Effects of phenobarbital on hypothalamic-pituitary-thyroid axis in the rat

It has been reported that phenobarbital (PB) increases the peripheral clearance of T4 and T3 and decreases serum T4 and T3 concentrations in the rat, but serum TSH remains unchanged. To explore a possible direct effect of PB on TSH secretion at the hypothalamic-pituitary level, adult male rats were given PB 100 mg/kg or vehicle IP for 10 days. No difference in their thyroid weights was observed. In the PB-treated group serum T4 was decreased (PB, 3 +/- 0.2 micrograms/dl vs. control, 3.8 +/- 0.1 micrograms/dl, mean +/- SE, p less than .002), as was serum T3 (PB, 51 +/- 6 ng/dl vs. control, 70 +/- 5 ng/dl, p less than .05), but serum TSH remained unchanged. Pituitary TSH and hypothalamic TRH contents also were unchanged. Further studies were carried out similarly in the thyroidectomized hypothyroid rat to eliminate the effect of PB on serum T4 and T3 levels. PB or vehicle were started two days after thyroidectomy. By postoperative day 12, TSH levels in the PB-treated rats were lower than in the controls (PB, 697 +/- 62 microU/ml vs. control, 891 +/- 53 microU/ml, p less than .05). Pituitary TSH and hypothalamic TRH contents again were similar in both groups. When TRH (500 ng/kg body weight, IV) was given, the increment in serum TSH at 10 minutes was significantly lower in the PB group (PB, 53 +/- 26 microU/ml vs. control, 131 +/- 18 microU/ml, p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Different rates of thyrotropin suppression after total body scan in patients with thyroid cancer: effect of an optimal saturation regimen with thyroxine or triiodothyronine

The rate of TSH suppression in patients with differentiated thyroid cancer, when therapy is re-started after total body scan, was investigated adopting an optimal saturation regimen, either with T4 or with T3. The first group of 6 patients received T4 as follows: from day 1 to 7 = 22, 11, 6, 4, 3.5, 3.2, 3.2 micrograms/day/kg body weight (b w) and continued with 3.2; the second group of 8 patients received T3 as follows: 2.4, 1.8, 1.4, 1.2, 1.1, 1.1 micrograms/day/kg BW and continued with 1.1. At time 0, TSH levels were high in all patients (range 80-180 microU/ml); T3 and T4 levels were below the limit of detectability. After the beginning of the therapy, the decrease of TSH levels and the inhibition of TSH response to TRH occurred faster in patients taking T3 than in patients taking T4. In the former, at day 7, mean basal TSH level was 1.9 +/- 0.5 microU/ml and 30 min after 200 micrograms TRH iv mean TSH level was 9.9 +/- 4.4 microU/ml; at day 10 they were 1.4 +/- 0.5 and 2.7 +/- 0.8 microU/ml respectively. In the latter, at day 7, mean basal TSH level was 4.6 +/- 3.9 microU/ml and 30 min after TRH mean TSH level was 42.2 +/- 34.2 microU/ml. Only at day 20 they were 0.8 +/- 0.2 and 1.2 +/- 0.9 microU/ml respectively. In patients taking T3 by saturation regimen, serum levels of T3 rose rapidly to supranormal values (at day 3, mean serum T3 level was 297 +/- 62 ng/100 ml), reached a peak at day 5 (340 +/- 62 ng/100 ml) and decreased thereafter, always remaining however above normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial

Controversy remains about the value of combined treatment with levothyroxine (LT4) and liothyronine (LT3), compared with LT4 alone in primary hypothyroidism. We compared combined treatment with LT4 and LT3 in a ratio of 5:1 or 10:1 with LT4 monotherapy. We conducted a double-blind, randomized, controlled trial in 141 patients (18-70 yr old) with primary autoimmune hypothyroidism, recruited via general practitioners. Inclusion criteria included: LT4 treatment for 6 months or more, a stable dose for 6 wk or more, and serum TSH levels between 0.11 and 4.0 microU/ml (mU/liter). Randomization groups were: 1) continuation of LT4 (n = 48); 2) LT4/LT3, ratio 10:1 (n = 46); and 3) LT4/LT3, ratio 5:1 (n = 47). Subjective preference of study medication after 15 wk, compared with usual LT4, was the primary outcome measure. Secondary outcomes included scores on questionnaires on mood, fatigue, psychological symptoms, and a substantial set of neurocognitive tests. Study medication was preferred to usual treatment by 29.2, 41.3, and 52.2% in the LT4, 10:1 ratio, and 5:1 ratio groups, respectively (chi2 test for trend, P = 0.024). This linear trend was not substantiated by results on any of the secondary outcome measures: scores on questionnaires and neurocognitive tests consistently ameliorated, but the amelioration was not different among the treatment groups. Median end point serum TSH was 0.64 microU/ml (mU/liter), 0.35 microU/ml (mU/liter), and 0.07 microU/ml (mU/liter), respectively [ANOVA on ln(TSH) for linear trend, P < 0.01]. Mean body weight change was +0.1, -0.5, and -1.7 kg, respectively (ANOVA for trend, P = 0.01). Decrease in weight, but not decrease in serum TSH was correlated with increased satisfaction with study medication. Of the patients who preferred combined LT4/LT3 therapy, 44% had serum TSH less than 0.11 microU/ml (mU/liter). Patients preferred combined LT4/LT3 therapy to usual LT4 therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT4/LT3 combination therapy. Decrease in body weight was associated with satisfaction with study medication.     

Effect of diabetes mellitus on thyrotropin release from isolated rat thyrotrophs.

The effect of streptozotocin-induced diabetes on thyrotropin (TSH) secretion was studied in vitro in male rats, using purified thyrotrophs isolated by centrifugal elutriation. The development of diabetes was associated with a significant fall in serum T4 (4.9 +/- 1.5 vs. 1.2 +/- 0.7 micrograms/dl, control vs. diabetic), T3 (59 +/- 16 vs. 20 +/- 9 ng/dl) and TSH (53 +/- 22 vs. 23 +/- 18 microU/ml). In vitro, basal TSH release was lower in cells from diabetic rats (1570 +/- 248 microU/10(6) cells) than in controls (2612 +/- 765 microU/10(6) cells) after 48 h in culture. Furthermore, thyrotropin-releasing hormone (TRH)-induced TSH release was decreased about 30% and the intracellular TSH content was also reduced 45% in diabetic rat thyrotrophs compared with controls. The addition of 200 microU/ml of insulin in the incubation media did not change the TRH-stimulated TSH release, but it decreased the basal TSH release by 42%. Preincubation of thyrotrophs with glucose (25 mM) did not impair the basal or TRH-stimulated TSH release. In the same experimental conditions, no effect of insulin or glucose was seen on the basal or TRH-stimulated TSH release from thyrotrophs of diabetic rats. Preincubation of thyrotrophs with 10, 100, or 1000 nM of T4 for 48 h decreased basal TSH release by 27%, 45%, and 48%, respectively, and reduced TRH-induced TSH release by 46%, 48%, and 55%; 100 nM T4 also reduced TRH-induced TSH release from diabetic thyrotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of methimazole on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat

Methimazole (MMI) administration decreases the incidence and intensity of experimentally induced lymphocytic thyroiditis (LT) in the female August rat and male A/J mouse. Spontaneous LT frequently occurs in the insulin-dependent type-I diabetic (DM) BB/W rat. Experiments were carried out to determine whether MMI administration to BB/W rats from 30 to 120 days of age would affect the incidence and intensity of spontaneous LT and the incidence of spontaneous DM. A total of 870 ng MMI/gm BW or saline (C) were administered ip daily to 77 BB/W rats beginning at age 30 days. Rats were killed at 120 days, blood obtained for measurement of serum T4, TSH, and anti-Tg Ab (ELISA), and thyroids removed for histology. MMI administration was associated with a decrease in the incidence of LT (31% vs. 55%; p less than 0.05) but no difference in the severity of the LT. Serum T4 was similar in the MMI and C groups, but serum TSH was slightly but significantly higher in MMI treated rats [43 +/- 6 (mean +/- SE) microU/ml vs. 30 +/- 2.5; p less than 0.05]. Serum anti-Tg Ab levels increased with age but MMI administration did not affect this rise. There was no significant difference in the incidence of insulin-dependent DM between the MMI and C rats (MMI, 56%; C, 74%). Conclusion: MMI administration to the genetically predisposed insulin-dependent diabetes and LT prone BB/W rat during the age when LT spontaneously occurs reduced the incidence of LT.     

Clinical evaluation of routinely applied highly sensitive TSH-RIA

Forty-one routine TSH assays were carried out by applying newly developed, highly sensitive TSH RIA (T. Mori, et al., Folia Endocrinol. Jap., 56: 1231, 1980). B/B0 percent of the least standard point (0.156 microU/ml) was consistently lower than B0 and higher than that of 0.31 microU/ml. The distributions of assayed TSH concentrations in 1394 sera revealed that 34.8% of the total were in an undetectable range when measured by conventional method (less than 1.0 microU/ml), but this method picked up 16.4% (0.156-1.0 microU/ml), and only 5.4% exceeded the upper limit (20 microU/ml). TRH test results (500 micrograms i.v. bolus) in 45 cases of thyroid disorders with low or normal basal TSH revealed that the peak TSH of those with basal TSH of 0.156-1.0 microU/ml (8.98 +/- 4.15 microU/ml) was significantly different from those of less than 0.156 microU/ml or 1.0-3.2 microU/ml. Further, TSH concentrations in 19 patients after T3 administration (75 micrograms X 7 days) were 0.183 +/- 0.073 microU/ml, and all but one (0.43 microU/ml) showed values lower than the normal range (0.31-3.2 microU/ml). Thyroid hormone concentrations in cases with TSH of 0.156-1.0 microU/ml were limited in the ranges of less than 300 ng/dl T3 and/or less than 15 micrograms/dl T4, and these were considered to be the threshold of definite TSH inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

IODIDE ADMINISTRATION ENHANCES THYROTROPHIN RESPONSIVENESS TO THYROTROPHIN-RELEASING HORMONE DURING FASTING: EVIDENCE FOR NORMAL PITUITARY FEEDBACK REGULATION

Short-term fasting in humans is associated with diminished delta TSH to TRH. The purposes of the present study were to reassess basal TSH levels and TRH responsiveness during fasting utilizing a sensitive radioimmunoassay (RIA: sensitivity 0.3 microU/ml; normal range 0.66-2.98 microU/ml) and to determine if normal feedback regulation is maintained during the fasting state. Eight control subjects (C) and six iodide-treated (I) subjects (262 mg/d) were studied in the fed state and on day 10 of fasting. T3, T4, and TSH were measured by RIA, and free T4 and free T3 by equilibrium dialysis. Basal serum TSH levels in the control group were 2.0 +/- 0.3 microU/ml (mean +/- SEM) in the fed state and increased to 14.7 +/- 3.5 microU/ml 20 min after TRH administration. The fasting basal TSH level of 1.6 +/- 0.3 microU/ml was significantly decreased (P less than 0.01) compared to control, as was the level of 8.8 +/- 2.3 microU/ml (P less than 0.01) obtained 20 min after TRH. In the iodide-treated group the basal TSH level was 1.4 +/- 0.2 microU/ml during feeding which increased (P less than 0.025) to 2.9 +/- 0.7 microU/ml during fasting; the TSH value 20 min after TRH was 12.6 +/- 2.5 microU/ml while feeding and 17.3 +/- 2.9 microU/ml while fasting. Free and total T3 decreased during fasting in both groups. Total T4 was unchanged between the fed and fasted periods in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoimmune thyroid disease in the puerperium. Predictive value of thyroid enlargement and related hormonal changes occurring during pregnancy

The incidence of goiter detected during pregnancy and its significance as an indicator of autoimmune thyroid disease after delivery was investigated in a sample of 707 pregnant women (81% in their 2nd trimester of gestation). Goiter was detected in 106 subjects (15%). Blood T4, T3, TSH, free T4 index (FT4I), antimicrosomal antibodies (AMA) and urinary iodine excretion were measured in these women and in a control group of gravidas without goiter. These measurements were repeated at 1 and 3 months after delivery. Compared with controls during pregnancy, subjects with goiter had lower FT4I values (11.0 +/- 2.8 vs 9.0 +/- 1.8; p less than 0.01) and higher TSH values (2.9 +/- 0.6 microU/ml vs 4.2 +/- 2.1 microU/ml; p less than 0.01). In contrast, T4, T3, AMA and urinary iodine excretion values were similar in both groups. In subjects with goiter FT4I values increased over pregnancy levels at 1 month (11.2 +/- 2.0; p less than 0.05) and 3 months (14.0 +/- 3.0; p less than 0.05) after delivery; in 29% a biochemical hyperthyroidism (FT4I greater than 13.5) was detected. During the same period TSH values decreased significantly (1 month: 1.9 +/- 0.7 microU/ml; p less than 0.05; 3 months: 2.7 +/- 3.0 microU/ml; p less than 0.05). Frequency of positive AMA increased from 8.6% during pregnancy up to 32.1% in the post-delivery period (p less than 0.01). In the control group no variation in the FT4I, TSH or AMA were observed after delivery. These results indicate that goiter during pregnancy is common in Chilean gravidas and that it has predictive value for the appearance of autoimmune thyroid disease after delivery.     

Effects of oestradiol benzoate on the pituitary secretion and peripheral kinetics of thyrotrophin in the rat

Previous works from this laboratory have demonstrated that oestradiol benzoate (EB) in euthyroid male and female rats induced a significant decrease in the pituitary content of TSH while serum levels of this hormone remained normal. The present work studied the effects of EB (25 micrograms/100 g body weight, during 9 days) on the peripheral metabolism of [125I]rTSH and on the pituitary and plasma concentration of TSH in euthyroid and hypothyroid rats. No significant variations were observed in [125I]rTSH kinetics of EB-treated euthyroid rats vs untreated controls: fractional turnover rate 2.8 +/- 0.2 vs 3.0 +/- 0.3%/min, distribution space 6.5 +/- 0.4 vs 6.8 +/- 0.5 ml/100 g body weight, disposal rate 18.4 +/- 2.4 vs 18.1 +/- 1.9 microU/100 g/min and extrapituitary pool 645 +/- 42 vs 614 +/- 43 microU/100 g body weight. Similarly, in hypothyroid rats oestrogens induced no changes in TSH kinetics except for an increase in distribution space (P less than 0.025). However, oestrogens decreased the pituitary pool of TSH (P less than 0.001) in both euthyroid and hypothyroid rats and increased the plasma TSH in hypothyroid animals (P less than 0.01), all vs their respective controls. Neither hypothyroid group had detectable plasma levels of T4 and T3. In summary: 1) the marked decrease of pituitary TSH with normal plasma TSH induced by EB appears unrelated to the peripheral metabolism of TSH, 2) the results from hypothyroid rats suggest that EB stimulates the release of TSH from the pituitary gland.     

Interaction of L-dopa and GHRH on GH secretion in normal men

To determine how L-dopa stimulates GH secretion, we investigated its interaction with GHRH in vivo. Six normal men were studied on 4 occasions: 1) L-dopa-TRH: 500 mg L-dopa orally followed by 200 micrograms TRH 60 min later; 2) L-dopa-GHRH-TRH: 100 micrograms GHRH 1-44 iv 30 min after L-dopa followed by 200 micrograms TRH iv; 3) GHRH-TRH: 100 micrograms GHRH iv at 0 min, 30 min later 200 micrograms TRH iv; 4) TRH test: 200 micrograms TRH iv as a bolus. After L-dopa-TRH GH-levels increased significantly from 0.6 micrograms/l to 25.8 +/- 9.6 (SE) micrograms/l at 60 min. Only a slight TSH and no PRL increase was observed after L-dopa-TRH. After L-dopa-GHRH-TRH the GH-increase was significantly higher (45.7 +/- 11.1 micrograms/l) compared to L-dopa-TRH alone. GHRH-TRH increased GH-levels to 52.5 +/- 12.1 micrograms/l, which was not significantly different from the GH-levels obtained when L-dopa-GHRH-TRH were given. TRH increased serum TSH and PRL to 6.3 +/- 0.7 microU/ml and 715 +/- 136 microU/ml, respectively, which was significantly higher compared to the TSH responses after L-dopa-TRH. The PRL and TSH increase after TRH only was also higher (TSH-max: 5.7 +/- 0.5 microU/ml; PRL-max: 899 +/- 154 microU/ml) compared to the TSH and PRL responses after L-dopa-TRH. Our results show that the combination of L-dopa with GHRH leads to the same GH response as GHRH only. However, both responses are significantly higher than the one after L-dopa alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The properties of prolactin secretion in patients with prolactin secreting pituitary adenomas

Plasma prolactin (PRL) responses to several exogenous agents are variable in patients with prolactinomas. In this study the factors determining the responsiveness to exogenous stimuli were investigated in 35 patients with prolactinomas. Among these patients, 14 patients were responder (greater than 150% increase of basal value) to TRH, sulpiride (DA D2-receptor blocker) and arginine, and remaining 21 were non-responder to these three agents. Plasma TSH responses to sulpiride, an indirect indicator of hypothalamic dopaminergic tone on pituitary gland, were similar between responder (delta TSH: M +/- SEM; 5.3 +/- 0.2 microU/ml) and non-responder (delta TSH: 5.6 +/- 0.2 microU/ml), and were greater than those in normal subjects (delta TSH: 0.7 +/- 0.2 microU/ml, n = 18) (P less than 0.001). The plasma PRL responses to dopaminergic agents (L-dopa, CB-154, dopamine) were greater in responders than in non-responders (% of basal: L-dopa, 33.7 +/- 3.7% vs 51.6 +/- 5.6% at 150 min, P less than 0.05; CB-154, 16.5 +/- 2.6% vs 30.9 +/- 2.8% at 6 hr, P less than 0.05; dopamine, 31.7 +/- 5.6% vs 44.9 +/- 4.3% at 90 min, P less than 0.05). When all patients were divided into microadenoma (n = 12) and macroadenoma patients (n = 23), there were no differences in plasma PRL responses to these agents between the two groups. Again, there were no differences in the duration of illness between the responder and non-responder patients (61.9 +/- 13.7 vs 54.1 +/- 12.0 months). During the short term CB-154 treatment (7.5mg/day for 3 approximately 5 weeks) in 8 responders and 15 non-responders, all responder patients showed normalization of plasma PRL levels, while such normalization was observed in only 6 non-responder patients. These results suggest that in prolactinoma patients variable responsiveness to several exogenous agents are depending on the sensitivity to several exogenous agents are depending on the sensitivity of prolactinoma itself, regardless of the endogenous hypothalamic dopaminergic tone, tumor size or duration of the illness.     

Caloric restriction does not alter thyrotropin secretion in hypothyroidism

The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.     

Thyrotropin releasing hormone (TRH) immunoreactivity and thyroid function in obesity

Circulating TRH-immunoreactive levels, the thyrotropin response to a TRH intravenous stimulation (200 micrograms) and thyroid hormone concentrations have been determined in 43 overweight subjects (body mass index 45 +/- 12 kg/m2, mean +/- s.d.) and 46 (body mass index 22 +/- 2 kg/m2) normal weight controls. The TRH levels measured by a recently developed, highly specific radioimmunoassay were similar among both groups (44 +/- 16 vs 40 +/- 12 fmol/ml, n.s.). The pattern of response of TSH to TRH was normal in the obese and no significant difference was observed between the peak TSH values of the obese and the normal group (8.3 +/- 2.8 vs 8.7 +/- 2.2 microU/ml, n.s.). No correlations were found between the degree of obesity and the concentrations of TRH, TSH and peripheral thyroid hormone levels. Three obese patients showed a delta-TSH of 18, 19 and 21 microU/ml at normal thyroid hormone concentrations as sign of latent hypothyroidism. These data indicate that in obesity: (a) the TSH response to i.v. TRH is not impaired, (b) circulating TRH-IR levels are not significantly changed and (c) the incidence of overt hypothyroidism is not increased.     

Serum thyrotropin concentrations in patients with Sheehan's syndrome: reevaluation of the usefulness in the diagnosis

Serum concentrations of thyroid-stimulating hormone (TSH) were determined, using a highly sensitive immunoradiometric assay (IRMA), in 10 patients with Sheehan's syndrome. Serum TSH levels in these patients were from 2.3 to 9.0 microU/ml, with the mean of 6.4 +/- 2.3(SD) microU/ml, and the data were similar to those measured by a conventional RIA method. The levels of serum TSH in these patients were normal or even higher than those of healthy women (1.8 +/- 1.3 microU/ml). After supplement therapy by cortisol, serum TSH levels decreased, but remained within the detectable range that was greater than 0.15 microU/ml. After supplement therapy by 1-thyroxine (T4), serum TSH levels moderately decreased in all patients, and excessive 1-T4 administration resulted in a fall of serum TSH levels to lower than the detectable limit. Thyroidal 123 I uptake was low in 3 out of 6 patients examined, which supports a recent hypothesis of reduced biological activity of the patient's TSH. While, the remaining 3 patients had normal thyroidal 123 I uptake, and administration of perchlorate had no effects on thyroidal radioactivity. Thus, it may be possible that in the former group of patients the TSH has a reduced biological activity, and in the latter group of patients, iodine trapping is intact but further synthesis and secretion of thyroid hormone from the gland are impaired. When the response of serum TSH to TRH was examined, the peak serum TSH levels increased in all patients. The peak TSH levels were 4.8 to 10.2 microU/ml with the mean of 7.5 microU/ml, but the data overlapped with those of normal subjects (peak level ranging 5.9 approximately 27.7 microU/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Iodine-induced thyroiditis and hypothyroidism in the hemithyroidectomized BB/W rat

We have recently reported that iodine administration (0.05% iodine in drinking water) to weanling, diabetes mellitus- and lymphocytic thyroiditis (LT)-prone Biobreeding Worcester (BB/W) rats strikingly increases the incidence of LT without occurrence of iodine-induced hypothyroidism, which frequently results when excess iodine is administered to euthyroid patients with Hashimoto's thyroiditis. Since hypothyroidism did not occur in the iodine-treated BB/W rats, hemithyroidectomy was carried out in 30-day-old BB/W rats to increase thyroid mass and functional reserve. Iodine administration for 60 days markedly increased antithyroglobulin antibodies (0.40 +/- 0.08 vs. 0.15 +/- 0.06 OD; P less than 0.02), the incidence of LT (68% vs. 13%; P less than 0.001), and thyroid weight of the residual lobe (10.5 +/- 0.7 vs. 6.3 +/- 0.3 mg/100 g BW; P less than 0.001) and induced hypothyroidism (T4, 2.5 +/- 0.2 vs. 3.0 micrograms/dL; P less than 0.05; T3, 25.1 +/- 1.9 vs. 37.5 ng/dL; P less than 0.001; TSH, 252 +/- 49 vs. 61 +/- 14 microU/mL; P less than 0.02). Hypothyroidism in the iodine-treated rats occurred primarily in those with LT. Similar studies were carried out in the non-diabetes mellitus-, non-LT-prone, genetically equivalent BB/W rats (W-line), the parent strain Wistar-Furth rats, and Sprague-Dawley rats. Iodine administration did not induce LT or antithyroglobulin antibodies in these three strains and did not affect thyroid function in Wistar-Furth and Sprague-Dawley rats. However, in the W-line rats, iodine excess did induce thyroid enlargement in the residual lobe (8.4 +/- 0.2 vs. 6.4 +/- 0.2 mg/100 g BW; P less than 0.001), a decrease in serum T3 (71.5 +/- 2.9 vs. 86.0 +/- 2.5 ng/dL; P less than 0.001), and an increase in serum TSH (344 +/- 65 vs. 69 +/- 6.0 microU/mL; P less than 0.001). It is evident, therefore, that hemithyroidectomy in BB/W rats sufficiently reduces functioning thyroid tissue, resulting in iodine-induced LT and hypothyroidism, similar to iodine-induced hypothyroidism in euthyroid patients with Hashimoto's thyroiditis. It is unclear, however, why iodine administration also induced hypothyroidism in hemithyroidectomized, genetically similar, W-line rats in the absence of LT. This observation suggests that iodine-induced hypothyroidism in rats may be genetically determined.     

Subclinical hypothyroidism is related to lower heel QUS in postmenopausal women

Recent findings suggest that thyroid stimulating hormone (TSH) is a negative regulator of skeletal remodeling by reducing both differentiation of osteoblasts and formation of osteoclasts. In addition, increased fracture risk in untreated hypothyroid patients has been reported to begin up to 8 years before diagnosis. The aim of the present study was to evaluate the effect of subclinical hypothyroidism on bone structure by using the heel QUS. Subjects were outpatients without any past or present history of thyroid disease. Among 210 postmenopausal women, 22 of 33 patients (Hypo), who had elevated serum TSH concentration (TSH>or=4 microU/ml) with normal serum free thyroxine (FT4) concentration, agreed to join to this study. We also randomly selected 24 control subjects (Cont) from 176 postmenopausal women with normal thyroid status. Calcaneus osteo sono assessment indices (OSI) of right feet were measured using the ultrasound bone densitometry AOS-100. Serum TSH concentrations in Hypo patients (5.31 +/- 1.3 microU/ml) were higher than those in Cont patients (2.05 +/- 1.1 microU/ml), and there was significant difference of FT(4) concentrations (Cont 1.33 +/- 0.15 ng/dl; Hypo 1.19 +/- 0.17 ng/dl). OSI and its Z-score in Hypo subjects (OSI, 2.138 +/- 0.152; Z-Score -0.322 +/- 0.504 SD, Mean SD) were significantly lower than those in Cont subjects (OSI, 2.347 +/- 0.243; Z-Score 0.322 +/- 0.91 SD, Mean +/- SD). Simple regression statistical analysis showed that OSI decreased according to the increase of serum TSH concentration (n = 47, P<0.037). In addition, multiple regression analysis showed that the elevation of serum TSH concentration was associated with the decrease of OSI. These results suggest that the elevation of serum TSH concentration in subclinical hypothyroidism affects not bone turnover but bone structure as assessed by QUS.     

Flow associated (endothelium dependent) vasodilation and TSH-levels in young normotensive and normoglycemic subjects.

BACKGROUND: Endothelial dysfunction (ED) is regarded as an early step in the development of atherosclerosis. Recent experimental data showed a crosstalk between endothelial NO-synthase activity and thyrotropin production. Therefore we studied whether basal TSH can predict flow associated vasodilation (FAD) in a cohort of healthy young subjects with normal TSH levels. PATIENTS AND METHODS: FAD was evaluated in 60 normotensive and normoglycemic subjects (mean age 34 years; range 18-50). The mean thyrotropin level was 1.43 +/- 0.11 microU/ml (range 0.18-3.52 microU/ml). RESULTS: Comparing subjects in the upper, middle and lower tertile of TSH (2.38 +/- 0.14 microU/ml, 1.23 +/- 0.04 microU/ml and 0.65 +/- 0.06 microU/ml respectively) there was no difference in terms of the classical cardiovascular risk factor profiles (24 h blood pressure, HDL- and LDL-cholesterol, triglycerides, oral glucose load and body fat content). Regarding the vascular parameters, we could neither find an independent association with FAD (7.0 +/- 1.1%, 6.4 +/- 1.0% and 5.8 +/- 1.1% respectively) nor with endothelial independent vasodilation (after application of glycerol trinitrate GTN, 17.3 +/- 1.9%, 18.4 +/- 1.7% bzw. 17.5 +/- 1.6% respectively) between the groups. Furthermore, we could not find a significant association between free thyroid hormones (fT3/fT4) and FAD or GTN-induced vasodilation. CONCLUSION: TSH has no predictive value towards endothelial dysfunction in subjects with thyrotropin levels within the normal range.     

How can we block sympathetic overactivity? Effects of rilmenidine and atenolol in overweight hypertensive patients

The aim of the present study was to evaluate effects of long-term treatment with rilmenidine compared with atenolol on lipid and glucose metabolism and cardiovascular remodelling in hypertension. In total, 37 patients with hypertension were randomised to rilmenidine 1-2 mg/day or atenolol 50-100 mg/day for 26 weeks. Standard oral glucose tolerance test with a parallel measurement of insulin and glucose levels was performed. The 'areas under the curve' (AUC) for insulin and glucose were calculated. Plasma lipids, left ventricular mass index (LVMI), and intima-media thickness (IMT) were measured. Brachial artery diameter during reactive hyperaemia was used to test endothelium-dependent vasodilatation (EDVD). Blood pressure reduction was equally achieved in both treatment arms. The fasting glucose level increased in the atenolol group from 4.8+/-0.6 to 5.2+/-0.7 mmol/l (P<0.01). The AUC of glucose in rilmenidine group decreased from 860+/-93 to 737+/-66 mmol/min/l (P<0.05), and in the atenolol group it increased from 937+/-86 to 989+/-88 mmol/min/l (P<0.05). Rilmenidine showed a positive effect on lipid levels, whereas in the atenolol group a significant decrease of high-density lipoprotein cholesterol was observed. Left ventricular mass index decreased with rilmenidine by 9.6% and by 6.9% with atenolol (P<0.05). Intima-media thickness significantly decreased in the rilmenidine group. Endothelium-dependent vasodilatation slightly increased on in the rilmenidine group, while on in the atenolol group it remained unchanged. Our data suggest that in hypertensive patients central inhibition of sympathetic drive can produce favourable effects on glucose and lipid metabolism compared with standard beta-blockade with a similar antihypertensive efficacy. Rilmenidine also provides beneficial effects on cardiovascular remodelling and altered endothelial function in hypertension.     

DOPAMINERGIC MODULATION OF TSH AND ITS SUBUNITS: IN VIVO AND IN VITRO STUDIES

We have studied the effects of dopamine on the secretion of TSH and its subunits in vivo and in vitro. Four normal controls, seven patients with primary hypothyroidism, two patients with peripheral resistance to thyroid hormone (PRTH), and two patients with alpha-secreting pituitary tumours underwent a 3-h dopamine infusion (4 micrograms/kg/min). Serial blood samples were drawn for TSH, PRL, alpha, and TSH-beta subunit. In normal subjects, TSH fell from 2.1 +/- 0.9 (+/- SE) to 0.7 +/- 0.1 microU/ml (P less than 0.05), and alpha declined from 1.5 +/- 0.4 to 1.0 +/- 0.1 ng/ml (P less than 0.01). TSH-beta was at or slightly above the detection limits of the assay before and after dopamine. In hypothyroidism, basal serum TSH was 81 +/- 14 microU/ml. With dopamine, TSH fell to 35 +/- 8 microU/ml (P less than 0.001), while alpha decreased from 3.2 +/- 0.4 to 2.0 +/- 0.3 ng/ml (P less than 0.01). Serum TSH-beta also declined from 0.97 +/- 0.06 to 0.57 +/- 0.05 ng/ml (P less than 0.001). A similar fall in TSH and alpha was seen in the two patients with PRTH. In normals and hypothyroid patients, the percentage change in alpha concentration was significantly less than that observed for intact TSH. This is due presumably to the contribution of the gonadotrophs to the circulating alpha pool. TSH and TSH-beta were undetectable in the two pituitary tumour patients, and alpha declined only slightly in each patient after dopamine. The in vitro effects of dopamine were studied using cultured bovine anterior pituitary cells. Dopamine (10(-4)-10(-8) mol/l) did not change basal TSH, alpha, or TSH-beta release. However, dopamine at all doses significantly blunted TRH (10(-7) mol/l)-stimulated TSH and TSH-beta release, and blunted TRH-mediated alpha release at the two highest dopamine doses. These data suggest that dopamine modulates both TSH and TSH subunit secretion. These effects may be exerted directly at the level of the thyrotroph.     

Effect of chronic endogenous hypercalcemia on prolactin and thyrotropin responsiveness in man

To investigate whether chronic endogenous hypercalcemia influences TSH and/or PRL release from pituitary thyrotrophs and lactotrophs in man, 10 patients with endogenous hypercalcemia, due either to cancer or to primary hyperparathyroidism, were injected with 25 micrograms TRH iv. The TSH and PRL responses were compared with those obtained in an age-, sex-, and weight-matched group of patients comprised of 10 normocalcemic individuals with other diseases. The mean maximal TSH response in the hypercalcemic group (3.7 +/- 0.4 microU/ml) was 46% lower than in the normocalcemic group (6.8 +/- 1.2 microU/ml; p less than 0.02). Similarly, the mean maximal PRL response was 45% lower in the hypercalcemic (31 +/- 5 ng/ml) than in the normocalcemic patients (57 +/- 9 ng/ml; p less than 0.05). Feasible mechanisms behind this inhibitory influence of chronic endogenous hypercalcemia on TSH and PRL responsiveness are discussed.