Thyroid-stimulating hormone and prolactin levels in breast cancer.

Serum thyroid-stimulating hormone (TSH) and prolactin (PRL) levels were measured before and after intravenous administration of protirelin to 148 patients with breast carcinoma. There was a high prevalence (36%) of elevated basal TSH; however, most of the patients were euthyroid and had normal serum thyroxine and T3 resin uptake. The PRL level was elevated in 22% of the cases. Both the mean PRL and the mean TSH levels for the breast cancer patients were significantly elevated above the respective means in a control group. We could find no correlation between serum TSH and PRL levels, suggesting that the purported association between a decreased thyroid state and breast cancer is probably not mediated through an increased PRL level. The mean survival and mean disease-free interval were shorter for patients with either elevated TSH or elevated PRL levels, but in neither case was the difference statistically significant.     

The genetics of euthyroid familial goiter.

In endemic goiters, thyroidal enlargement reflects an increase in cell proliferation triggered by low dietary iodine. However, not all individuals in the same iodine-deficient regions develop a goiter, and iodine supplementation does not prevent goiter development in all treated subjects. Familial clustering of goiters, usually with an autosomal-dominant pattern of inheritance, has repeatedly been reported. Moreover, other environmental and etiological factors are likely to be involved in the development of euthyroid goiter. Therefore, a multifactorial etiology based on complex interactions of an individual's genetic makeup and environment is likely. Family and twin studies suggest a considerable influence by a strong genetic component in euthyroid familial goiter.     

Thyroid-stimulating antibody in a patient with euthyroid Graves' disease

We report an 11-year-old girl with euthyroid Graves' disease. She was referred to our clinic because of left exophthalmos without other symptoms suggestive of hyperthyroidism. Her serum concentration of free thyroxine (FT4) and free triiodothyronine (FT3) were normal, but thyroid-stimulating hormone (TSH) was below normal and impaired TSH response to TSH releasing hormone (TRH) was found. Although the sera were positive for anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb), both titers were not as high as usually observed in Graves' disease. Three months later, she developed hyperthyroidism and was treated with propylthiouracil. Within 2 weeks of the initiation of therapy, all symptoms except exophthalmos disappeared, and after 2 months of treatment TRAb was negative though TSAb remained positive. TSAb is therefore a good indicator to use in the diagnosis and follow-up of euthyroid Graves' disease and should be measured in patients with exophthalmos of unknown origin, even in children.     

Association of thyroid-stimulating immunoglobulins and thyrotropin-releasing hormone responsiveness in women with euthyroid goiter

Thyroid-stimulating immunoglobulins (TSI) were measured, using a highly sensitive cytochemical bioassay, in plasma from 26 euthyroid women with idiopathic diffuse or multinodular goiter selected on the basis of their serum TSH responses to TRH stimulation. Thirteen were chosen because they were previously identified to have impairment in TRH responsiveness and were compared with 13 consecutive patients who had normal responses to TRH. TSI were present in a significantly greater number of those who had subnormal TRH responses (11:13) compared to those who had normal responses (3:13) P less than 0.005. Although serum T4, T3, and basal TSH values were all within the normal range, mean serum T4 and T3 values were significantly higher and basal TSH significantly lower in the 14 patients who had TSI than in the 12 in whom TSI was absent. The coexistence of impaired TRH responsiveness and TSI was associated with a family history of thyroid disease. The data suggest that TSI in patients with euthyroid goiter cause a modest increase in thyroid secretion sufficient to blunt the TSH response to TRH but not to cause clinical hyperthyroidism.     

Suppressive therapy with levothyroxine for euthyroid diffuse and nodular goiter.

In this study, 35 patients with euthyroid diffuse goiter and 35 patients with euthyroid nodular goiter were treated with Levothyroxine (L-T4) for six months. The aim was to evaluate the efficacy of treatment on thyroid and nodule volumes and to evaluate the correlation between volume changes and thyroglobulin levels. Serum thyroid hormones, TSH, thyroglobulin, thyroid and nodule volumes were measured at the initial visit and after 6 months. Radioactive iodine uptakes of the thyroid gland were evaluated before treatment. The mean decrease of thyroid volume at six months was about 20% (20.4 +/- 8.8 ml vs. 16 +/- 7.9 ml, P<0.001) in patients with diffuse goiter. All patients with diffuse goiter showed some decrement in their goiter sizes. Thyroid nodules, in response to thyroid hormone treatment, showed a variable behavior. A reduction of 50% or more in volume was detected in 31% (11/35) of the patients. 54% of the patients (19/35) showed a 10-49% decrease in nodule volume. Five of the patients were found to be insensitive to the therapy. Their nodule volumes either increased or did not change during therapy. Free T4 and free T3 levels increased and TSH levels decreased with L-T4 treatment in all patient groups. Patients with higher TSH levels (within normal limits) showed more volume reduction in the diffuse goiter group. No uniform correlation was found between volume changes and thyroglobulin levels in either of the patient groups. In conclusion, suppressive thyroxine treatment is effective in reducing the size of the goiter, and nodules and thyroglobulin levels cannot be taken as an indicator of the efficacy of L-T4 therapy.     

Thyroid-stimulating autoantibodies in the blood of patients with diffuse toxic goiter

The level of thyrostimulating autoantibodies (TSA) in IgG fraction isolated from the blood serum by precipitation of (NH4)2SO4 was determined in 36 patients with diffuse toxic goiter (DTG) and in 8 healthy donors. TCA which were assessed by a rise of the level of cAMP in human thyroid sections (obtained at operation from extranodal tissue of patients with nodal euthyroid goiter) after 2 h-incubation at 37 degrees C with IgG, were determined in 32 DTG patients (89%). The patients were divided into 2 groups with respect to their clinical and thyroid status: with a high and normal or subnormal content of the blood thyroid hormones. In the 1st group the frequency of detection (96%) and the level of TSA (570.64 +/- 109.63%) were much higher than in the 2nd group of patients (70 and 186.29 +/- 23.06%, respectively). The highest levels of TSA (1085.25 +/- 551.27%) were found in 4 of 26 patients (the 1st group) who had not received specific therapy.     

Thyroid-stimulating activity of chorionic gonadotropin and luteinizing hormone.

While recent evidence indicates that the hCG molecule has intrinsic thyroid-stimulating activity (TSA), it is not clear whether a thyrotropic molecule other than hCG accounts for some of the TSA apparent in the crude or highly purified hCG. To determine if a thyrotropic factor is excluded from crude urinary hCG during purification of hCG, the ratio of interstitial cell-stimulating activity (ICSA) to TSA was determined in the starting material used for hCG preparation as well as in the highly purified hCG preparation. The ratio of the two biological activities did not change significantly during purification, suggesting that no factor present in crude hCG other than hCG itself accounts for the TSA. The highly purified hCG preparation was gel-filtered on Sephadex G-100 and the main protein peak was divided into three fractions. The ratio of TSA to ICSA was the same in each fraction, further indicating that these activities are intrinsic to the same molecule. If hCG has intrinsic thyrotropic activity, as these data indicate, then thyrotropic activity would be expected to be a secondary biological activity of LH, since there are strong structural and functional similarities between LH and hCG. In order to assess the LH molecule for intrinsic TSA, an LH preparation with minimal TSH contamination was prepared by recombining subunits exhibiting minimal TSH immunoreactivity. The LH molecule formed from the recombination of highly purified hCG alpha and ovine LH beta subunits exhibited TSA in the bioassay that was 25 times greater than that expected based on the immunoreactive TSH contamination. There was no evidence to support the existance of a thyrotropic factor other than hCG in either crude or highly purified hCG preparations. Our finding that a hybrid LH molecule structurally similar to hCG with potent ICSA also exhibits intrinsic TSA further extends and supports the hypothesis that TSA is an intrinsic property of the hCG molecule.     

Molecular pathogenesis of euthyroid and toxic multinodular goiter

The purpose of this review is to summarize current knowledge of the etiology of euthyroid and toxic multinodular goiter (MNG) with respect to the epidemiology, clinical characteristics, and molecular pathology. In reconstructing the line of events from early thyroid hyperplasia to MNG we will argue the predominant neoplastic character of nodular structures, the nature of known somatic mutations, and the importance of mutagenesis. Furthermore, we outline direct and indirect consequences of these somatic mutations for thyroid pathophysiology and summarize information concerning a possible genetic background of euthyroid goiter. Finally, we discuss uncertainties and open questions in differential diagnosis and therapy of euthyroid and toxic MNG.     

The treatment of diffuse euthyroid goiter with indomethacin

Clinico-instrumental and hormonal investigation of 31 patients with diffuse euthyroid goiter was conducted. To test the efficacy of indometacin as an antigoitrogenic drug, these patients were given it for 2 mos. Combined examination of the patients showed the absence of thyroid decrease and changes in thyroid function against a background of indometacin monotherapy. The results point out to the fact that the drug should not be used for elimination of thyroid hyperplasia in persons with diffuse euthyroid goiter.     

Thyroid-stimulating hormone regulation of ornithine decarboxylase activity in the thyroid.

TSH (1.0 U im) caused a 22-fold increase in thyroidal ornithine decarboxylase activity (ODC) 6 hours after administration in intact rats. Hypophysectomized rats treated with 1 U TSH showed a 5-fold increase in thyroid ODC activity. This stimulation appeared to be specific for TSH since hormones known to induce ODC activity in other target tissues, such as ACTH or LH, showed no significant stimulation. DIBUTYRYL CYCLIC AMP and aminopylline caused a 12-fold increase in ODC activity 5 hours after administration. Prostaglandins have also been implicated in the TSH-induced stimulation of cyclic AMP. Indomethacin (1.0 mg/100 g body wt, ip), an inhibitor of prostaglandin synthesis, was administered 3 hours before TSH with a resulting 30% diminution (P less than .001) in ODC activity compared with the administration of TSH alone. To rule out the possibility that the increase in ODC activity with TSH might be due to increased thyroid hormone secretion, ODC activity was evaluated 6 hours after triiodothyronine administration (60 mug/100 g body wt), and no significant increase in thyroid ODC activity was found. Stimulation of ODC activity was 90% inhibited by the intraperitoneal administration of actinomycin D (80 mug/100 g body wt) or cycloheximide (400 mug/100 g body wt) given simultaneously with TSH. These results indicated that TSH specifically stimulated thyroid ODC activity, which may be important for the growth-promoting action of the hormone on the thyroid gland. This action may be mediated by cAMP and prostaglandins and may require new protein synthesis.     

Thyroid-stimulating hormone receptor activity after internalization

The thyroid-stimulating hormone (TSH) receptor (TSHR) belongs to the large family of G-protein-coupled receptors (GPCRs) and is predominantly coupled to G_s. Thus, the effects of TSH are largely mediated by the stimulation of adenylyl cyclase and the ensuing rise of intracellular cyclic AMP (cAMP) concentrations. Like for other GPCRs, a prolonged stimulation of the TSHR leads to its internalization into endosomes followed by its recycling to the cell surface. Until recently, GPCRs were believed to activate “classical” G-protein-dependent pathways only when located on the cell surface and to cease doing so upon agonist-induced internalization. However, our recent findings on the TSHR and similar ones on the parathyroid hormone and sphingosine receptors suggest that internalized GPCRs can continue to signal through G_s-cAMP in an intracellular compartment. Interestingly, this type of intracellular cAMP signaling differs from that occurring on the cell surface, as it is persistent and apparently leads to specific signaling outcomes. Although further studies are needed to investigate the possible physiological and pathophysiological consequences of GPCR-cAMP signaling in the endocytic compartment, endosomes should no longer be viewed as passive carriers for receptors en route to degradation but rather as specialized intracellular platforms for GPCR signaling.