Increase In Plasma TSH Research Articles

Characteristics of girls with pituitary hyperplasia and sexual precocity secondary to primary hypothyroidism

To investigate the different characteristics of girls with pituitary hyperplasia secondary to primary hypothyroidism (PPH), with and without sexual precocity. Pituitary hyperplasia secondary to primary hypothyroidism girls were divided into two groups: group A, with sexual precocity (n=8), and group B, without sexual precocity (n=14). The following values were measured before and after 3months levothyroxine therapy: free triiodothyronine (FT3 ), free thyroxine (FT4 ), thyrotropin (TSH), follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin (PRL), estradiol (E2 ), testosterone (T), pituitary height, uterine volume (UV), ovarian volume (OV) and follicular diameter (FD). Thyrotropin, FSH, PRL, E2 , T, pituitary height, UV, OV and FD were higher in group A than group B (all p<0.05); FT3 , FT4 and LH levels were not different (all p>0.05). In all of the PPH girls, pituitary height was correlated with FT3 , FT4 and PRL (r=-0.545, p=0.009, r=-0.567, p=0.006 and r=0.666, p=0.001, respectively). PRL was positively correlated with UV, FD and FSH (r=0.581, p=0.005, r=0.482, p=0.031 and r=0.667, p=0.001, respectively), and FSH was positively correlated with OV (r=0.522, p=0.013). These abnormalities regressed after therapy. Pituitary hyperplasia secondary to primary hypothyroidism girls with sexual precocity have increased plasma TSH, FSH, PRL, E2 and T levels, pituitary height and uterine, ovarian and follicular size.

Deiodinase Activities in Thyroids and Tissues of Iodine-Deficient Female Rats

Severe iodine deficiency is characterized by goiter, preferential synthesis, and secretion of T(3) in thyroids, hypothyroxinemia in plasma and tissues, normal or low plasma T(3), and slightly increased plasma TSH. We studied changes in deiodinase activities and mRNA in several tissues of rats maintained on low-iodine diets (LIDs) or LIDs supplemented with iodine (LID+I). T(4) and T(3) concentrations decreased in plasma, tissues, and thyroids of LID rats, and T(4) decreased more than T(3) (50%). The highest type 1 iodothyronine deiodinase (D1) activities were found in the thyroid, kidney, and the liver; pituitary, lung, and ovary had lower D1 activities; but the lowest levels were found in the heart and skeletal muscle. D1 activity decreased in all tissues of LID rats (10-40% of LID+I rats), except for ovary and thyroids, which D1 activity increased 2.5-fold. Maximal type 2 iodothyronine deiodinase (D2) activities were found in thyroid, brown adipose tissue, and pituitary, increasing 6.5-fold in thyroids of LID rats and about 20-fold in the whole gland. D2 always increased in response to LID, and maximal increases were found in the cerebral cortex (19-fold), thyroid, brown adipose tissue, and pituitary (6-fold). Lower D2 activities were found in the ovary, heart, and adrenal gland, which increased in LID. Type 3 iodothyronine deiodinase activity was undetectable. Thyroidal Dio1 and Dio2 mRNA increased in the LID rats, and Dio1 decreased in the lung, with no changes in mRNA expression in other tissues. Our data indicate that LID induces changes in deiodinase activities, especially in the thyroid, to counteract the low T(4) synthesis and secretion, contributing to maintain the local T(3) concentrations in the tissues with D2 activity.

Maternal-fetal glucocorticoid milieu programs hypothalamic-pituitary-thyroid function of adult offspring.

To assess the role of maternal glucocorticoid milieu on the hypothalamic-pituitary-thyroid function of the offspring, we adrenalectomized (ADX) pregnant dams on gestation d 8 and implanted a placebo pellet or a continuous release 50- or 75-mg corticosterone (CORT) pellet. Maternal ADX led to realignment of the balance between maternal and fetal plasma CORT levels, resulting in an increase in CORT of fetal origin in the maternal compartment. Maternal ADX and low levels of CORT replacement had no discernable effect on maternal pituitary-thyroid measures. In contrast, the increase in fetal CORT, as a consequence of the absence of maternal glucocorticoids, decreased birth weight in neonates, decreased adult hypothalamic TRH mRNA levels, and increased plasma TSH levels in both male and female adult offspring, all of which were reversed by administration of basal levels of CORT to the pregnant ADX dam. Decreased plasma T3 concentrations in female offspring were reversed by administration of the higher levels of CORT to the ADX dams. Our data indicate that maternal glucocorticoids modulate the developing hypothalamic-pituitary-thyroid axis.

Effects of centrally administered orexin-B and orexin-A: a role for orexin-1 receptors in orexin-B-induced hyperactivity

Orexin-A and orexin-B are hypothalamic neuropeptides derived from a 130-amino acid precursor, prepro-orexin, and are potent agonists at both the orexin-1 (OX1) and orexin-2 (OX2) receptors. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and a role in the regulation of sleep-wake function. The in vivo role of orexin-B is not as clear. To investigate the behavioural, endocrine and neurochemical effects of orexin-B in in-vivo tests. In a number of experiments, these effects were compared with those of orexin-A. Experiments were carried out in male, Sprague-Dawley rats with a guide cannula directed towards the lateral ventricle. The effects of orexin-B (ICV) upon grooming behaviour were compared with those of orexin-A. The effects of orexin-B upon the motor activity response to both novel and familiar environments were assessed in an automated activity monitor. Orexin-B was tested upon startle reactivity and body temperature. Further, plasma hormones and [DOPAC+ HVA]/[DA] and [5-HIAA]/[5-HT] ratios in six brain areas were measured 40 min post-orexin-B or orexin-A. The clearest behavioural response to orexin-B was increased motor activity in both novel and familiar environments. Orexin-B-induced hyperactivity was blocked by an OX1 receptor antagonist, SB-334867-A, implicating OX1 receptors in this behavioural response. In common with orexin-A, orexin-B reduced plasma prolactin and failed to influence startle reactivity. However, in contrast with orexin-A, orexin-B increased head grooming but failed to cause a robust whole body grooming response or increase plasma corticosterone levels. Further, orexin-B, but not orexin-A, increased plasma TSH and increased hypothalamic and striatal [5-HIAA]/[5-HT] ratios. The present study has demonstrated a number of behavioural, neuroendocrine and neurochemical effects of orexin-B that distinguish it from orexin-A. Further, we have demonstrated a role for OX1 receptors in the actions of orexin-B upon motor activity.

Extrathyroidal effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on thyroid hormone turnover in male Sprague-Dawley rats.

Treatment of rats with different polyhalogenated aromatic hydrocarbons strongly decreases plasma T4, with little or no decrease in plasma T3. The extrathyroidal effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thyroid hormone turnover were studied by i.p. administration of a single dose of 10 microg TCDD/kg BW or vehicle (corn oil) to euthyroid (Eu) rats, thyroidectomized (Tx) rats, and Tx rats infused with 1 microg T4 (Tx+T4) or 0.4 microg T3 (Tx+T3)/100 g BW x day by osmotic minipumps. Tx rats showed decreased plasma T4 and T3 and increased plasma TSH levels, decreased hepatic type I deiodinase (D1) and malic enzyme activities, and increased brain type II deiodinase (D2) activities. All parameters were largely restored to Eu levels in Tx+T4 rats and, except for plasma T4 and brain D2 activity, in Tx+T3 rats, validating the thyroid hormone-replaced Tx rats as models to study the peripheral effects of TCDD. Three days after TCDD administration, plasma T4 and free T4 levels were significantly reduced in Eu and Tx+T4 rats, and plasma T3 was significantly reduced in Tx+T3, but not in Eu or Tx+T4 rats. Plasma TSH was not affected by TCDD in any group. Hepatic T4 UDP-glucuronyltransferase (UGT) activity was induced approximately 5-fold by TCDD, whereas T3 UGT activity was only increased by about 20% (P = NS) in the different groups. TCDD produced an insignificant decrease in liver D1 activity in Tx rats and an insignificant increase in brain D2 activity in Tx rats and hormone-replaced Tx rats. Hepatic malic enzyme activity was significantly increased by TCDD in all groups, except Tx rats. These results strongly suggest that the thyroid hormone-decreasing effects of TCDD are predominantly extrathyroidal and mediated by the marked induction of hepatic T4 UGT activity.

Interleukin-1 beta inhibits rat thyroid cell function in vivo and in vitro by an NO-independent mechanism and induces hypothyroidism and accelerated thyroiditis in diabetes-prone BB rats.

Interleukin-1 beta has been implicated as a pathogenic factor in the development of autoimmune thyroiditis. When given for 5 days to normal non-diabetes-prone Wistar Kyoto rats, it decreased plasma concentrations of total tri-iodothyronine and thyroxine and increased plasma TSH. These effects were not prevented by co-injection of nitroarginine methyl ester or aminoguanidine, inhibitors of NO synthases. Exposure to interleukin-1 beta dose-dependently reduced iodine uptake in FRTL-5 cells, but had no effect on thyroglobulin secretion. Nitrite was not detected in the FRTL-5 cell culture media after exposure to interleukin-1 beta. However, reverse transcription PCR analysis of mRNA isolated from interleukin-1 beta-exposed FRTL-5 cells revealed a transitory expression of the inducible NO synthase, which was markedly lower than inducible NO synthase induction in interleukin-1 beta-exposed isolated rat islets of Langerhans. Co-incubation with the NO synthase inhibitor NG-monomethylarginine did not ameliorate the effect of interleukin-1 beta on FRTL-5 cell iodine uptake. Furthermore, we demonstrate that daily injections of interleukin-1 beta for 13 weeks aggravated spontaneous thyroiditis and induced severe hypothyroidism in non-diabetic diabetes-prone BB rats. The data suggest that NO does not mediate interleukin-1 beta-induced inhibition of rat thyroid function in vivo or in vitro in FRTL-5 cells, and the induction of hypothyroidism by interleukin-1 beta in diabetes-prone BB rats is speculated to be due to exacerbation of recruitment and activation of intrathyroidal mononuclear cells.

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 (T 4) at a dose of 0.8 or 2.0 μg/100 g body weight/day 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<0.01) in euthyroid SHR compared to WKY control rats while thyroid hormone (T 3 and T 4) levels were in the normal range. Hypothyroidism induced by either methimazole or thyroidectomy caused a significant ( P<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<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<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<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.

A Case of Panhypopituitarism with Normal Height Manifesting the Transection of the Pituitary Stalk and the Formation of the Ectopic and Eutopic Posterior Lobes

A 33-year-old man with hypopituitarism is documented. He was born at breech presentation without asphyxia. He was the shortest in his class throughout his school days. He kept slowly growing and reached 172.8 cm at the age of 33. He was devoid of secondary sexual characteristics. Endocrinological studies showed panhypopituitarism with elevated levels of plasma TSH (15.0 microU/ml). TRH administration resulted in a marked increase in plasma TSH. Posterior pituitary function was normal. MR imaging showed transection of the pituitary stalk and the presence of ectopic and eutopic posterior lobes. The replacement of corticosteroid was initiated, and exaggerated response of TSH to TRH disappeared. Delayed bone maturation due to hypogonadism and hypothyroidism was one of the reasons why he had normal height without GH therapy. The significance of his peculiar MRI findings remains to be determined.

Thyroidectomy Induces Fos-like Immunoreactivity Within Thyrotropin-Releasing Hormone-Expressing Neurons Located in the Paraventricular Nucleus of the Adult Rat Hypothalamus*

Effects of thyroidectomy on Fos-like immunoreactivity (IR) in the rat brain were examined using single and double-label immunocytochemical techniques. In particular, the possibility that Fos might be involved in thyroid hormone regulation of thyrotropin releasing hormone (TRH)-containing neurons located in the parvocellular region of the paraventricular nucleus of the hypothalamus (pPVN) was examined. Adult, male, Sprague-Dawley rats were used and all animals received either surgical removal of the thyroid gland or sham surgery. Two experiments were performed. In the first experiment, animals were killed 1, 3, or 6 days after surgery and numbers of Fos-like IR cells in the parvocellular (pPVN) and magnocellular (mPVN) regions of the PVN, the anterior hypothalamic nucleus (AH), the lateral hypothalamic nucleus (LH), and the pyriform cortex were determined. In the second experiment, animals received an intracerebroventricular injection of colchicine 5 days after surgery. The next day, animals were killed and numbers of Fos-like IR cells double-labeled for either TRH, corticotropin releasing factor (CRF), or methionine-enkephalin (met-Enk) were determined. Six days after thyroidectomy there was a significant increase in the number of Fos-like IR cells detected in the pPVN. No induction in the pPVN was observed 1 and 3 days after thyroidectomy, and no effects attributable specifically to thyroidectomy (as opposed to stress) on Fos expression in the mPVN, AH, LH, or pyriform cortex were observed. In addition, a rapid, stress-related, induction of Fos-like IR was detected in the mPVN, AH, and LH and was easily distinguished from Fos expression induced in the pPVN as a function of thyroidectomy. The time course for the effect of thyroidectomy on Fos expression in the pPVN paralleled increased plasma TSH concentration. A significant correlation between numbers of Fos-like IR cells in the pPVN and plasma TSH concentration following thyroidectomy was also observed, suggesting that plasma levels of TSH correlate directly with the number of activated TRH-containing neurons located in the pPVN. Double staining for Fos and TRH, CRF, or met-Enk revealed that thyroidectomy induced Fos-like IR specifically within TRH-, but not within CRF-, or met-Enk, expressing neurons in the pPVN. Taken together, the data suggest that Fos-like IR is induced within TRH-expressing neurons in the pPVN as a consequence of decreasing levels of circulating thyroid hormone (TH). Whether this reflects a direct effect of decreasing TH on Fos expression is not yet known; however, the data are consistent with the hypothesis that Fos is involved in TH-associated regulation of TRH production and release.

The role of somatostatin and/or dopamine in basal and TRH-stimulated TSH release in food-restricted rats

The present study was carried out to examine the role of endogenous dopamine and somatostatin in the mechanisms involved in the restricted feeding-induced inhibition of TSH secretion in rats. GH secretion was examined in parallel. Restricted feeding by 50% or 75% was associated with a decrease in the pituitary and circulating levels of TSH and GH in both untreated and TRH-treated groups (p less than 0.001), the changes being proportional to the feeding level. Intravenous injections of the dopamine antagonists, domperidone or haloperidol, failed to affect the magnitude of the differences in plasma TSH and GH levels among control and food-restricted groups, indicating that dopaminergic mechanisms had little effect on the regulation of TSH and GH secretion during restricted feeding in rats. Cerebroventricular injection of somatostatin anti-serum resulted in a marked increase in plasma TSH and GH levels in all the experimental groups (p less than 0.001). The increase in plasma GH and TSH induced by somatostatin anti-serum was greater in rats fed a 25% diet than in either controls or rats fed 50% of the diet; the values for the latter two groups were also different (p less than 0.001). The decreased TSH and GH values in somatostatin anti-serum-treated food restricted rats as compared with those in control animals on somatostatin anti-serum or normal rabbit serum can probably be attributed to the decreased available pituitary TSH and GH pools. The data indicate that long-term restricted feeding affects anterior pituitary function in rats, presumably reflecting alterations in the secretion of an inhibiting hormone, somatostatin.

Thyroid Vascular Conductance: Differential Effects of Elevated Plasma Thyrotropin (TSH) Induced by Treatment with Thioamides or TSH-Releasing Hormone*

We have reported previously that thyroid gland blood flow, expressed as vascular conductance (C) per mass, is decreased at very low and increased at very high chronic plasma TSH concentrations, but is apparently unchanged over a broad range of plasma TSH concentrations encompassing normal levels. The aim of the present study was to examine the apparently very steep dose-response relationship between elevated plasma TSH and thyroid vascular C/mass. In the first series of experiments, endogenous plasma TSH concentrations were manipulated by treating male Sprague-Dawley rats (250-280 g) for 6 days as follows: 1) controls (0.5 ml saline/day, ip), 2) propylthiouracil injections (2.0 mg PTU/day, ip), 3) PTU plus partial thyroid hormone replacement (2.0 mg PTU/day and 0.3-0.9 microgram T4 plus 0.075-0.225 microgram T3/100 g.day via continuous sc infusion), or 4) TRH (9-1200 micrograms TRH/100 g.day via continuous iv infusion). The vascular C values of the thyroid gland, salivary gland, kidney, and pancreas were determined using the reference sample version of the radioactive microsphere technique. PTU treatment led to the expected hypothyroidism, increased plasma TSH concentrations (959 +/- 66 vs. 154 +/- 22 ng/dl), increased thyroid weight (9.19 +/- 0.36 vs. 4.60 +/- 0.15 mg/100 g), and increased thyroid vascular C/mass (495 +/- 51 vs. 127 +/- 20 microliters/mm Hg.g/min). PTU-treated rats receiving partial thyroid hormone replacement demonstrated a dose-related suppression of plasma TSH, thyroid weight, and thyroid vascular C. Although, TRH treatments resulted in increased plasma TSH concentrations (e.g. 1200 micrograms TRH, 706 +/- 46 ng/dl) and thyroid weight (e.g. 1200 micrograms TRH, 7.45 +/- 0.41 mg/100 g), thyroid vascular C per tissue mass was not significantly increased after any TRH treatment (e.g. 1200 micrograms TRH, 166 +/- 19 microliters/mm Hg.g/min). Thus, at similarly elevated plasma TSH concentrations, the thyroid vascular C/mass of PTU- and TRH-treated rats constituted separate populations. Both PTU- and TRH-induced thyroid growth were accompanied by similar alterations in thyroid gland morphology (i.e. increased cellular mass with little change in the total amount of colloid). To investigate the mechanisms involved, groups of rats were treated for 6 days as follows: 1) control, 2) PTU or methimazole (25 mg MMI/day, ip), 3) PTU or MMI plus thyroid hormone replacement (1.2 micrograms T4 plus 0.3 microgram T3/d.100 g), 4) TRH (12 micrograms/100 g.day), and 5) PTU or MMI, thyroid hormones, and TRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Testosterone Increases TSH-β mRNA, and Modulates α-Subunit mRNA Differentially in Mouse Thyrotropic Tumor and Castrate Rat Pituitary

TSH, LH and FSH, the three pituitary glycoprotein hormones, are each composed of a common alpha-subunit and a hormone specific beta-subunit. Testosterone is known to regulate all three intact hormones differently in the rodent. However, there is only one gene encoding the common alpha-subunit. In order to elucidate the effects of testosterone on TSH subunit synthesis and its regulation of the common alpha-subunit, two in vivo models were studied: castrate rat pituitary was used as a gonadotropin-enriched tissue; and mouse thyrotropic tumor was used as a thyrotropin-enriched tissue. Male castrate rats were treated with testosterone propionate, 500 micrograms/100 g BW, sc, for 11 days. Testosterone increased plasma TSH to 131% of control values (P less than 0.02), while plasma LH fell to undetectable levels, and plasma alpha-subunit fell to 14% of control values (P less than 0.001). Testosterone increased TSH-beta mRNA to 237% of control values (P less than 0.02), while alpha-subunit mRNA fell to 20% of control values (P less than 0.001). Hypothyroid mice bearing thyrotropic tumors were treated with testosterone propionate, 150 micrograms/100 g BW, sc, for 11 days. In this model plasma TSH-beta and alpha-subunit concentrations are 1000-fold higher than in non-tumor bearing animals, and the contribution of pituitary gonadotropes to plasma subunit concentrations is negligible. "Total" TSH-beta and alpha-subunit concentrations were estimated as one-half of intact TSH plus the respective free subunit concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The Paraventricular Nucleus of the Hypothalamus Has a Major Role in Thyroid Hormone Feedback Regulation of Thyrotropin Synthesis and Secretion

The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.

Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923)

Thyroid hyperplasia and/or hepatomegaly were observed in a 14-week oral toxicity study with L-649,923, a leukotriene antagonist, at doses of 50 and 150 mg/kg/day. In a 16-day study, L-649,923 caused an increase in plasma TSH and hepatic enzyme induction, but did not affect plasma T 3 and T 4 levels. Light microscopy and ultrastructural examination of the liver and thyroid showed changes indicative of hepatic enzyme induction and increased stimulation of the thyroid by TSH. Because other hepatic enzyme inducers cause thyroid hyperplasia by increasing the turnover of plasma T 3 and T 4 it was hypothesized that L-649,923-induced thyroid hyperplasia might be occurring by the same mechanism. To examine this theory, rats were treated po with 300 mg/kg/day of L-649,923 for 17 days. On Day 15, all rats were dosed iv with [ 125I]thyroxine (33 μCi/rat). At various times after dosing, blood was collected and plasma levels of 125I were determined. The clearance and elimination rate constant were significantly larger in treated animals than in the control group ( p < 0.01). This work demonstrates that L-649,923 increases the plasma turnover of thyroxine which is associated with a stimulation of TSH and thyroid hyperplasia.

Effects of sauna and glucose intake on TSH and thyroid hormone levels in plasma of euthyroid subjects

The effect of sauna on thyroid function parameters and its modification by glucose was studied in young euthyroid male volunteers. A 30-minute stay in sauna resulted in an increase in plasma TSH; the response was exaggerated if glycemia had been increased by oral glucose intake at the beginning of the experiment. Plasma rT 3 also increased in sauna, this response was, however, blunted by the higher glycemia. TSH response to sauna was definitely present in young men (aged 20 to 25) and absent in middle-aged ones (50 to 55). To explore the mechanism of the effect of increased glycemia, TRH tests were performed and dopamine infusions were administered with and without glucose pretreatment. Increased glycemia did not affect TSH and T 3 response to TRH in young volunteers; however, 90 minutes after the administration, plasma rT 3 levels were significantly lower in glucose pretreated subjects than in those receiving TRH injections after water pretreatment. Simultaneous infusion of glucose prevented the inhibitory effect of dopamine infusion on plasma TSH. It was concluded that glucose directly modulates the effect of sauna on plasma TSH at a suprapituitary level, while the inhibiting effect of glucose on plasma rT 3 response to sauna and TRH is probably mediated by the insulin effect on thyroid hormone metabolism.

Uninhibited Thyroidal Uptake of Radioiodine Despite Iodine Excess in Amiodarone-Induced Hypothyroidism*

Iodine excess is associated with a low thyroidal radioiodine uptake due to dilution of the radioisotope by the increased stable iodide pool. We studied thyroidal uptake of radioisotopes in cardiac patients with iodine excess due to amiodarone treatment. 99mTc-pertechnetate scintigraphy was performed in 13 patients receiving long term amiodarone therapy. Five patients had a clearly visible thyroid gland, and 8 patients had no or a very faint thyroid image. All patients with positive scans had an increased plasma TSH level, whereas all patients with negative scans had a normal or absent TSH response to TRH. Thyroidal uptake and discharge of 123I were studied in 30 other patients. Group I (n = 11) had normal plasma TSH responses to TRH and no iodine excess, group II (n = 7) had normal TSH responses to TRH and excess iodine from metrizoate angiography in the previous month, group III (n = 7) had normal or decreased TSH responses to TRH while receiving long term amiodarone therapy, and group IV (n = 5) had increased TSH responses to TRH while receiving long term amiodarone therapy. The mean radioiodine uptake value in group I [5.4 +/- 0.8% (+/- SE) at 60 min] was higher than those in group II (2.3 +/- 0.7%; P = 0.009) and group III (0.8 +/- 0.3%; P = 0.0005), but not different from that in group IV (5.3 +/- 1.2%; P = NS). Radioiodine discharge after perchlorate (expressed as a percentage of the 60 min uptake) in group I (10.1 +/- 2.2%) was lower than those in group II (24.9 +/- 10.6%; P = 0.05) and group III (28.8 +/- 5.3%; P less than 0.005), whereas discharge in group IV (58.0 +/- 6.1%) was greater than those in group II (P less than 0.05) and group III (P less than 0.01). In conclusion, 1) thyroid visualization by 99mTc-pertechnetate and thyroid radioiodine uptake during iodine excess are decreased in euthyroid and hyperthyroid patients, but preserved in hypothyroid patients. 2) The organification defect induced by iodine excess is greater in iodide-induced hypothyroidism than in eu- or hyperthyroidism. These findings may be explained by the increased TSH secretion in hypothyroidism and/or by decreased thyroidal concentration of an unknown specific iodinated compound (whose concentration and action vary with the total organic iodine content of the thyroid) that mediates the inhibition of iodide transport.

Hypothalamic control of pituitary and adrenal hormones during hypothermia

In order to investigate neuroendocrinological mechanisms of hypothermia, we determined the changes in plasma concentrations of corticosterone (CS), prolactin (PRL), and thyrotropin (TSH), and their correlations with alterations in hypothalamic dopamine (DA) and thyrotropin releasing hormone (TRH), in rats restrained and immersed in a water bath at various temperatures. A graded decrease of body temperature induced a progressive increase in the plasma level of CS, whereas that of PRL showed a drastic decrease. The plasma level of TSH also showed an increase during mild hypothermia (about 35°C), but this increase was not evident during profound hypothermia (below 24°C). The changes in these hormones were readily reversed by rewarming animals. Although DA content in the hypothalamus was not affected, its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), showed an increase following the decrease of body temperature. Pretreatment of the animals with sulpiride, a D 2-antagonist, prevented the hypothermia-induced inhibition of PRL release. Hypothalamic TRH was significantly decreased during mild hypothermia, and it returned to control levels after rewarming. These results suggest that the decrease in plasma PRL induced by hypothermia may be associated with the activation of hypothalamic DA neurons, whereas the increase in plasma TSH during mild hypothermia seems to be caused by the increased release of TRH in the hypothalamus.

Evidence that thyrotropin-releasing hormone is not a major prolactin-releasing factor during suckling in the rat.

The purpose of this study was to investigate whether TRH could be an important PRL-releasing factor during suckling in the rat. Plasma PRL, TSH, beta-endorphin-like immunoreactivity, and GH responses in serial blood samples from unanesthetized suckled rats were determined. The resulting hormonal profile was compared with that obtained when TRH (500 ng/kg BW, iv) was injected at the onset of suckling. Suckling evoked a rise in plasma levels of PRL, beta-endorphin-like immunoreactivity, and GH, but not in TSH. In contrast, exogenous TRH caused a 9-fold increase in plasma TSH levels during suckling without further increasing the PRL response. Since plasma PRL responses are reportedly enhanced by previous suckling, we also determined plasma PRL and TSH levels when TRH (25 ng/rat, iv) was given 30 min after a brief suckling episode. TRH caused a 2.5-fold increase in plasma TSH, but did not significantly increase plasma PRL levels. Since suckling increases plasma PRL without increasing plasma TSH, and TRH increases TSH but not PRL levels, we conclude that TRH is not a major PRL-releasing factor during suckling.

Plasma somatostatin level during natural and interrupted nocturnal sleep in man.

The plasma levels of somatostatin (SRIF), growth hormone (GH) and thyrotrophin (TSH) in 4 normal men were measured during nocturnal sleep on 6 nights. In the waking state, the fluctuation of plasma SRIF level was within +/- 2.1 pg/ml (SD) of the mean value for each individual (range of mean value, 10.7 pg/ml-15.4 pg/ml). A marked episodic surge of GH release (peak value, 24.4 +/- 6.3 ng/ml (mean +/- SD] was noted in the initial period of slow wave sleep (SWS) in all subjects, but no significant negative correlation was observed between SRIF and GH in the plasma during either increase or decrease in the GH surge. There was no relation between the distribution of the plasma SRIF concentration and the stage of sleep, including the period before sleep, judged by electroencephalography (EEG). A small, but significant, increase of plasma TSH (10.0 muU/ml) independent of the SWS-related GH burst was detected in 1 of 4 subjects, but in that period the plasma SRIF level did not change. Even when the GH surge was suppressed by interruption of SWS, the plasma levels of SRIF and TSH did not show any significant change. From these findings, it is concluded that SRIF in the peripheral plasma does not fluctuate during the sleeping period as in the waking state and that, whatever its source, it is not related to the plasma GH or TSH level in the systemic circulation.

Variable thyrotropin response to thyrotropin-releasing hormone after small decreases in plasma thyroid hormone concentrations in patients of advanced age

It was recently reported that TSH regulation was abnormal in 50% of patients hospitalized for nonthyroidal diseases because the TSH response to TRH was not augmented following an iodide-induced small decrease in serum T 4 and T 3 concentrations. Since the mean age of that group was 65.0 years, we considered the possibility that some of the findings of that study were due to the advanced age of the patients in addition to the presence of nonthyroidal illness. Accordingly, some aspects of TSH regulation in 24 outpatients of advanced age followed for routine health maintenance have now been studied; eight young adults (28–49 years of age) were studied as controls. Six patients were between 60 and 69 years of age, nine were between 70 and 79 years of age, and nine were between 80 and 89 years of age. TSH regulation was studied by measuring the TSH response to injected thyrotropin-releasing hormone (TRH) before and after a small decrease in plasma thyroid hormone concentrations had been produced by a 10-day treatment course with iodides (262 mg/d). Iodide treatment resulted in a 10% or greater decrease in serum T 4, FT 4, or T 3 levels in 20 of the 24 patients. A significant decrease in the mean plasma T 4 level from 7.6 ± 0.5 μg/dL to 6.7 ± 0.4 μg/dL ( P < 0.01) was noted; however, the decrease in the mean plasma T 3 level from 116 ± 5 ng/dL to 110 ± 4 ng/dL was significant only at the P < 0.1 > 0.05 level. No major difference in the mean T 4, FT 4, or T 3 levels or the integrated TSH response to TRH were observed between the men (13) and women (11) in the different age groups except in the 70–79-year-old group, in which the integrated TSH response of the men was decreased. Iodide treatment did not affect basal plasma TSH levels but the mean integrated TSH response to TRH was increased from 801 ± 123 μU·min to 996 ± 135 μU·min ( P < 0.025). In contrast to this modest increase, a mean 137% increase in the integrated TSH response to TRH was noted in the control subjects (28–49 years old), who exhibited a similar decrease in serum T 4 and T 3 levels after iodide treatment. Whereas the TSH response to TRH after iodide treatment was augmented in all of the younger control subjects, only 9 of the 20 aged patients who responded to iodide treatment had normal TSH responsiveness. There was no significant age or sex difference between the TSH responders and nonresponders. Similarly, there was no significant difference between the mean plasma T 4, FT 4, and TSH levels between these groups; the mean plasma T 3 level in the TSH responsive group, 103 ± 4 ng/dL, wss significantly lower than that of the TSH nonresponders, 128 ± 7 ng/dL. Because the anticipated increase in plasma TSH in response to a small decrease in T 4, FT 4, or T 3 occurred in less than one-half of patients of advanced age, a normal plasma TSH level may not be a reliable index of the euthyroid state in aged patients.