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A. Eugene Pekary, Jerome M. Hershman and Clark T. Sawin

Abstract.

Basal serum TSH and the peak TSH response to a 500 μg TRH bolus were measured in 57 euthyroid and in 29 hypothyroid subjects either receiving graded thyroid hormone replacement or acutely removed from full replacement therapy. Serum TSH, total T4 and T3 were determined by sensitive radioimmunoassay methods. The peak versus basal TSH data for hypothyroid patients were linear within individuals. The regression slope of the peak versus basal TSH data for all hypothyroid subjects did not differ significantly from the corresponding slope for all euthyroid subjects. Basal and peak TSH versus T3 and T4 data for hypothyroid patients were also linear within each individual. Moreover, the regression of the basal TSH values averaged over the non-replacement to full replacement state against the TSH versus T3 slope had a significant negative correlation. This trend leads to an array of regression lines which average to the familiar hyperbolic relationship between thyrotrophin and thyroid hormone levels in man.

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Ge Chen, A Eugene Pekary, Masahiro Sugawara and Jerome M Hershman

Hydrogen peroxide plays an important role in the regulation of iodination and thyroid hormone formation. In the present study, the effect of exogenous H2O2 on 125I transport and organification was investigated in FRTL-5 rat thyroid cells. Less than 20 passages after subcloning, cells in 24-well plates (6 × 104 cells/well) were maintained in a thyrotropin (TSH)-containing medium (6H) for 3 days. A TSH-free medium (5H) was then used for the next 7 days. A 1-h exposure to H2O2 stimulated 125I transport and 125I organification at 0.1–0.5 mmol/l H2O2 and had a toxic effect on FRTL-5 cells at 5 mmol/l. Hydrogen peroxide (0.5 mmol/l) augmented the iodide transport and iodine organification induced by TSH (333U/l) by two- and threefold, respectively. The biphasic effect of H2O2 was blocked totally by 5–200 μg/l of catalase. Catalase by itself did not influence TSH-mediated 125I transport and 125I organification. Hydrogen peroxide (0.5 mmol/l) added to cells in 5H medium increased Na+K+-ATPase activity twofold. Ouabain (1 mmol/l), an inhibitor of Na+K +-ATPase, completely inhibited the twofold increase in 125I transport induced by 0.5 mmol/l H2O2 but only inhibited H2O2-induced 125I organification by 28%. Methimazole (1 mmol/l), an inhibitor of thyroid peroxidase, had no effect on H2O2-mediated 125I transport but totally blocked the fivefold rise in 125I organification induced by 0.5 mmol/1 H2O2. The effect of H2O2 on intracellular cyclic adenosine monophosphate (cAMP) levels also was studied. Hydrogen peroxide (0.5 mmol/l) decreased baseline and 160 mU/l TSH-induced cAMP levels by 35 and 87%, respectively, while a 3-h incubation with 0.5 mmol/l H2O2 increased Na + K +-ATPase in 5H and 6H media. We conclude that H2O2 plays an important role in the regulation of iodide transport and organification and also may affect signal transduction and the electrochemical gradient in thyroid cells. Our results also provide evidence that functional thyroid peroxidase activity is present in FRTL-5 cells.

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Jean-Noel Hugues, Albert G. Burger, A. Eugene Pekary and Jerome M. Hershman

Abstract. Nutrition influences thyroid function at the level of TSH secretion, at the level of monodeiodination, and possibly elsewhere. In order to study the effect of starvation on TSH secretion, 8 healthy male volunteers fasted for 30 h and were then refed with 800 kcal. Refeeding was performed at 19.00 h and blood was sampled at 20 min intervals until midnight. Control experiments were performed in the same subjects both when they were normally fed and when the starvation period was prolonged a further 5 h until midnight. Starvation decreased serum TSH levels to below 1 mU/l, and without refeeding the nocturnal peak of the TSH nycthemeral rhythm was abolished. With refeeding serum TSH tended to increase towards midnight and was significantly higher than during starvation. However, the serum TSH levels remained significantly below those at the same time of the day in the absence of a preceding starvation period.

Serum T3 levels were significantly lower than in the fed state. The mean values were 1.84 ± 0.03 vs 2.30 ± 0.06 nmol/l (120 ±2 vs 150 ± 4 ng/100 ml, mean ± sem P < 0.01). Refeeding did not result in a measurable change in serum T3 concentration (1.80 ± 0.05 nmol/l; 120 ± 3 ng/100 ml, mean ± sem, n.s.). The contrary was true for rT3 levels which increased in starvation and tended to fall with refeeding, but this decrease was not significant.

As glucocorticoids have been implicated in the control of monodeiodination and TSH secretion, serum cortisol levels were also measured. They did not differ during the 3 experimental periods. The results show that short-term starvation and refeeding may be a valuable tool for studying in vivo control of TSH secretion.

The results show that short-term starvation and refeeding may be a valuable tool for studying in vivo control of TSH secretion.

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Marie Simard, Carol J. Mirell, A. Eugene Pekary, Jerry Drexler, Kalman Kovacs and Jerome M. Hershman

Abstract. Pituitary thyrotrope tumours are a rare cause of hyperthyroidism. Prior in vitro studies of these tumours have revealed various patterns of differentiation and secretory activity. We have characterized the histological, biochemical, molecular and physiological features of a thyrotrope adenoma in order to define its origin and autonomy. Histochemical and electron micrograph findings confirmed the diagnosis of a thyrotrope cell adenoma. Immunostaining was positive for TSH and GH in the cytoplasm of the adenoma cells. Tissue extracts contained TSH-IR which co-eluted with authentic hTSH when analysed by gel filtration. Tumour fragments studied in a tissue culture system secreted TSH, α-subunit and GH. TRH (30 nmol/l) stimulated TSH and GH secretion. T3 (1.5 nmol/l) inhibited GH release and had no effect on TSH secretion. GnRH (50 nmol/l), dexamethasone (10−4 mol/l), SRIH (1 μmol/l) and TRH-glycine, a tetrapeptide precursor of TRH, stimulated TSH release. Dexamethasone inhibited GH and α-subunit secretion. Stable transcripts for α- and β-subunits of TSH and GH messenger RNAs were detected by molecular hybridization in cytosolic fractions. Immunohistochemistry, in vitro secretory function, and mRNA analysis suggest multidirectional differentiation of the tumour cells. TRH-glycine may have a direct stimulatory effect upon pituitary thyrotropes.

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Burt Sharp, Shlomo Melmed, Ronald Goldberg, Harold E. Carlson, Samuel Refetoff and Jerome M. Hershman

Abstract.

Using a sensitive and precise radioimmunoassay for human β-endorphin, we have demonstrated the sustained secretion of opioid peptides from human pituitary tumour cells. Pituitary tumour tissue obtained from a patient with Nelson's syndrome was maintained in continuous monolayer culture and secreted both β-lipotropin and β-endorphin, with predominance of the latter. This is compatible with the idea that the β-endorphin in normal human serum is secreted as such despite the predominance of β-lipotropin compared with β-endorphin in the anterior pituitary.

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Xuan-Ping Pang, An Ouyang, Tian-Sue Su and Jerome M. Hershman

Abstract. Endemic goitre and cretinism are still a public health problem in China. An epidemiological survey showed that about 5% of the inhabitants in Daxin village, Henan province, had goitre or cretinism after an iodized salt prevention programme had been carried out for two decades. The main food for the inhabitants of this area has an iodine content <30 nmol/kg and the water for cooking and drinking has an iodine concentration between 7–12 nmol/l. We studied thyroid function in subjects of this village. There were 42 with grade 0 goitre (males 29, females 13), 42 grade I (males 23, females 19), 27 grade II (males 9, females 18), 31 grade III (males 14, females 17) and 34 cretinism patients (males 30, females 4) diagnosed and classified according to WHO criteria. Serum T4, free T4, T3, free T3, T3 uptake, TSH and thyroglobulin were measured in these subjects. The patients with goitre or cretinism had significantly decreased serum free T4 and increased serum T3 and free T3 levels compared with those of controls. Thyroid size was positively correlated with age and serum thyroglobulin concentrations. Serum thyroglobulin was significantly increased even in the grade 0 goitre subjects. The percentages of subjects with serum free T4 < 12 nmol/l, T3 >2.5 nmol/l, free T3 >5.2 pmol/l, TSH >3.5 mU/l, T3/T4 ratio >0.03 and free T3/free T4 ratio >0.36 were significantly higher among goitre and cretinism patients than among controls. The data suggest that there is partial compensation for a marginal deficiency of iodine in the inhabitants of this village.

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Xuan-Ping Pang, Jerome M. Hershman, Vierka Smith, A. Eugene Pekary and Masahiro Sugawara

Abstract.

Previous work showed that treatment of rats with tumour necrosis factor-α produced a model of nonthyroid illness in which there was reduction of circulating thyroid hormones and TSH, reduced thyroid response to TSH, and reduced thyroid iodide uptake. In vitro studies showed that tumour necrosis factor-α binds to a specific receptor on FRTL-5 rat thyroid cells, that TSH increases the number of tumour necrosis factor-α receptors, and that tumour necrosis factor-α inhibits iodide uptake by these cells. In the present study, we obtained additional data on the effects of tumour necrosis factor-α on FRTL-5 cells and studied the mechanism of action of tumour necrosis factor-α in these cells. Tumour necrosis factor-α inhibited both basal and TSH-stimulated [125I]iodide uptake; tumour necrosis factor-α slowed the recovery of [125I]iodide trapping after the cells were exposed to TSH and augmented the loss of the [125I]iodide trapping function after the cells were deprived of TSH; tumour necrosis factor-α inhibited [125I]iodide trapping in a noncompetitive manner; tumour necrosis factor-α did not affect cell growth of FRTL-5 cells. Interleukin-1 (IL-1) also inhibited basal and TSH-stimulated [125I]iodide uptake, but it stimulated cell growth. Tumour necrosis factor-α and IL-1 did not affect the generation of cAMP in the presence or absence of TSH; these cytokines blocked the cAMP-induced stimulation of [125I]iodide uptake. Tumour necrosis factor-α did not affect [3H]arachidonic acid uptake or release by FRTL-5 cells. The inhibitors of the phospholipase A2-arachidonic acid pathway did not affect the action of tumour necrosis factor-α. The H2O2 scavenger, catalase, did not block the action of tumour necrosis factor-α. The results show that both tumour necrosis factor-α and IL-1 inhibit FRTL-5 function and that the site of action of these cytokines is distal to the production of cAMP. The actions of tumour necrosis factor-α on FRTL-5 cells do not appear to be mediated by the phospholipase A2-arachidonic acid pathway or by H2O2.

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Jerome M. Hershman, Koonlawee Nademanee, Masahiro Sugawara, A. Eugene Pekary, Richard Ross, Bramah N. Singh and J. J. DiStefano III

Abstract. Cardiac patients taking amiodarone, a potent anti-arrhythmic drug, often have supranormal serum thyroxine (T4) levels and normal or mildly reduced serum triiodothyronine (T3) levels. We studied T4 and T3 kinetics and conversion of T4 to T3 in 5 men with recurrent paroxysmal tachycardia before and after 5–6 weeks of therapy with amiodarone (dose 200–800 mg/day). The patients were also receiving various medicines for cardiac disease. Each was injected with tracer doses of labelled T4 and T3; serum samples were processed by TCA precipitation and ethanol extraction. The data were analyzed with the aid of six-compartment model for T4 and T3 kinetics. Mean total body T3 production rate, total body T3 pool size, and conversion of T4 to T3 were all reduced in patients taking amiodarone.

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Masayoshi Yoshimura, A Eugene Pekary, Xuan-Ping Pang, Loretta Berg, Laurence A Cole, Andrew Kardana and Jerome M Hershman

Yoshimura M, Pekary AE, Pang X-P, Berg L, Cole LA, Kardana A, Hershman JM. Effect of peptide nicking in the human chorionic gonadotropin β-subunit on stimulation of recombinant human thyroid-stimulating hormone receptors. Eur J Endocrinol 1994;130:92–6. ISSN 0804–4643

It is now generally accepted that human chorionic gonadotropin (hCG) has thyroid-stimulating activity. Heterologous forms of the hCG molecule occur in the purified preparations extracted from urine of pregnant women and patients with trophoblastic diseases. This work was undertaken to determine the effect of peptide nicking in the hCG-β subunit on its thyrotropic potency. Using Chinese hamster ovary cells expressing functional human thyroid-stimulating hormone (TSH) receptors, we examined the effect of nicked hCG on cyclic AMP (cAMP) production and receptor binding. The effect of human leukocyte elastase (hLE), a nicking enzyme, on standard hCG also was examined in the cAMP assay and on receptor binding. We studied five hCG preparations extracted from the urine of normal pregnancy (CR-127 and P8) and trophoblastic diseases (C2, C5 and M4). Two preparations (C2, 96% nicked and M4, 100% nicked in the β44–49 region) showed about a 1.5-fold potency of standard hCG CR-127, which is also 20% nicked in the same region. Non-nicked hCG (P8) had the weakest potency among all of the samples tested. Treatment of standard hCG with hLE increased the cAMP response about two-fold. Dose-dependent displacement of bovine [125I]TSH by standard hCG and hLE-digested hCG was observed and was almost identical. We have confirmed the increased in vitro thyrotropic activity of hCG nicked in the β-intercysteine loop on recombinant human TSH receptors. These data suggest that peptide heterogeneity of the hCG molecule may modulate the in vivo thyrotropic activity of hCG in pregnant women and patients with trophoblastic diseases.

Jerome M Hershman, Endocrinology-W111D, West Los Angeles VA Medical Center, Los Angeles, California 90073, USA