Deficiency of immunoreactive somatostatin in the median eminence of Snell dwarf mice

Snell dwarf mice (dw/dw) are characterized by a genetically determined, congenital lack of pituitary GH, TSH and prolactin. Given that hypothalamic somatostatin is involved in the regulation of pituitary GH and TSH release, it was decided to investigate the content of immunoreactive somatostatin (IRS) in the median eminence of dw/dw and phenotypically normal mice of the same strain. The content of IRS in the pyloric antrum and pineal gland of these animals was also examined. The effects of ovariectomy and of hyperprolactinemia (induced by a pituitary graft under the kidney capsule) on the median eminence content of IRS were also studied in both normal and dwarf mice. Median eminence IRS content was significantly lower in the dw/dw (23.6 +/- 1.8 ng) than in normal mice (57.4 +/- 7.1 ng); no difference was found in the pyloric IRS content of dw/dw (16.9 +/- 1.6 ng/mg of protein) and normal animals (13.8 +/- 1.9 ng/mg of protein), nor in the pineal content of IRS (639.4 +/- 64.4 pg/gland in the dw/dw; 732 +/- 265 pg/gland in normals). Neither ovariectomy nor hyperprolactinemia were found to affect the IRS content in the tissues studied in normal or dwarf mice. Treatment of an additional group of 9 dwarf mice with L-thyroxine (L-T4 2 micrograms/48 h. s.c. for 2 weeks) significantly increased the animals weight (10.2 +/- 0.4 g versus 7.4 +/- 0.3 g) and produced maturation of facial features; however, it did not change the IRS content in any of the tissues studied. It is concluded that the content of IRS in the median eminence of mice with a congenital lack of GH, TSH and prolactin is significantly reduced and that this is unlikely to be related to the deficiency of thyroid hormones in these animals.     

Human epidermal growth factor concentrations in urine, but not in saliva and serum, depend on thyroid state

To evaluate the effects of thyroid hormones on the concentration of epidermal growth factor (EGF), we determined values for the immunoreactive EGF concentration in the urine (U-irEGF) of newborn infants with congenital hypothyroidism (N = 19), and in urine, saliva and serum of adult patients with hypothyroidism (N = 11) and hyperthyroidism (N = 8). The values were expressed as SD score (SDS), i.e. deviation in SD units from their mean value of healthy subjects of the same age and sex. The SDS of relative U-irEGF (ng/mg creatinine) was lower (P less than 0.01) in newborn infants with congenital hypothyroidism (-0.8 +/- 0.2; mean +/- SEM) than in healthy infants. Their relative U-irEGF correlated with their serum T4 concentrations (r = 0.59, P less than 0.01). The SDS of relative U-irEGF was lower (P less than 0.01) in adult hypothyroid patients (-1.2 +/- 0.5) and higher (P greater than 0.05) in adult hypothyroid patients (0.9 +/- 0.6) than in healthy adult subjects. When subsequently euthyroid, their SDS of relative U-irEGF increased to -0.5 +/- 0.3 (P less than 0.01), and decreased to -0.7 +/- 1.1 (P less than 0.05), respectively. The irEGF concentrations in saliva and serum were not significantly different between the hypothyroid and hyperthyroid patients. Our results indicate that urinary excretion of irEGF in man is dependent on thyroid hormone.     

Changes in the tumor marker concentration in female patients with hyper-, eu-, and hypothyroidism

The levels of 6 circulating tumor markers were evaluated in a total of 131 female subjects with altered thyroid states; 36 normal subjects, 46 hyperthyroid patients with Graves' disease, and 49 primary hypothyroid patients. The mean CEA concentration was observed to be significantly higher (p less than 0.02) in hypothyroid patients than in normal and hyperthyroid patients (1.1 +/- 0.1 ng/ml, 0.8 +/- 0.1 ng/ml and 0.8 +/- 0.1 ng/ml, respectively). Similarly, the mean serum CA 125 concentration in hypothyroid patients was higher (p less than 0.02) than in normal and hyperthyroid patients (13.0 +/- 2.6 U/ml, 7.6 +/- 1.1 U/ml and 5.5 +/- 0.8 U/ml, respectively), and the mean serum CA 15-3 concentration in hypothyroid patients was significantly higher than in normal subjects (p less than 0.01) and hyperthyroid patients (p less than 0.001) (16.2 +/- 0.9 U/ml, 13.9 +/- 0.6 U/ml and 10.6 +/- 0.5 U/ml, respectively). No statistical difference was found in mean CA 19-9 in the three subject groups. AFP in the hypothyroid patients (3.6 +/- 0.3 ng/ml) was significantly higher (p less than 0.05) than in normal subjects (2.6 +/- 0.2 ng/ml) and hyperthyroid patients (1.7 +/- 0.2 ng/ml) (p less than 0.01). On the other hand, serum ferritin was low in the hypothyroid patients (65.9 8.0 ng/ml) and significantly increased (69.1 +/- 9.0 ng/ml) (p less than 0.02) with the normalization of thyroid function. In hyperthyroidism, serum ferritin (70.2 +/- 7.0 ng/ml) was significantly higher than in the hypothyroid patients (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth hormone and carbohydrate intolerance in cirrhosis

Patients with cirrhosis of the liver often have insulin resistance and elevated circulating growth hormone levels. This study was undertaken (a) to evaluate glucose intolerance, insulin resistance and abnormal growth hormone secretion and (b) to determine if GH suppression improves insulin resistance. Glucose tolerance tests (GTT), intravenous insulin tolerance tests (IVITT), arginine stimulation tests (AST) and glucose clamp studies before and during GH suppression with somatostatin were performed in a group of patients with alcohol-induced liver cirrhosis. During GTT cirrhotic subjects had a 2-hour plasma glucose of 200 +/- 9.8 ng/dl (N = 14) compared to 128 +/- 8.0 ng/dl in normal controls (N = 15), P less than 0.001. Basal GH was elevated in cirrhotic patients and in response to arginine stimulation reached a peak of 17.0 +/- 5.4 ng/ml (N = 7), compared to a peak of 11.3 +/- 1.8 ng/ml in 5 normal controls (P = NS). During IVITT patients with cirrhosis had a glucose nadir of 60.0 +/- 4.0 mg/dl (N = 9), compared to 29.0 +/- 7.0 mg/dl in controls (N = 5), P less than 0.001. Peak GH levels during IVITT were not significantly different in cirrhotics and controls. Glucose utilization rates in 4 patients with cirrhosis of the liver before somatostatin mediated GH suppression was 3.1 +/- 0.5 mg/kg/min and 6.5 +/- 1.5 mg/kg/min during somatostatin infusion, P less than 0.025. We conclude that patients with alcohol induced cirrhosis have sustained GH elevations resulting in insulin resistance which improves after GH suppression.     

The ex-vivo effects of thyroid status and extracellular calcium concentration on rat atrial and ventricular electrophysiology

The purpose of this study was to explore the relationship between the thyroid status and both ventricular and atrial electrophysiology in the rat. The study was extended to consider the effects of altering the extracellular calcium concentration. The work was performed in two sections. First, hypothyroid animals were compared with euthyroid (untreated animals); second, hypothyroid animals were compared with hyperthyroid animals. Rats were rendered hypothyroid by pretreatment with the goitrogen methimazole and hyperthyroid by additional treatment with triiodothyronine. Action potential recordings were obtained using standard microelectrode techniques. Action potential measurements were made initially in a Krebs solution to which had been added 2.55 mM calcium (higher Ca Krebs solution) and at the end of each experiment after stabilization with Krebs solution to which had been added 1.28 mM calcium (lower Ca Krebs solution). Assessment of the change in action potential duration on transition from higher to lower Ca Krebs solution revealed that the euthyroid preparations demonstrated less prolongation of action potential duration than the hypothyroid group, and the hyperthyroid group showed hardly any response to reduction in calcium concentration.     

The effects of hypothyroidism on nerve growth factor and norepinephrine concentrations in weight-bearing and non-weight-bearing bones of rats

Thyroid hormones affect bone remodelling directly via receptors in osteoblasts. Previously, however, we have shown that the euthyroid and hyperthyroid states significantly influence the concentrations of both nerve growth factor (NGF) and norepinephrine (NE) in particular bones. Both NGF and NE directly affect bone metabolism and therefore it is possible that thyroid hormone action on bone may also be indirect via its actions on these two neural-related substances. In light of previous studies, the current experiments aimed to investigate whether hypothyroidism also influenced NGF and NE concentrations in weight-bearing and non-weight-bearing rat bones. Hypothyroidism was induced by oral ingestion of propylthiouricil (PTU; 3.8+/-0.2 mg/kg/day) for 21 days. Histological examination on distal femurs and microparticle enzyme immunoassayed plasma concentrations of T3 and T4 verified the hypothyroid status in treated rats. NGF concentrations were assayed via enzyme-linked immunosorbent assay (ELISA) and NE concentrations were measured via high performance liquid chromatography (HPLC) with electrochemical detection (ECD). NGF concentrations: Femoral NGF concentrations were 207% higher in hypothyroid rats (674.9+/-88.3 ng/g) than in euthyroid rats (326.7+/-63.6 ng/g; p < 0.05). Rib NGF concentrations in hypothyroid rats (3125.1+/-450.2 ng/g) were increased by 342% compared to euthyroid ribs (914.5+/-128.6 ng/g; p < 0.01). Rib NGF concentrations in hypothyroid rats were 463% higher than in femurs of hypothyroid rats (p < 0.001). NE concentrations: In hypothyroid rats, NE concentrations were reduced by approximately 50% in both ribs (38.9 ng/g) and calvaria (41.5 ng/g) compared to euthyroid rats (74.7 ng/g and 87.4 ng/g respectively; p < 0.05 for both). These findings on hypothyroid rats may be taken in conjunction with our companion work on hyperthyroid rats (Yao et al., 2002, JMNI 2:327-334) and put in context with other reports, to indicate that (i) there are several sources of NGF in bone, some of which are stimulated by hypothyroidism and others by hyperthyroidism and (ii) the concentrations of both NGF and NE in bone are sensitive to weight-bearing and thyroid hormone status.     

Effects of thyroid status and fasting on hepatic metabolism of apolipoprotein A-I

Metabolism of apolipoprotein (apo)A-I was studied in normal and chow-fed hyperthyroid rats, in 24-h fasted untreated male rats, and in rats after thyroparathyroidectomy (TXPTX). Rats were made hyperthyroid by administration of T3 (9.6 micrograms/day) or T4 (30 micrograms/day) with an Alzet osmotic minipump. Hyperthyroidism produced a similar two- to threefold elevation in plasma levels of apoA-I in male or female animals. During treatment with T3, plasma levels of T3 ranged from 200 to 400 ng/dl and did not correlate with plasma apoA-I levels. The net mass secretion and synthesis ([3H]leucine incorporation) of apoA-I by perfused livers from male hyperthyroid rats was elevated, while secretion of albumin was not different than that of euthyroid rats. Furthermore, the incorporation of [3H]leucine into total perfusate and hepatic protein was not altered by hyperthyroidism. The effect of thyroid hormone on apoA-I synthesis, therefore, does not appear to be a general effect on protein synthesis. After longer periods of treatment (28 days) with T3 (9.6 micrograms/day), hepatic apoA-I production decreased from that observed after 7 or 14 days of treatment, yet plasma apoA-I concentrations remained elevated. Plasma T3 decreased from 100 ng/dl to 40 ng/dl, in the hypothyroid rat resulting from TXPTX, but the plasma concentration of apoA-I did not change during the 2-week experimental period. The net secretion of apoA-I by livers from hypothyroid animals was depressed and albumin was uneffected compared to the euthyroid. Overnight fasting of euthyroid rats did not alter hepatic apoA-I secretion or plasma apoA-I levels, although under fasting conditions we had reported that hepatic output of apoB and E of VLDL is depressed. The addition of oleic acid to the perfusion medium, sufficient to stimulate VLDL production, did not affect net hepatic secretion of apoA-I by livers from euthyroid, hyperthyroid, or hypothyroid rats. In summary, hepatic synthesis of apoA-I appears to be controlled independently of other apo-lipoproteins and secretory proteins (albumin). Hepatic apoA-I synthesis is sensitive to thyroid status, increased in the hyperthyroid and decreased in the hypothyroid state. The specific stimulation of hepatic synthesis and secretion of apoA-I in the hyperthyroid state, however, tends to normalize over an extended period, perhaps from compensatory effects of a hormonal nature.     

Serum concentrations of 3, 3'-diiodothyronine, 3', 5'-diiodothyronine, and 3, 5-diiodothyronine in altered thyroid states

To investigate the thyroid hormone metabolism in altered states of thyroid function, serum concentrations of 3, 3'-diiodothyronine (3, 3'-T2), 3', 5'-T2 and 3, 5-T2 as well as T4, T3 and rT3 were determined by specific radioimmunoassays in 17 hyperthyroid and 10 hypothyroid patients, before and during the treatment. Serum T4, T3, rT3, 3, 3'-T2 and 3', 5'-T2 concentrations were all higher in the hyperthyroid patients than in age-matched controls and decreased to the normal ranges within 3 to 4 months following treatment with antithyroid drugs. In the hypothyroid patients, these iodothyronine concentrations were lower than in age-matched controls and returned to the normal ranges after 2 to 3 months treatment with T4. In contrast, serum 3, 5-T2 concentrations in hyperthyroid patients (mean +/- SE : 4.0 +/- 0.5 ng/dl) were not significantly different from those in controls (3.9 +/ 0.4 ng/dl), although they tended to decrease in 3 of 6 patients after the antithyroid drug therapy. Serum 3, 5-T2 levels in the hypothyroid patients (3.8 +/- 0.6 ng/dl) were also within the normal range and showed no significant change following the T4 replacement therapy. However, serum 3, 5-T2 as well as 3, 3'T2 concentrations rose significantly with a marked rise in serum T3 following T3 administration, 75 micrograms/day for 7 days, in Graves' patients in euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thyroid hormone may induce changes in the concentration of the mitochondrial calcium uniporter

We explored the possibility that the hormone 3,3',5-tri-iodothyronine can regulate the biosynthesis of the mitochondrial calcium uniporter. To meet this objective experiments on Ca(2+) transport, and binding of the specific inhibitor Ru(360) were carried out in mitochondria isolated from euthyroid, hyperthyroid and hypothyroid rats. It was found that V(max) for Ca(2+) transport increased from 11.67+/-0.8 in euthyroid to 14.36+/-0.44 in hyperthyroid, and decreased in hypothyroid mitochondria to 8.62+/-0.63 nmol Ca(2+)/mg/s. Furthermore, the K(i) for the specific inhibitor Ru(360), depends on the thyroid status, i.e. 18, 19 and 13 nM for control, hyper- and hypothyroid mitochondria, respectively. In addition, the binding of 103Ru(360) was increased in hyperthyroid and decreased in hypothyroid mitochondria. Scatchard analysis for the binding of 103Ru(360) showed the following values: 28, 40 and 23 pmol/mg for control, hyper- and hypothyroid mitochondria, respectively. The K(d) for 103Ru(360) was found to be 30.39, 37.03 and 35.71 nM for controls, hyper- and hypothyroid groups, respectively. When hypothyroid rats were treated with thyroid hormone, mitochondrial Ca(2+) transport, as well as 103Ru(360) binding, reached similar values to those found for euthyroid mitochondria.     

Radioiodine (131I) therapy of Graves' disease: use of the new high resolutional ultrasonic scanner for the determination of the accurate weight of the thyroid gland

In this series, eighteen patients with Graves' disease were treated with 8000 rads (80 Gy) of radioiodine (131I), using the new high resolutional ultrasonic scanner for the determination of the accurate weight of the thyroid gland. The mean dose of radioiodine administered orally was 4.6 +/- 3.0 mCi (170.2 +/- 110.0 MBq) and 133.7 +/- 44.6 microCi/g (4.95 +/- 1.65 MBq). At one year after treatment, twelve of eighteen patients (66.7%) became euthyroid, five (27.8%) remained hyperthyroid and one (5.6%) became hypothyroid. Analysis of various factors which may be related to the effect of radioiodine therapy revealed that the weight of the thyroid gland in the hyperthyroid and euthyroid groups was significantly different (61.7 +/- 33.5 g vs. 25.1 +/- 9.1 g, p less than 0.05). Furthermore, all patients with larger glands (more than sixty grams) remained hyperthyroid, while the incidence of euthyroidism was as high as 80% in patients with smaller glands (less than forty grams). Although the number of patients studied was small, these results indicate that a larger thyroid gland requires a larger radioiodine dose per gram of tissue than a smaller gland, suggesting that the therapeutic radiation dose should be graded according to the gland size even when the gland size is accurately estimated by ultrasound. Further study is required to determine the appropriate radiation dose graded according to the gland size.     

Effect of thyroid state on cytosolic free calcium in resting and electrically stimulated cardiac myocytes

The effects of the thyroid state on the cytosolic free Ca2+ concentration, [Ca2+]i, of resting and K+-depolarized cardiomyocytes were studied using the fluorescent Ca2+ indicator fura2. The mean resting [Ca2+]i in euthyroid myocytes (89 +/- 8 nM) was not significantly different from that in hyperthyroid myocytes (100 +/- 14 nM). The resting O2-consumption rate was identical for both groups when expressed per mg protein, but a 35% higher value was observed in the hyperthyroid group when expressed per cell on account of the cellular hypertrophy induced by thyroid hormone. Potassium induced depolarization (50 mM [K+]0) raised the level of [Ca2+]i by 50% in both groups. When ATP-coupled respiration was blocked with oligomycin, the 50 mM K+-induced rise in [Ca2+]i was accompanied in both groups by a 40% rise in glycolytic activity as inferred from measurement of lactate production. Ca2+-fluorescence transients were recorded from electrically stimulated myocytes of euthyroid, hyperthyroid and hypothyroid rats. The time taken to reach peak fluorescence (TPL) and that to 50% decay of peak fluorescence (RL0.5) decreased in the direction hypothyroid----hyperthyroid, indicating an increase in Ca2+ fluxes in the same direction. Isoproterenol (1 microM) enhanced the peak Ca2+ fluorescence in electrically stimulated hypothyroid and euthyroid myocytes but not in hyperthyroid myocytes. Both the TPL and RL0.5 were decreased by isoproterenol in euthyroid, but more so in hypothyroid myocytes. None of these parameters were influenced by isoproterenol in the hyperthyroid group. We conclude that (1) thyroid hormone increases neither the O2-consumption rate nor the level of [Ca2+]i of resting cardiomyocytes and (2) the effects of the beta-receptor-agonist isoproterenol on Ca2+ transients of electrically stimulated myocytes, are inversely related to the documented changes in beta-receptor density in heart tissue occurring with alterations in the thyroid state.     

Changes of beta-endorphin and somatostatin concentrations in different hypothalamic areas of female rats after chronic starvation

To study the effect of starvation on hypothalamic beta-endorphin and somatostatin (SRIF) concentrations in relation to starvation induced anestrus, groups of 8 rats were fed 50% of their normal daily chow consumption. Rats were sacrificed after 4, 8, 12, and 16 days during diestrus or anestrus. beta-endorphin concentrations decreased in the preoptic suprachiasmatic area (0.52 +/- 0.13 vs 0.21 +/- 0.05 ng/mg tissue wet weight) and increased in the posterior hypothalamus (0.31 +/- 0.06 vs 0.57 +/- 0.11 ng/mg) after 4 days of starvation. No significant change occurred in the arcuate nucleus or in the median eminence. On day 8 and 12 of starvation, beta-endorphin was unaltered in all areas compared to controls. Vaginal smears showed constant diestrus in a significant number of rats (5 out of 8) after 12 days. beta-endorphin concentrations in the arcuate nuclei of these rats were significantly reduced on day 16 (1.00 +/- 0.33 vs 0.30 +/- 0.11 ng/mg). The SRIF levels changed only in the median eminence with increased concentrations on day 12 (45.2 +/- 8.4 vs 79.5 +/- 14.8 ng/mg). At this time serum levels of luteinizing hormone (LH), prolactin (PRL), and growth hormone (GH) were significantly reduced. The results indicate that changes in hypothalamic beta-endorphin accompany the events leading to starvation induced anestrus.     

Altered relationship between protonmotive force and respiration rate in non-phosphorylating liver mitochondria isolated from rats of different thyroid hormone status

We have determined the relationship between rate of respiration and protonmotive force in oligomycin-inhibited liver mitochondria isolated from euthyroid, hypothyroid and hyperthyroid rats. Respiration rate was titrated with the respiratory-chain inhibitor malonate. At any given respiration rate mitochondria isolated from hypothyroid rats had a protonmotive force greater than mitochondria isolated from euthyroid controls, and mitochondria isolated from hyperthyroid rats had a protonmotive force less than mitochondria isolated from euthyroid controls. In the absence of malonate mitochondrial respiration rate increased in the order hypothyroid less than euthyroid less than hyperthyroid, while protonmotive force increased in the order hyperthyroid less than euthyroid less than hypothyroid. These findings are consistent with a thyroid-hormone-induced increase in the proton conductance of the inner mitochondrial membrane or a decrease in the H+/O ratio of the respiratory chain at any given protonmotive force. Thus the altered proton conductance or H+/O ratio of mitochondria isolated from rats of different thyroid hormone status controls the respiration rate required to balance the backflow of protons across the inner mitochondrial membrane. We discuss the possible relevance of these findings to the control of state 3 and state 4 respiration by thyroid hormone.     

Tissue calmodulin levels in normal and Graves' thyroids

Calmodulin levels in normal human thyroids and Graves' disease thyroids were measured by specific radioimmunoassay in the presence of ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). The calmodulin levels in tissues from patients with Graves' disease treated with thionamide drugs were significantly higher than those in normal tissues from euthyroid patients with solitary cold nodules (normal: 484 +/- 50 ng/mg protein, mean +/- SE, n = 15; Graves': 901 +/- 54 ng/mg protein, n = 48, p less than 0.001). Such a rise in calmodulin levels in Graves' disease thyroids was also present even after the administration of 50 micrograms of T3 for 5 days before operation (828 +/- 137 ng/mg protein, n = 6, p less than 0.01). Calmodulin levels in Graves' disease thyroids were closely related to the cell height of follicular epithelium. Calmodulin levels in a columnar cell predominant group were significantly higher than those in a flat cell predominant or a cuboidal cell predominant group (columnar cell predominant: 1150 +/- 118 ng/mg protein, n = 13; flat cell predominant: 561 +/- 125 ng/mg protein, n = 3, p less than 0.05; cuboidal cell predominant: 596 +/- 40 ng/mg protein, n = 25, p less than 0.001). The increase in calmodulin content in Graves' disease thyroid could therefore possibly be attributed to the stimulation of the thyroid gland by the thyroid stimulating antibody. An immunofluorescence study demonstrated the presence of calmodulin immunoreactivity in the thyroid epithelial cells, particularly enriched in the apical border in the form of a granulated structure.     

Effects of ketoconazole on rat testicular steroidogenic enzymatic activities

Ketoconazole (K) is an antifungal imidazole derivative which has been shown to be a potent inhibitor of testosterone (T) biosynthesis in rodents and humans. To study the effect of K on rat testicular steroidogenesis we measured the activities of five testicular microsomal steroidogenic enzymes in K-treated rats and controls. Thirty male adult rats were given either 2 mg K or water every 12 hours by mouth during 5 days. Mean testicular weight was similar in both groups of animals. The K-treated group had a T serum concentration of 83 +/- 14 ng/dL whereas it was 94 +/- 16 ng/dL in the control group (NS). The K-treated animals had decreased activities of the 3 beta-hydroxysteroid dehydrogenase (830 +/- 48 vs 2,245 +/- 109 pmol/mg protein/min, P less than 0.001), 17-hydroxylase (243 +/- 5 vs 676 +/- 17 pmol/mg protein/min, P less than 0.001), 17-ketosteroid reductase (31 +/- 2 vs 169 +/- 7 pmol/mg protein/min, P less than 0.001), and aromatase enzymes (92 +/- 6 vs 123 +/- 7 pmol/mg protein/min, P less than 0.01). The 17,20-desmolase activity was similar in both groups of animals (210 +/- 4 vs 171 +/- 18 pmol/mg protein/min). We conclude that K given orally to rats inhibits the activity of several testicular steroidogenic enzymes.     

Serum bone Gla protein (BGP) during treatment of hyperthyroidism and hypothyroidism. A longitudinal study

Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (BGP) was measured before and with initially 2 weeks, later 4-8 weeks intervals for 20-58 weeks during treatment of patients with hyperthyroidism (n = 10) and hypothyroidism (n = 4). Biochemical euthyroidism was obtained in the hyperthyroid patients after a median of 3 weeks (range 1-8 weeks), and in the hypothyroid patients after a median of 17 weeks (range 10-27 weeks). Serum BGP levels closely followed the thyroid state, being high respectively low in the hyperthyroid and hypothyroid state and reaching a stable plateau just at the time biochemical euthyroidism was obtained. These data suggest that osteoblastic activity is enhanced in hyperthyroidism and reduced in hypothyroidism, and that normalization occurs in close conjunction with the normalization of the thyroid state, without any delay, indicating a direct effect on the function of the excisting osteoblasts by the thyroid hormones.     

Endothelin-1 and endothelin-3 stimulate prostaglandin E2 secretion from the rat median eminence.

The in vitro effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on the release of prostaglandin (PG)E2 from the rat median eminence were investigated. The addition of ET-1 from 10(-9) M to 10(-6) M stimulated PGE2 release in a dose-dependent manner (from 10.5 +/- 2.1 to 54.4 +/- 5.6 pg/ME fragment/30 min; mean +/- SEM, p less than 0.001). ET-3 also stimulated the release of PGE2 from 10(-7) M to 10(-5) M dose dependently (from 18.1 +/- 0.7 to 60.9 +/- 17.4 pg/ME fragment/30 min p less than 0.05). The time course effect of ET-3 (10(-6) M) showed that PGE2 release was stimulated within five minutes (control, 1.5 +/- 0.5; ET-3, 15.8 +/- 3.0 pg/ME fragment/5 min, p less than 0.01). These results suggest that ET-1 and ET-3 have some physiological effects on the rat median eminence.     

Changes in adipocyte hormones leptin, resistin, and adiponectin in thyroid dysfunction

Thyroid hormones as well as the recently discovered secretory products of adipose tissue adiponectin and resistin take part in energy metabolism. To study the changes in the adipocyte hormones with changes in the thyroid functional status, we measured adiponectin, resistin, and leptin in 69 subjects with Graves' disease before and 32 patients at follow up after treatment for hyperthyroidism at hypothyroid state. Concentrations of serum adiponectin and resistin were higher in hyperthyroid state than in hypothyroid state (adiponectin: 5.73 +/- 1.1 vs. 3.0 +/- 0.5 ng/ml, P = 0.03) (resistin: 6.378 +/- 0.6 vs. 5.81 +/- 0.57 ng/ml, P < 0.0001). Resistin levels correlate positively with free t4(r = 0.37, P < 0.01), free t3 levels(r = 0.33, P < 0.01) and negatively with TSH(r = -0.22, P < 0.05). Adiponectin levels correlate with free t4(r = 0.33, P < 0.01) and free t3 (r = 0.44, P < 0.01). Though the adiponectin levels did not correlate with leptin or resistin levels, strong positive correlation of both resistin and adiponectin with thyroid hormones is noted. Serum levels of leptin did not change with change in the thyroid functional status (leptin: 53.38 +/- 2.47 vs. 55.10 +/- 2.58 NS). Leptin levels did not correlate with resistin and adiponectin. We conclude that thyroid function has effect on adipocyte hormones adiponectin and resistin but not leptin.     

Thyroid status and beta-agonistic effects on cytosolic calcium concentrations in single rat cardiac myocytes activated by electrical stimulation or high-K+ depolarization.

The effects of the thyroid status on the cytosolic free Ca2+ concentration ([Ca2+]i) in single cardiomyocytes were studied at rest and during contraction. The mean resting [Ca2+]i increased significantly from the hypothyroid (45 +/- 4 nM) through the euthyroid (69 +/- 12 nM) to the hyperthyroid condition (80 +/- 11 nM) at extracellular Ca2+ concentrations ([Ca2+]o) up to 2.5 mM. At [Ca2+]o above 2.5 mM the differences in [Ca2+]i between the groups became less. The amplitude of the Ca2+ transients became higher in all groups with increasing [Ca2+]o (1, 2.5 and 5 mM), and was highest at all [Ca2+]o in hyperthyroid myocytes. The beta-agonist isoprenaline elevated peak [Ca2+]i during contraction and increased the rate of the decay of the Ca2+ transients to a greater extent in hypothyroid myocytes than in hyperthyroid myocytes. Depolarization with high [K+]o induced a large but transient [Ca2+]i overshoot in hypothyroid myocytes, but not in hyperthyroid myocytes, before a new elevated steady-state [Ca2+]i was reached, which was not different between the groups. When isoprenaline was added to K+ o-depolarized myocytes after a steady state was reached, a significantly larger extra increase in [Ca2+]i was measured in the hypothyroid group (28%) compared with the hyperthyroid group (8%). It is concluded that in cardiac tissue exposed to increasing amounts of thyroid hormones (1) [Ca2+]i increases at rest and during contraction in cardiomyocytes and (2) interventions which favour Ca2+ entry into the cytosol [( Ca2+]o elevation, high [K+]o, beta-agonists) tend to have less impact on Ca2+ homoeostasis.