintain normal serum lipid levels in the presence of low-normal or slightly low thyroid hormone concentrations. Thus, animals with increased serum TSH levels and low-normal or slightly low thyroid hormone levels are either not hypothyroid or serum lipid levels are an insensitive indicator of hypothyroidism.