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Purpose: To test the hypothesis that during the natural history of sporadic nontoxic goiter (SNG), a diffuse goiter precedes a multinodular goiter with gradual development of autonomous thyroid function., Patients and Methods: A cross-sectional survey of 102 consecutive patients with SNG (seven male, 95 female) was performed. Thyroid volume was measured by ultrasonography, and plasma thyroid-stimulating hormone (TSH) by a sensitive assay (TSH immunoradiometric assay)., Results: Patients with a multinodular goiter were older and had a larger thyroid volume than patients with a diffuse or uninodular goiter. Plasma free thyroxine (T4) and total triiodothyronine (T3) were higher and plasma TSH was lower in patients than in normal subjects. Free T4 was higher in the subgroup of patients with a multinodular goiter and a decreased TSH response to thyrotropin-releasing hormone. Plasma TSH (y, in mU/L) was negatively related to thyroid volume (x, in mL): y = 8.2x-0.667 (r = 0.578, p less than 0.001). Thyroid volume (y, in mL) was positively related to age (x, in years): y = -21.8 + 2.0x (r = 0.455, p less than 0.001); and to duration of goiter (x, in years): y = 40.6 + 2.1x (r = 0.505, p less than 0.001). The annual increase in thyroid volume was calculated at 4.5%., Conclusion: The data suggest a continuous growth of SNG and provide support for the concept of increasing thyroid nodularity and autonomy of thyroid function--related to increasing thyroid volume--during the natural history of this disorder.

The efficacy of treatment with TSH-suppressive doses of L-thyroxine (T4, 2.5 micrograms/kg body weight daily) either alone or combined with carbimazole (CBZ, 40 mg daily) was studied in 78 patients with sporadic non-toxic goitre in a prospective placebo-controlled double-blind randomised clinical trial. Treatment was given for 9 months, with 9 months of follow-up. A response to treatment as measured by ultrasonography was found in 58% of the T4 group, in 35% of the T4/CBZ group, and in 5% of the placebo group. The mean (SEM) decrease of thyroid volume at 9 months in the responders was 25% (2). After discontinuation of treatment, thyroid volume increased in the responders and had returned to base-line values after 9 months of follow-up. In the placebo group mean thyroid volume had increased by 6% (4) at 4 months, 20% (7) at 9 months, and 27% (8) at 18 months. The findings show that untreated sporadic non-toxic goitre continues to increase in size; T4 is effective in the treatment of the disorder; and the addition of CBZ has no therapeutic advantage.

Iodine excess is associated with a low thyroidal radioiodine uptake due to dilution of the radioisotope by the increased stable iodide pool. We studied thyroidal uptake of radioisotopes in cardiac patients with iodine excess due to amiodarone treatment. 99mTc-pertechnetate scintigraphy was performed in 13 patients receiving long term amiodarone therapy. Five patients had a clearly visible thyroid gland, and 8 patients had no or a very faint thyroid image. All patients with positive scans had an increased plasma TSH level, whereas all patients with negative scans had a normal or absent TSH response to TRH. Thyroidal uptake and discharge of 123I were studied in 30 other patients. Group I (n = 11) had normal plasma TSH responses to TRH and no iodine excess, group II (n = 7) had normal TSH responses to TRH and excess iodine from metrizoate angiography in the previous month, group III (n = 7) had normal or decreased TSH responses to TRH while receiving long term amiodarone therapy, and group IV (n = 5) had increased TSH responses to TRH while receiving long term amiodarone therapy. The mean radioiodine uptake value in group I [5.4 +/- 0.8% (+/- SE) at 60 min] was higher than those in group II (2.3 +/- 0.7%; P = 0.009) and group III (0.8 +/- 0.3%; P = 0.0005), but not different from that in group IV (5.3 +/- 1.2%; P = NS). Radioiodine discharge after perchlorate (expressed as a percentage of the 60 min uptake) in group I (10.1 +/- 2.2%) was lower than those in group II (24.9 +/- 10.6%; P = 0.05) and group III (28.8 +/- 5.3%; P less than 0.005), whereas discharge in group IV (58.0 +/- 6.1%) was greater than those in group II (P less than 0.05) and group III (P less than 0.01). In conclusion, 1) thyroid visualization by 99mTc-pertechnetate and thyroid radioiodine uptake during iodine excess are decreased in euthyroid and hyperthyroid patients, but preserved in hypothyroid patients. 2) The organification defect induced by iodine excess is greater in iodide-induced hypothyroidism than in eu- or hyperthyroidism. These findings may be explained by the increased TSH secretion in hypothyroidism and/or by decreased thyroidal concentration of an unknown specific iodinated compound (whose concentration and action vary with the total organic iodine content of the thyroid) that mediates the inhibition of iodide transport.

PRL was measured radioimmunologically in plasma and cerebrospinal fluid (CSF) samples obtained simultaneously in 31 patients with various neurological or infectious, but non-endocrine diseases (group A), 12 patients (7 pregnant women and 5 newborns) with physiological hyperprolactinemia (group B),10 psychiatric patients with pharmacologically induced hyperprolactinemia (group C) 12 normoprolactinemic patients with pituitary adenoma and suprasellar extension (SSE) (group D), And 14 hyperprolactinemic patients with pituitary adenoma with and without SSE (group E). Plasma PRL and CSF PRL concentrations (ng/ml, mean and range in brackets) of the various groups were: group A, 6.2 (1.3-14.5) and 1.3 (0.6-4.7); group B, 85.2 (31-200) and 13.2 (3-28); group C, 54.3 (3.5-160) and 6.5 (0.7-18); group D, 17.2 (5.4-30) and 9.7 (2.7-34); and group E, 2,529 (115-10,000) and 1,449 (6-13,000). The plasma to CSF concentration ratios (mean and range in brackets) were: group A, 5.2 (1.4-13.0); group B, 7.0 (2.9-10.3); group C, 7.3( 3.9-11.3); group D, 2.6 (0.9-7.1); and group E, 10.9 (0.2-34.9). The ratio was greater than 3 in 87% of the non-tumor patients; in 42% of the tumor patients the ratio was less than 3. The correlation between plasma and CSF PRL levels of all 53 subjects without a pituitary tumor (groups A, B, and C) was positive (r=0.9097; P=0.00001); in the 26 tumor patients (groups D and E) the correlation was also positive (r=0.7141; P=0.00002). These results indicate that 1) PRL is a normal constituent of CSF, 2) the CSF PRL level is a function of the plasma level, 3) detectable, or even high, CSF PRL levels per se are not indicative in the presence of a pituitary tumor, with or without SSE, and 4) abnormally low ratios may be found in patients with a pituitary tumor with SSE.

Studies were undertaken to elucidate whether orphenadrine influences thyroid function. Seven volunteers were given orphenadrine in weekly increasing dosage up to 300 mg per day; in 5 patients chronically treated with 300 mg orphenadrine daily the drug was gradually discontinued. No changes were found in PBI, RT3U, TT3 and TSH during or after orphenadrine medication; also TSH- and TT3-responses to 200 microgram TRH iv were not influenced by the drug. Orphenadrine medication increased serum thyroxine values (P less than 0.001) as measured with the competitive protein binding (CPB) technique, but did not influence serum thyroxine values measured by radioimmunoassay. Orphenadrine added to serum in vitro in the Murphy-Pattee assay did not increase thyroxine values; two out of eight tested metabolites however did. It is concluded that orphenadrine in a dosage up to 300 mg per day does not influence thyroid function. It increases serum thyroxine levels as measured by the competitive protein binding technique of Murphy and Pattee. This is due to an in vitro competition between ethanol-extractable orphenadrine metabolites and thyroxine for binding sites on the thyroxine binding globulin.

Hypergastrinaemia was found in 11 out of 24 untreated hyperthyroid patients (Graves' disease or nodular goitre). Seven patients had a co-existent (autoimmune) atrophic gastritis. In the remaining 17 patients plasma T3 was positively related to plasma gastrin, and negatively to gastric acid output; there was no relation between gastrin levels and acid output. Acid instillation into the stomach revealed a normal negative feedback of acid upon gastrin release. Sixteen hyperthyroid patients were restudied when euthyroid. Plasma gastrin decreased from 171 (51-1188) ng/l before treatment to 69 (39-392 ng/l after treatment (P < 0.002), and maximal acid output increased from 1.55 (0.00-22.75) to 8.03 (0.00-26.60) mmol H+/h (P < 0.01) (median values; range in brackets). However, in 4 patients with complete achlorhydria before and after treatment plasma gastrin decreased to the same extent as in the patients with gastric acid secretion. We conclude that thyrotoxic hypergastrinaemia cannot be fully explained by the low gastric acid output in hyperthyroidism.

Gastrin release was studied in 5 hypergastrinemic patients, both during calcium infusion and EDTA infusion. In each patient, gastrin decreased in conjunction with the fall in plasma calcium, and increased during calcium infusion. Plasma gastrin and calcium levels were strongly correlated.

Plasma and cerebrospinal fluid (CSF) levels of two hormones of similar molecular size, pituitary prolactin (PRL) and human chorionic somatomammotropin (hCS), and of the bigger hormone human chorionic gonadotropin (hCG) were measured in six pregnant women without pituitary disease. For all three hormones, the plasma and CSF levels were closely correlated. The plasma/CSF concentration ratio for hCG (571 +/- 378, mean +/- SD) was significantly different (P less than 0.01) from the hCS ratio (24.6 +/- 6.1); the hCS ratio was significantly different (P less than 0.005) from the PRL ratio (7.2 +/- 1.5). We conclude that (1) the CSF concentration of a protein hormone depends on the plasma concentration and on its molecular size, and (2) pituitary hormones reach the CSF not only via filtration of peripheral blood at the choroid plexuses, but also more directly via retrograde transport from the pituitary to the brain.

The plasma Prl response to 200 micrograms TRH iv was evaluated in 6 hyperprolactinaemic women without radiological evidence of a pituitary tumour (group I), in 15 hyperprolactinaemic women with dubious (group II) and in 17 normo- or hyperprolactinaemic women with clear (group III) radiological abnormalities, in 18 normo- or hyperprolactinaemic men with clear radiological abnormalities (group IV), and in 4 women and 3 men with hyperprolactinaemia and sellar destruction who had been treated in the past for pituitary adenoma (group V). The responses were compared with those obtained in a control group of 83 (42 women, 41 men) normoprolactinaemic healthy individuals. The Prl response was defined as a ratio (R2): the 20 min value minus the 0 min value, divided by the 0 min value. The median R2 values were: female controls 5.1, male controls 3.1, group I 0.1, group II 0.2, group III 0.3, group IV 0.55, group V females 0.45 and males 0. It is concluded that 1) subjects suspected of harbouring a microprolactinoma (groups I and II) demonstrate absent or attenuated responses similar to those found in patients with definite prolactinomas and 2) a value of plasma Prl 20 min after 200 micrograms TRH iv greater than 3.5 times the basal level (R2 > 2.5) rules out the presence of a prolactinoma.

The effect of the beta-adrenoceptor blocking agent propranolol on plasma levels of thyroxine and triiodothyronine was studied in eleven hyperthyroid patients and in six hypothyroid patients on L-thyroxine substitution therapy. In all patients a decrease in plasma-triiodothyronine was found. The per cent decrease of plasma-triiodothyronine was the same in both groups. Plasma levels of thyroxine and thyrotropin increased in the hypothyroid patients, but remained constant in the hyperthyroid subjects. The decrease in plasma-triiodothyronine during propranolol medication is most likely caused by an inhibition of the peripheral conversion of thyroxine into triiodothyronine.