Shih-Lieh Fang

The Physiological Role of Thyrotropin-Releasing Hormone in the Regulation of Thyroid-Stimulating Hormone and Prolactin Secretion in the Rat

The physiological role of thyrotropin-releasing hormone (TRH) in the regulation of thyrotropin (thyroid-stimulating hormone, TSH) and prolactin (Prl) secretion has been assumed but not proven. Stimulation of their release requires pharmacologic doses of TRH. Lesions of the hypothalamus usually induce an inhibition of TSH secretion and an increase in Prl. To determine whether TRH is essential for TSH and Prl secretion in the rat, 0.1 ml of TRH antiserum (TRH-Ab) or normal rabbit serum was administered to normal, thyroidectomized, cold-exposed, and proestrus rats through indwelling atrial catheter. Serum samples were obtained before and at frequent intervals thereafter. Serum TSH concentrations in normal, thyroidectomized, cold-exposed, and proestrus rats were not depressed in specimens obtained up to 24 h after injection of normal rabbit serum. In contrast, serum TSH was significantly decreased after the administration of TRH-Ab in all normal (basal, 41+/-8 muU/ml [mean+/-SE]; 30 min, 6+/-2; 45 min, 8+/-3; 75 min, 4+/-2); thyroidectomized (basal, 642+/-32 muU/ml; 30 min, 418+/-32; 60 min, 426+/-36; 120 min, 516+/-146); coldstressed (basal, 68+/-19 muU/ml; 30 min, 4+/-3; 180 min, 16+/-8); and proestrus (basal, 11 a.m., 57+/-10 muU/ml; 1 p.m., 20+/-3; 3 p.m., 13+/-4; 5 p.m., 19+/-3) rats. However, 0.1 ml of TRH-Ab had no effect on basal Prl concentrations in normal or thyroidectomized rats and did not prevent the Prl rise in rats exposed to cold (basal, 68+/-7 ng/ml; 15 min, 387+/-121; 30 min, 212+/-132; 60 min, 154+/-114), or the Prl surge observed on the afternoon of proestrus (basal 11 a.m., 23+/-2 ng/ml; 1 p.m., 189+/-55; 3 p.m., 1,490+/-260; 5 p.m., 1,570+/-286). These studies demonstrate that TRH is required for TSH secretion in the normal, cold-exposed and proestrus rat and contributes, at least in part, to TSH secretion in the hypothyroid rat, but is not required for Prl secretion in these states.

Effect of starvation on hypothalamic-pituitary-thyroid function in the rat.

Total starvation in the rat for 2 days did not alter the hypothalamic content of thyrotropin-releasing hormone (TRH), but did decrease both pituitary TSH content and serum TSH concentration. Five days starvation resulted in a significant decrease in serum TSH and a slightly enhanced serum TSH response to exogenous TRH, suggesting that the pituitary retains its sensitivity to TRH. Fasting for 5 days resulted in a decreased 1 and 4th, but an increased 24th thyroid 131I uptake. Other starvation-induced abnormalities of intrathyroid 131I metabolism were a consistent increase in the percent of organified 131I present as MIT and DIT and a decreased percent 131I labeled T4 AND T3. These alterations in the intrathyroid metabolism of 131I in the starved rat probably reflect both a decrease in serum TSH concentration and a decrease in urinary and fecal loss of administered 131I. The serum total and free T4 and total and free T3 concentrations were decreased following 2 and 5 days of starvation.

Suppression of thyroid radioiodine uptake by various doses of stable iodide.

We studied the effect of various doses of sodium iodide on thyroid radioiodine uptake in euthyroid volunteers by giving single doses of 10, 30, 50, and 100 mg and then daily doses of 10, 15, 30, 50, or 100 mg for 12 days thereafter. All single doses above 10 mg suppressed 24-hour thyroid uptake of 123I to 0.7 to 1.5 per cent. Continued daily administration of 15 mg of iodide or more resulted in values consistently below 2 per cent. A small but statistically significant fall in serum thyroxine (T4) and triiodothyronine (T3) and a rise in serum thyrotropin (TSH) concentrations were observed after eight and 12 days of iodide treatment. These data suggest that the thyroid uptake of radioactive iodine can be markedly suppressed by single-dose administration of 30 mg of stable iodide and that suppression can be maintained with daily doses of at least 15 mg. This study provides guidelines for stable iodide prophylaxis in the event of exposure to radioactive iodine.

THYROID BINDING ANTIBODIES AND OTHER IMMUNOLOGICAL ABNORMALITIES IN PATIENTS WITH GRAVES’OPHTHALMOPATHY: EFFECT OF TREATMENT WITH CYCLOPHOSPHAMIDE

Patients with Graves’ophthalmopathy were studied for a possible role of thyroid binding antibodies (TBAb) as measured by a radioreceptor assay, and for in vitro evidence of immunoreactivity to orbital antigens. The effect of cyclophosphamide (CY) treatment on the immunological parameters and the clinical course of the eye disease was also studied. The mean TBAb index for all patients with eye disease was significantly less than that for normals and for patients with Graves’hyperthyroid‐ism who lacked eye disease. The mean TBAb index for patients with ophthalmopathy and past or present hyperthyroidism was significantly less than for those patients with eye disease but no associated hyperthyroidism (‘euthyroid Graves’ disease). TBAb levels did not correlate with the severity or duration of the eye disease and did not change during treatment with CY. Significant titres of serum antibodies against human eye muscle extract or subcellular fractions, or macro‐phage inhibitory factor (MIF) production in response to human orbital tissue extract were not detected in patients with eye disease. The congestive changes improved in all patients treated with CY, although the degree of proptosis and eye muscle involvement improved in only 3 of 24 and 11 of 20 patients respectively with these abnormalities. TBAb are unlikely to play a role in the pathogenesis of Graves’ophthalmopatliy and the hyperthyroidism and eye disease should be considered separate autoimmune disorders. The apparently anomalous finding of a higher mean TBAb index in patients with eye disease and hyperthyroidism than in those with hyperthyroidiam alone may reflect a more severe defect of suppressor T cell function in the former group. Because evidence for specific immunoreactivity

Effects of Amiodarone and Desethylamiodarone on Pituitary Deiodinase Activity and Thyrotropin Secretion in the Rat

The effect of acute administration of amiodarone, its major metabolite desethylamiodarone and iodine in an amount equal to that contained in amiodarone on serum thyroid hormone and thyrotropin (TSH) concentrations and hepatic and pituitary 5′ deiodination of thyroxine (T4) in the euthyroid and hypothyroid rat was evaluated. Amiodarone, desethylamiodarone and iodine all caused a decrease in serum T4 and triiodothyronine (T3) concentrations in euthyroid rats, while serum TSH concentrations and pituitary and hepatic 5′ deiodinase activities were decreased only in the amiodarone and desethylamiodarone-treated animals. Serum TSH was increased in the iodine treated rats. Amiodarone, but not iodine, decreased serum T3 and TSH concentrations and pituitary and hepatic 5′ deiodinase activities in hypothyroid rats. Inhibition of hepatic 5′ deiodinase activity was also observed by the addition of amiodarone in vitro in the absence of dithiothreitol (DTT) but not in the presence of DTT. The decrease in the serum T4 concentration observed with amiodarone and desethylamiodarone administration is probably secondary to the inhibitory effect of iodine released from the drugs on thyroidal T4 synthesis and secretion. Iodine inhibition of thyroidal T3 synthesis and secretion, decreased T4 substrate for a peripheral generation of T3 and inhibition of T4 to T3 conversion all contribute to the decrease in serum T3 observed. The decrease in the serum TSH concentration, despite low serum T4 and T3 concentrations and inhibition of pituitary 5′ deiodinase, suggest that amiodarone may function as a thyroid hormone agonist in the pituitary. Finally, the observation that amiodarone inhibits hepatic 5′ deiodination in vitro allows further evaluation of its mechanism of action.

Prevalence of familial dysalbuminemic hyperthyroxinemia in Hispanics.

Excerpt To the editor: Familial dysalbuminemic hyperthyroxinemia is a recently recognized autosomal dominant syndrome often confused with thyrotoxicosis in laboratory tests (1-3). This syndrome is ...

Studies of immunoreactivity to human lacrimal gland fractions in patients with ophthalmic Graves’ disease

In vitro evidence for immunoreactivity against human lacrimal gland fractions was sought in patients with ophthalmic Graves’ disease. There was no significant increase in interstitial lymphoid tissue on lacrimal gland biopsy. Serum antibodies against lacrimal fractions were not detected using the indirect immunofluorescent technique. Using the tanned cell hemagglutination test with lacrimal antigen, antibodies were detected in 2 of 15 patients with eye disease, 2 of 15 hyperthyroid patients without eye disease, and 2 of 20 normal subjects. Macrophage inhibitory factor (MIF) production in response to human lacrimal extract was not demonstrated in any of 11 patients with eye disease tested. On the other hand, MIF was demonstrated in 2 of 10 patients with Graves’ disease selected for absence of eye disease. Significant peripheral blood lymphocyte transformation in response to human lacrimal extract, or a soluble or membrane fraction, was demonstrated in 9 of 22 patients tested; in 6 of 21 patients to extract, in 3 of 21 patients to a soluble fraction and in 7 of 10 patients to a membrane fraction. The possible significance of lacrimal gland inflammation and role(s) in the pathogenesis of ophthalmic Graves’ disease are discussed.

Free triiodothyronine toxicosis in a patient with multinodular goiter

The patient, a 75-year-old man with a history of hypertension, renal calculi, gout, and colon diverticulosis, presented for a routine clinic visit on June 29, 1987, with complaints of nervousness, insomnia, excessive sweating, breathlessness, and fatigue for 1 month. He denied exposure to excess iodide. Physical examination revealed an anxious, elderly man with facial flushing. The blood pressure was 170/90 mm Hg and the pulse was 100/minute and regular. Examination of the head, eyes, ears, nose, and throat was significant for conjunctival injection without proptosis, chemosis, or lid lag. The thyroid gland was three times enlarged with multiple nodules and mild tenderness. Cardiac examination revealed a loud

Ammonium persulfate: a safe alternative oxidizing reagent for measuring urinary iodine.

1 and a systolic ejection murmur. On neurologic examination, there was a fine tremor of the hands and brisk deep tendon reflexes, but no muscle weakness. Routine thyroid function tests were performed to confirm the clinical impression of hyperthyroidism. However, results were within the normal range (Table I). Total serum T3 was measured by solid-phase radioimmunoassay (RIA) using a kit obtained from Diagnostic Products Corporation (Los Angeles, California) according to manufacturers instructions. Serum free thyroxine (T4) and free T3 concentrations were then measured by equilibrium dialysis. Total T4 and T3 concentrations were again normal and the free T4 concentration was in the upper range of normal. The serum free T3 concentration, however, was distinctly elevated, conf i rming our cl inical impression of thyrotoxicosis. Serum thyrotropin (TSH) concentration was low and failed to increase after thyrotropinreleasing hormone (TRH) administration. Weakly positive antithyroglobulin and antimicrosomal antibody titers were 1:320 and 1:400, respectively. The