A case of the syndrome of inappropriate secretion of TSH.

A girl aged 4 years with goiter and accelerated physical and skeletal growth was found to be hyperthyroid on the basis of elevated serum thyroid hormone level, nevertheless both the basal TSH and TSH responsiveness to TRH were maintained within the normal range. Serum TSH was suppressed by exogenous T3 and dexamethasone administration, but not significantly changed after propylthiouracil (PTU) treatment. The diurnal rhythmicity of anterior pituitary hormones was preserved with the high nocturnal peak of TSH and prolactin. Clinically, neither thyrotoxic signs nor evidences of pituitary tumor were observed. Her accelerated growth and elevated thyroid hormone level appeared to be induced by inappropriate secretion of TSH. In view of the literature, this is the first case of the syndrome of inappropriate secretion of TSH excluding the neoplastic origin in Japan.     

Clinical study on early changes in thyroid function of hyperthyroidism treated with propylthiouracil and a relatively small dose of iodide.

In order to compare the acute effects of three kinds of antithyroid agents of iodide (I-), propylthiouracil (PTU) and PTU combined with iodide (PTU+I-) on thyroid function in hyperthyroid patients with diffuse goiter, serum concentrations of thyroxine (T4), triiodothyronine (T3), T3-resin sponge uptake (T3-RU) and free thyroxine index (FT4I) were employed as thyroid function parameters. In the group given iodine (1 mg/day) as iodinated-lecithine, the initial values of T4, T3, T3-RU and FT4I were 20.9 +/- 1.6 microng/100 ml (T4), greater than 740 ng/100 ml (T3), 49.5 +/- 2.3% (T3-RU) and 14.7 +/- 1.8 (FT4I). At the end of one week of therapy, they decreased clearly to 15.6 +/- 2.2 microng/100 ml, 457 +/- 87 ng/100 ml, 42.2 +/- 4.0% and 9.7 +/- 2.4. The so-called "escape phenomenon" from iodide inhibition was observed in serum T4, T3-RU and FT4I values at the end of two weeks of iodide therapy, while serum T3 continued to decrease but the value of T3 was far outside of the normal range. In the PTU group (300 mg/day), thyroid function parameters were 22.5 +/- 0.8 microng/100 ml (T4), greater than 592 ng/100 ml (T3), 54.9 +/- 1.0% (T3-RU) and 18.7 +/- 1.0 (FT4I) before treatment. They decreased continually week by week. At the end of four-week treatment with PTU, the value of each thyroid function parameter was 11.1 +/- 1.9 microng/100 ml, 229 +/- 56 ng/100 ml, 36.6 +/- 4.4% and 5.7 +/- 1.7. In the group of hyperthyroidism simultaneously given both PTU and iodide (300 mg/PTU and 1 mg/iodine), these thyroid function parameters decreased as well as in the group treated with PTU alone for more than two weeks. More rapid or significant decrease of T4, T3, T3-RU and ft4i in PTU+I- group than in PTU group was observed in the present study. These results suggested strongly that iodide alone was not an adequate therapy for hyperthyroidism as well known and they were also compatible with the idea that the concomitant administration of PTU and iodide was more effective in the early phase of therapy of hyperthyroidism than PTU alone.     

Effect of active and passive immunization with TRH on plasma TSH response to propylthiouracil.

The role of thyrotropin-releasing hormone (TRH) in the secretion of TSH from the anterior pituitary was investigated in rats by active and passive immunization with TRH. The plasma TSH response to propylthiouracil (PTU) in TRH-bovine serum albumin (BSA)-immunized rats was significantly lower than that of BSA-immunized or non-immunized rats. Similarly, the increased plasma TSH level following PTU treatment was significantly suppressed after iv injection of antiserum to TRH. However, the decline in plasma TSH levels was not complete. The results of the present study indicate, at least in part, the physiological significance of endogenous TRH in the regulation of pituitary TSH secretion.     

Development of young rats and rabbits exposed to a strong electric field

Body growth and circulating levels of hormones were assessed in young rats and rabbits exposed to a 50-Hz electric field of 50 kV/m. Eight-week-old male rats were exposed 8 h/day for 4 weeks and rabbits were exposed 16 h/day from the last 2 weeks of gestation to 6 weeks after birth. The body and the organ growth of exposed rats were not statistically different from those of sham-exposed controls. No important differences from controls were observed in plasma levels of corticosterone, TSH, ACTH, and T4 or in adrenal levels of epinephrine, norepinephrine, and corticosterone although T3 was slightly, but significantly, decreased. No large histological changes in the thyroid or adrenals were noted. In rabbits, organ and body weights of exposed animals were comparable to those of controls. Plasma levels of various hormones (ACTH, GH, T3, T4, corticosterone, cortisol), serum glucose, triglycerides, and cholesterol were not significantly altered. Adrenal content of cortisol was lower, however, in exposed rabbits. No histological changes of the thyroid or adrenal glands were observed.     

Insulin secretion and action in the hyperthyroid rat

To gain insight into the mechanism of the altered carbohydrate metabolism in thyrotoxicosis, intravenous glucose tolerance tests (IVGTT) and pancreatic suppression tests (PST) were performed in hyperthyroid rats (0.1 mg/kg T4 X 5 days) to assess insulin secretion and action in vivo. Thyroid hormone injections significantly increased T4 levels (182.8 nM +/- 11.6 (SEM) versus 50.2 +/- 6.4; P less than 0.001) and baseline glucose concentrations (9.3 mM +/- 0.2 versus 7.1 +/- 0.2; P less than 0.001). Body weights, basal insulin concentrations, glucose concentrations during IVGTT, glucose disappearance rates and steady state plasma glucose levels (SSPG) were normal. Insulin concentrations during the glucose tolerance test and during the PST were significantly decreased. The metabolic clearance rate of insulin (ml/min/kg +/- SEM) was significantly (P less than 0.01) increased (54.4 +/- 3.5 versus 41.6 +/- 2.3) in the hyperthyroid rats. If the different baseline glucose values were subtracted from the glucose concentrations achieved during the 2 tests, both the glucose disappearance rate and the fall in SSPG levels were significantly enhanced in the T4-injected animals. Thus, in the hyperthyroid rat, insulin secretion is decreased, the clearance of insulin is increased and insulin sensitivity is either normal or possibly enhanced.     

Partial hepatectomy alters serum hormone levels in rats.

The level of thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), thyroxine (T4), 3,5,3'-L-triiodothyronine (T3), corticosterone, testosterone and insulin in serum were measured at 1, 12, 48 and 120 h after partial hepatectomy (PH) or sham operation in rats. After PH the level of ACTH and corticosterone was significantly elevated while that of TSH, T4 and testosterone was decreased and returned to the values found in sham operated animals within 5 days. The level of T3 was unchanged. These results show an increase in the function of pituitary-adrenal axis and a decrease in that of pituitary-thyroid axis shortly following PH with the tendency to return to normal function within five days.     

Vasopressin and A1 noradrenaline turnover during food or water deprivation in the rat

In the present study, we have examined in Wistar rats the effects of food or water deprivation of 3 days on the hypophyso-adrenal axis, vasopressinergic system and activity of A1 noradrenergic brain stem cell group, which is involved in the control of the hypothalamic neuro-endocrine activity. Levels of adrenocorticotropic hormone (ACTH) and vasopressin (AVP) were determined by radio-immunoassay, and corticosterone level was determined by fluorimetric method. Plasma levels of ACTH and corticosterone were greatly increased in both groups of rats. In water-deprived rats, plasma AVP (13.83 +/- 1.63 vs. 3.03 +/- 0.23 pg/ml) and osmolality levels were significantly elevated with a marked decrease of AVP hypophysis content (272 +/- 65 vs. 1098 +/- 75 ng/mg protein), but not in food-deprived rats in which osmolality did not change and AVP remained stocked (2082 +/- 216 ng/mg protein) in the hypophysis without release in the plasma (1.11 +/- 0.23 pg/ml). These observations indicated that both food-deprivation and water-deprivation stimulated the pituitary adrenal axis thereby suggesting a stress state. AVP production is stimulated both by fluid and food restriction but is secreted with differential effects: during food restriction AVP secretion is limited to supporting the hypothalamic pituitary-adrenal system.     

Competitive protein-binding radioassay of corticosterone in the plasma of the frog, Rana esculenta L. (author's transl)]

1. Plasma corticosterone levels were measured in the plasma of the edible frog, Rana esculenta, by a competitive protein-binding radioassay method using baboon plasma as CBG source. 2. This technique was sensitive enough to make the assessment of corticosterone levels in 50 microliter plasma samples possible. The assay sensitivity threshold reached 0.5 ng per tube and the corticosterone rate assessment was correct between 0 and 5 ng. The specificity was tested, using 12 different steroids (fig. 2) : baboon CBG had very slight avidity for aldosterone, the second circulating steroid in frog plasma. 3. Using this technique, we have shown that plasma corticosterone underwent seasonal variations. Plasma corticosterone levels, in animals captured in nature during February and June, were 1.51 +/- 0.06 microgram/100 ml (n = 60) and 2.76 +/- 0.14 microgram/100 ml (n = 36), respectively, as appeared in table III. 4. It appeared that the interrenal gland of the frog was not totally dependent on pituitary ACTH, since total hypophysectomy reduced, but did not suppress, corticosterone secretion (table III).     

Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats

Hyperalphalipoproteinemia, characterized by increased plasma concentrations of apoA-I and of HDL lipid and protein, was observed in rats treated with triiodothyronine (T(3)) for 7 days. The increase in the plasma HDL apoproteins was general for apoC, apoE plus A-IV, and apoA-I, as determined by isoelectric focusing. Hypotriglyceridemia, characterized by decreased concentrations of VLDL and apoB, was also observed in the hyperthyroid state. Although in the mildly hypothyroid animals (propylthiouracil-treated), hepatic metabolism of free fatty acid is shifted toward esterification to triglyceride and VLDL formation, as we reported previously, plasma HDL and apoA-I concentrations were not different from control plasma values, while the d 1.006-1.063 g/ml (IDL + LDL) lipoprotein fraction tended to be increased. In general, the proportion of apoE in the (IDL + LDL) fraction of the hypothyroid rat was greater than in controls and hyperthyroid animals, while the proportion of apoE tended to be lower in VLDL from both hypo- and hyperthyroid rats than in VLDL from controls. An enhanced release of apoA-I by perfused livers isolated from rats treated with T(3) was also observed; this enhanced output of apoA-I may explain, in part, the hyperalphalipoproteinemia observed in these rats. The depressed net output of apoA-I in vitro by perfused livers from rats treated with propylthiouracil (PTU) was not expressed in a statistically significant diminished plasma concentration of HDL or apoA-I in the intact animals. Treatment with T(3) also resulted in modification of the content of essential fatty acids in various lipid classes. Linoleic acid residues were significantly reduced and arachidonic acid content was increased in plasma phospholipids and esterified cholesterol in T(3)-treated rats. However, the relative fatty acid composition of unesterified fatty acids and triglyceride fatty acids was not altered by T(3) treatment. PTU treatment had no effect on fatty acid distribution in any of the plasma lipids. Secretion of biliary lipids was increased in perfused livers from T(3)-treated rats, while treatment with PTU did not affect release of lipids in the bile. These observations suggest a regulatory role for thyroid hormones that determine concentration and composition of plasma HDL and other lipoproteins.-Wilcox, H. G., W. G. Keyes, T. A. Hale, R. Frank, D. W. Morgan, and M. Heimberg. Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats.     

Inhibitory effect of large doses of propylthiouracil and methimazole on an increase of thyroid radioiodine release in response to thyrotropin.

Thyroidal radioiodine release increased shortly after a single injection of small doses of PTU, while moderate doses of MMI produced a similar increase of thyroidal radioiodine release with a latency of 7-9 hr. Large doses of PTU and MMI failed to augment thyroidal radioiodine release for at least 29 to 34 hr after the initial administration of goitrogens, although plasma TSH increased significantly because of goitrogen administration. An increase of thyroid hormone release in response to exogenous TSH was depressed by PTU and MMI in rats and mice treated with T4. Since this depression of TSH action only continued for a short period in spite of continuous administration of goitrogens, and since final thyroidal radioiodine release rate was similar to that produced by small doses of PTU, the effects mentioned were not simply due to general toxic action of goitrogens. It is suggested that large doses of PTU and MMI not only block thyroid hormone synthesis but also interfere with the action of TSH on thyroid hormone secretion.     

Abnormalities of the thyroid hormone negative feedback regulation of TSH secretion in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) are characterized by several neuroendocrine abnormalities including a chronic hypersecretion of thyrotropin (TSH) of unknown etiology. We hypothesized that the inappropriately high TSH secretion in SHR may be the result of an impaired thyroid hormone negative feedback regulation of hypothalamic thyrotropin-releasing hormone (TRH) and/or pituitary TSH production. To test this hypothesis, SHR or their normotensive Wistar-Kyoto (WKY) controls were treated with either methimazole (0.02% in drinking water) to induce hypothyroidism or administered L-thyroxine (T4) at a dose of 0.8 or 2.0 micrograms/100 g body weight/day to induce hyperthyroidism. All treatments were continued for 14 days after which animals were killed under low stress conditions. TSH concentrations in plasma and anterior pituitary tissue were 2-fold higher (P less than 0.01) in euthyroid SHR compared to WKY control rats while thyroid hormone (T3 and T4) levels were in the normal range. Hypothyroidism induced by either methimazole or thyroidectomy caused a significant (P less than 0.01) rise of plasma TSH levels in both WKY and SHR rats. However, relative to the TSH concentrations in control animals, the increase of plasma TSH in SHR was significantly blunted (P less than 0.01) in comparison to the WKY group. Hypothyroidism caused a significant depletion of TRH in stalk-median eminence (SME) tissue in both groups of rats. However, no differences between SHR and WKY rats were observed. The administration of thyroid hormone caused a dose dependent suppression of plasma TSH levels in both strains of rats. However, at both doses tested plasma TSH concentrations in SHR rats were significantly less suppressed (P less than 0.05) than those in WKY animals. Under in vitro conditions basal and potassium induced TRH release from SMEs derived from SHR was significantly (P less than 0.05) higher than that from WKY rats, whether expressed in absolute terms or as percent of content. These findings suggest that the thyroid hormone negative feedback regulation of TSH secretion may be impaired in SHR rats. Our data do not allow conclusions as to whether defects in the regulation of TSH production are located exclusively at the hypothalamic level. Since the overproduction of hypothalamic TRH and hypophysial TSH should lead to an increased thyroid hormone biosynthesis other defects in the hypothalamus-pituitary-thyroid-axis may contribute to the abnormal regulation of TSH secretion in SHR rats.     

Effects of lithium on the hypothalamo-pituitary-adrenal axis

The effect of lithium on the hypothalamo-pituitary-adrenal axis was studied in vivo and in vitro. The levels of plasma vasopressin, ACTH and corticosterone increased after the administration of lithium (LiCl 4 mmol/kg BW, 11 days) in rats, while the tissue vasopressin concentration in the median eminence, the rest of the hypothalamus and the posterior pituitary was decreased. The CRF concentration in the posterior pituitary increased markedly, but it did not change significantly in the median eminence or the rest of the hypothalamus. The elevated plasma ACTH level might be at least partly due to the increased vasopression secretion. Lithium stimulated ACTH secretion per se and also enhanced vasopressin-induced ACTH secretion in cultured pituitary cells and in half pituitary incubations, while it did not affect CRF-induced ACTH secretion. Lithium inhibited CRF-induced cAMP accumulation in half pituitary incubations, while lithium and vasopressin did not affect cAMP accumulation per se or even when administered together. The results suggest that lithium-induced ACTH release is via a cAMP-independent mechanism. Thus, it is possible that lithium stimulates ACTH release by acting directly on the corticotroph, stimulating vasopressin release and potentiating vasopressin-induced ACTH release.     

Effect of synthetic atrial natriuretic polypeptide on hemorrhage-induced adrenocorticotropin secretion of the rat

The effect of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on the in vivo and in vitro release of ACTH and corticosterone was examined. In the in vivo study ACTH and corticosterone responses to rapid 2-ml/rat hemorrhage were measured in sixteen conscious rats after alpha-hANP administration. The hemorrhage increased plasma ACTH and corticosterone concentrations in the control group of rats (p greater than 0.01). ANP inhibited hemorrhage-induced ACTH secretion (p less than 0.05), but the plasma corticosterone response was not affected. In the in vitro study a high concentration of ANP (1 microM) reduced basal corticosterone secretion from the isolated rat adrenal gland (p less than 0.05), but the response to ACTH (10 ng/ml) and dibutyryl cyclic AMP (0.5 mM, 5.0 mM) was not affected. Our data suggest that ANP inhibits hemorrhage-induced ACTH secretion from the anterior pituitary but inhibits corticosterone secretion from the adrenal gland very weakly.     

Effect of L-NAME, a specific nitric oxide synthase inhibitor, on corticotropin-releasing hormone-elicited ACTH and corticosterone secretion.

This study was designed to determine the role of endogenous nitric oxide (NO) in the corticotropin-releasing hormone (CRH)-induced ACTH and corticosterone secretion, as well as possible involvement of hypothalamic dopamine and noradrenaline in that secretion in conscious rats. CRH given i.p. stimulated dose-dependently the pituitary-adrenocortical activity measured 1 h later. Dexamethasone (0.2 mg/kg i.p.) injected 1 h before CRH (1 microg/kg i.p.) totally abolished the CRH-elicited ACTH and corticosterone secretion, indicating a predominantly pituitary site of CRH-evoked stimulation. L-arginine (120 mg/kg i.p.) and N(omega)-nitro-L-arginine methyl ester (L-NAME 5-10 mg/kg i.p.) did not markedly affect the basal plasma ACTH and corticosterone levels. L-NAME given 15 min before CRH markedly, but not significantly, augmented the CRH-induced ACTH response, and enhanced more potently and significantly the corticosterone response. Pretreatment with L-arginine, a substrate for NOS, slightly diminished the CRH-induced ACTH response and considerably reduced the corticosterone response. L-arginine also significantly reversed the L-NAME-evoked increase in the CRH-induced ACTH and corticosterone secretion. L-NAME did not markedly alter the CRH-induced hypothalamic dopamine and noradrenaline levels, while L-arginine significantly increased noradrenaline level. However, those alterations were not directly correlated with the observed changes in ACTH and corticosterone secretion. These results indicate that in conscious rats NO plays a marked inhibitory role in the CRH-induced ACTH secretion and inhibits more potently corticosterone secretion. Hypothalamic dopamine and noradrenaline do not seem to be directly involved in the observed alterations in ACTH and corticosterone secretion.     

Potentiation by indomethacin of TRH-induced TSH secretion in the rat.

We have studied the effect of two inhibitors of prostaglandin synthesis on the basal and TRH-stimulated plasma TSH levels in the rat. Animals were injected sc daily with indomethacin 3 mg/0.5 ml) or aspirin (16--30 mg/0.5 ml) for 3 days. The plasma T4 and T3 were consistently lower in the indomethacin or aspirin groups than in the controls, while the basal TSH levels did not change. Indomethacin treatment significantly potentiated the TSH response to synthetic TRH (20 ng. iv) in intact and thyroidectomized rats. The pituitary TSH content was markedly increased by indomethacin, while hypothalamic TRH content did not change. In contrast, aspirin inhibited the TSH response to TRH in intact rats, when pituitary TSH content decreased significantly. No potentiation by aspirin of TRH-stimulated TSH response in the thyroidectomized rats was observed. The increased sensitivity of plasma TSH response to exogenous TRH in the indomethacin group is presumably due to higher pituitary TSH content than in the controls. The action of indomethacin appears to be mediated, at least in part, at the pituitary level. In addition, there is a dissociation between the action of indomethacin and the action of aspirin in the TSH response to TRH.     

Sex differences in adrenocortical structure and function. XXVIII. ACTH and corticosterone in intact, gonadectomised and gonadal hormone replaced rats

Plasma ACTH and corticosterone (B) concentration, ACTH content in the anterior pituitary gland and B content in the adrenals were measured in intact, gonadectomised and testosterone or estradiol replaced rats. Plasma ACTH and B levels and adrenal B content were higher in female than male rats. Neither orchiectomy nor testosterone replacement had an effect on plasma ACTH and B concentration. Orchiectomy did not affect adrenal B content and decreased pituitary ACTH while testosterone significantly lowered ACTH and B content in studied glands. On the other hand ovariectomy did not change pituitary ACTH and adrenal B content and notably lowered concentrations of these hormones in the blood. Estradiol replacement resulted in an increase in plasma ACTH and B concentrations, an effect accompanied by a marked drop in pituitary ACTH and an increase in adrenal B. These findings indicate the distinct sex differences in basal plasma ACTH and B concentrations with higher values in female rats, an effect dependent on the stimulatory action of estradiol on pituitary-adrenocortical axis.     

Sleep-related growth hormone release in thyrotoxic patients before and during propylthiouracil therapy

Hyporesponsiveness of GH to insulin-induced hypoglycemia has previously been reported in hyperthyroid patients. In order to clarify the GH secretion in thyrotoxic patients, sleep-related increases in the serum GH concentration were investigated. Eight thyrotoxic females ranging in age from 7 to 15 were treated with PTU. Blood samples for measurement of GH were drawn every 15 minutes during the first few hours of sleep before and during the treatment lasting about three months. The mean maximum serum GH level before the treatment was 10.0 +/- 5.5 ng/ml (mean +/- SD); this rose to 23.2 +/- 14.6 ng/ml (P less than 0.02) during the treatment. The maximum value of more than 10 ng/ml was detected in only 3 out of the 8 patients before treatment. On the other hand, serum GH levels during PTU administration rose to above 10 ng/ml in all patients except one. It was revealed that sleep-related elevations of GH occurred early in sleep and in close association with a slow-wave EEG pattern. The results show that sleep-related GH release is low in the hyperthyroid state, but becomes significantly elevated during PTU administration. However, even in the hyperthyroid state, the sleep-related secretion of GH is closely correlated with the slow-wave sleep stage as in the euthyroid condition.     

An elevation of plasma ISH concentration in spontaneously hypertensive rats (SHR).

Thyroid activity was tested in two substrains of SHR. Plasma level and pituitary content of TSH increased significantly in both substrains of SHR. As a result, the thyroid weight and thyroidal radioiodine uptake increased significantly. Plasma T3 concentration was decreased in Kyoto substrain but was normal in NN substrain, while plasma T4 concentration decreased significantly in both substrains. Since the pituitary content and plasma level of TSH were significantly higher in spite of the normal concentration of plasma T3, it is concluded that the pituitary "hormostat" is set at a higher level at least in the NN substrain of SHR.     

Role of the pituitary in the effects of tonin on adrenal secretion of the rat

Chronically catheterized conscious rats were infused intravenously with tonin at 2.4 and 12 micrograms x kg-1 x min-1 for 2 h. Plasma aldosterone concentration (PAC) at the end of the experiment was 11.2 +/- 2.4 ng% in controls, 8.5 +/- 2.8 ng% in rats infused with tonin at the lower rate, and 26.2 +/- 3.6 ng% (p less than 0.01 vs. controls) in rats infused at the higher rate. Plasma corticosterone (PC) was significantly higher (p less than 0.05) in the group infused at the high rate while plasma renin activity (PRA) was significantly reduced in this group of rats. Plasma angiotensin II (AII) concentration was similar in all three groups. PAC was elevated after tonin infusion in the presence of AII blockade. PAC in conscious sodium-depleted rats infused with tonin was not significantly changed, but PRA was significantly reduced (p less than 0.01). In chronically hypophysectomized rats, PAC remained unchanged by tonin infusion. The failure of tonin to stimulate aldosterone in hypophysectomized animals indicates a role of a pituitary hormone (probably ACTH) in the effect of tonin on adrenal secretion.