Regulation of the alpha and thyrotropin beta-subunit messenger ribonucleic acids by thyroid hormones

We studied the regulation of mRNAs encoding the alpha- and beta-subunits of TSH by thyroid hormones (T4 and T3) in mouse thyrotropic tumors and pituitary glands. Hypothyroid male (LAF1) mice bearing thyrotropic tumor (TtT97) were injected daily with T4 for 0, 1, 5, 12, or 33 days. After day 33, plasma levels of TSH and free (unassociated) TSH beta-subunit were reduced to less than 1% of control levels, whereas free alpha-subunit was reduced to 6% of control levels. Steady state levels of subunit mRNAs in extracts of the thyrotropic tissues were measured by blot hybridization analyses using mouse subunit-specific cloned cDNAs. Treatment of mice with T4 caused a rapid decline in the levels of tumor mRNAs for both alpha and TSH beta; after day 1, alpha and TSH beta mRNA levels decreased to 35% and 10% of control values, respectively. Levels of TSH beta mRNA were undetectable after 5 days of T4 treatment, whereas levels of alpha-subunit mRNA remained at 30-35% of control levels even after day 33. In a separate experiment, TSH beta mRNA decreased to 42% of the control level (P less than 0.05), whereas alpha-subunit mRNA remained at 64% of the control level (P = NS) 4 h after a single injection of T4. Finally, T3 also caused a rapid decrease in the levels of both subunit mRNAs in the anterior pituitary glands of hypothyroid mice, but the effect was more complete on TSH beta mRNA levels. We conclude that thyroid hormones have rapid suppressive effects on the levels of mRNAs encoding the subunits of mouse TSH in the thyrotrope. The suppressive effects of thyroid hormones occur more rapidly and are greater for TSH beta than alpha-subunit mRNAs. The parallel changes observed in the subunit mRNA levels and the plasma subunit protein levels in animals treated with thyroid hormones suggest that the changes in the plasma levels of TSH and subunits may reflect effects of thyroid hormones on TSH gene expression in addition to effects on secretion.     

Effects of long-term treatment with thyroxine on pituitary TSH secretion and heart action in patients with hypothyroidism

The effects of thyroxine (T4) treatment on pituitary thyrotroph cells and on the heart were studied in 68 female patients with hypothyroidism. During the initial 12 months of T4 treatment, relatively small doses of T4 (1.3 micrograms/kg) normalized serum T4, triiodothyronine (T3), TSH and lipid concentrations in mild hypothyroidism, while moderate doses of T4 (1.7-2.0 micrograms/kg) normalized serum T4, T3 and lipid concentrations but not serum TSH levels or the volume of sella turcica in moderate and severe hypothyroidism; however, serum TSH levels and the volume of sella turcica returned to normal with continuation of these doses of T4. Systolic time intervals (ET/PEP) can discriminate between euthyroid and hyperthyroid states and agree well with serum TSH levels. However, ET/PEP was unequivocally elevated in about 40% of treated hypothyroid patients with normal serum T3, T4 and TSH levels which had been maintained over 48-54 months. Since the reciprocal relationship between free T4 and TSH levels was maintained in all treated patients, elevated ET/PEP with normal TSH levels indicates that the heart is more sensitive to thyroid hormones than the pituitary thyrotroph in 40% of treated hypothyroid patients. During T4 treatment in patients with hypothyroidism, ET/PEP should be followed and T4 doses adjusted to maintain normal ET/PEP rather than normal serum TSH levels, especially in older patients in whom T4 may aggravate angina pectoris or provoke myocardial infarction.     

ALTERATIONS IN THYROID HORMONE METABOLISM DURING CHEMOTHERAPY IN PATIENTS WITH TESTICULAR CARCINOMA

In a prospective study, the effects of chemotherapy on thyroid function in patients with non-seminoma testicular carcinoma were evaluated. Thirty-one patients were studied; in sixteen immunoassayable HCG was present, but altered thyroid function could not be established. In fifteen patients an exaggerated TSH response to TRH was observed. In these patients, although T3 and T4N values were normal, basal TSH levels were higher compared to patients with a normal TSH response, probably due to preceding lymphangiography.During chemotherapy, T4N, T3 and rT3 levels rose significantly, but basal TSH levels and the TSH response to TRH decreased. In contrast, the prolactin responses to TRH increased. The observed changes in thyroid function during chemotherapy appear to result from delayed thyroid hormone clearance, probably caused by an effect of chemotherapy on deiodinating enzyme activity. This would result, in an increase in T4N and rT3 levels and a fall in TSH levels and in the TSH response to TRH. Furthermore, after therapy the raised T4N and lowered TSH levels remained, whilst the FT3 level did not change either during or after therapy, suggesting an unaltered hypothalamic/pituitary axis.     

Bexarotene-induced hypothyroidism: bexarotene stimulates the peripheral metabolism of thyroid hormones

OBJECTIVE: Therapy with the retinoid X receptor agonist bexarotene is associated with hypothyroidism caused by decreased pituitary TSH secretion. To evaluate the effects of bexarotene on peripheral thyroid hormone metabolism, we performed a study in athyreotic subjects on a fixed substitution dose with L-T4. DESIGN: The design was an open prospective 6-wk intervention study. METHODS: Ten athyreotic patients with pulmonary metastases of differentiated thyroid carcinoma received 6-wk redifferentiation treatment with 300 mg bexarotene/d. L-T4 doses were kept stable. Before and in the sixth week of therapy, serum levels of total T4, free T4 (FT4), T3, reverse T3 (rT3), and TSH were measured. To study nondeiodinase-mediated thyroid hormone degradation, serum levels of T4 sulfate (T4S) were measured. Recombinant human TSH was administered before and in the sixth week of bexarotene therapy. RESULTS: Bexarotene induced profound decreases in total T4 (56% of baseline), FT4 (47%), T3 (69%), rT3 (51%), and T4S (70%) in all patients, whereas TSH levels were not affected. The T3/rT3 ratio increased by 43%, and the T4S/FT4 ratio increased by 48%. Serum TSH levels before and after recombinant human TSH were unaffected by bexarotene. CONCLUSIONS: In the present study, we demonstrate that increased peripheral degradation of thyroid hormones by a nondeiodinase-mediated pathway contributes to bexarotene induced-hypothyroidism.     

Thyrotropin secretion in thyrotoxic and thyroxine-treated patients: assessment by a sensitive immunoenzymometric assay

A new TSH immunoenzymometric assay was found to be capable of discriminating between the serum TSH values of normal subjects [2.28 +/- 1.02 (+/-SD); range, 0.6-6.5 microU/ml] and those of clinically euthyroid, antithyroid drug-treated (n = 22) or clinically thyrotoxic (n = 34) patients. While a wide spectrum of basal TSH values was found in the antithyroid drug group [ranging from undetectable (less than 0.05 microU/ml: 57%) to 17.9 microU/ml], all clinically thyrotoxic patients had undetectable values. In 33 patients receiving chronic oral T4 therapy for treatment of goiter (n = 15) or thyroid cancer (n = 18), 48% (6 of 33) had undetectable basal TSH levels and no TSH response to TRH stimulation. Detectable TSH levels were found in 42% (14 of 33), and TRH responsiveness was found in 52% (17 of 33). The TSH response to TRH stimulation was less than 2.0 microU/ml in 7 patients. Serum free T4 index, free T3 index, and free T4 levels and oral T4 dosage were inferior predictors of TRH responsiveness compared to the basal TSH value. No patient receiving more than 0.2 mg T4 daily or having a free T4 index above 18, a free T3 index above 205 or a free T4 level above 3.0 ng/dl had a TSH response to TRH. Seventy-six percent (16 of 21) of the patients, when reevaluated 1-6 weeks after increased oral T4 dosage, had a significant reduction in their serum thyroglobulin level. This was true of both patients with initially detectable (11 of 14) as well as undetectable (5 of 7) basal serum TSH levels. These findings support the concept that subnormal and, for that matter, as yet undetectable levels of circulating TSH may exert stimulatory effects on thyroid tissue.     

Continuous infusion of interleukin-1 beta induces a nonthyroidal illness syndrome in the rat.

We studied the effects of continuous administration of recombinant human interleukin-1 beta (IL-1) on pituitary-thyroid function. Rats were equipped with minipumps loaded with either IL-1 (delivery rate, 0.5, 2.0, or 4.0 micrograms/day, ip, for 1 week) or saline. Infusion of 2.0 and 4.0 micrograms IL-1/day caused a significant decrease in plasma free T4 levels during the first 2-4 days, whereas plasma total T4 levels and T4 binding were significantly lowered throughout the week of the study. The infusion of 0.5 micrograms IL-1/day did not significantly change plasma TSH or total and free T4 levels. During the infusion of 2.0 micrograms IL-1/day, the decrease in plasma free T4 levels was paralleled by a significant decline in plasma TSH values and an impaired TSH responsiveness to TRH administration on the second day of infusion. IL-1 (2.0 micrograms/day) treatment significantly lowered plasma levels of T4-binding prealbumin, whereas it did not influence the plasma T3/T4 ratio or hepatic 5'-deiodinase activity. Plasma rT3 levels remained undetectable in both control and IL-1-treated rats. Chronic infusion of rats with 4.0 micrograms IL-1/day induced prolonged fever, whereas at the lower doses of IL-1, temperatures were elevated only on the first 2 days. IL-1 at doses of 2.0 and 4.0 micrograms/day induced a transient decrease in food intake and a suppression of body weight gain. Restriction of food consumption to the level observed in the 2.0 micrograms IL-1 experiment caused small decreases in T3, total and free T4, and TSH levels compared to those in ad libitum fed rats, but had no effects on T4 binding. We conclude that 1) continuous infusion of rats with 2.0 and 4.0 micrograms IL-1/day induces changes in thyroid economy commonly seen during infectious diseases and other systemic illnesses in rats [decreased plasma levels of TSH, T3, and (free) T4; diminished T4 binding; and decreased plasma T4-binding prealbumin levels], 2) the decrease in food intake during IL-1 treatment cannot completely explain the observed changes in thyroid hormone and TSH levels; and 3) it is highly unlikely that the decrease in thyroid hormone binding during chronic IL-1 infusion is caused by decreased food intake. Further studies are needed to clarify whether the observed alterations in thyroid economy during IL-1 infusion reflect direct effects of IL-1 per se or indirect effects caused by the mild illness induced by the cytokine.     

Sequential changes in the pituitary thyroid axis after chronic TRH administration: effects on euthyroid and thyroxine treated female rats

The effect of chronic oral thyrotrophin-releasing hormone (TRH) administration on thyrotrophin (TSH), L-triiodothyronine (T3) and L-thyroxine (T4) serum levels, pituitary TSH concentration and serum response to acute TRH injection, has been studied in female rats under different thyroidal conditions: sham-operated control animals, and thyroidectomized animals receiving 25 micrograms L-T4/100 g body weight/day. After 30 days, these groups were divided into two subgroups (6-10 animals per group), one receiving the aforementioned treatment and the other the same plus 2 mg TRH/10 ml distilled water (DW), as drinking water. TRH-treated sham-operated animals showed significantly reduced serum and pituitary TSH levels and increased serum T3 levels at most of the times studied (1, 6, 10, 18 and 34 days of oral TRH or DW administration), and a transient elevation in serum T4 between day 1 and 6. Thyroidectomized-L-T4-treated animals showed increased serum and pituitary TSH levels throughout the treatment and reduced T3 and T4 serum levels at the beginning, as compared to thyroidectomized-L-T4-treated animals. TSH response to iv TRH administration on the 10th day of oral TRH administration was reduced in controls chronically treated with oral TRH as compared to non-treated controls, and was increased in thyroidectomized-L-T4-treated animals on chronic TRH vs the same group on oral DW. These results suggest that chronic TRH administration can stimulate TRH synthesis in vivo, bypassing the inhibitory effects of thyroid hormones, the increased pituitary TSH reserve being responsible for the partial restoration of a response to acute TRH injection in the thyroidectomized-L-T4-treated animals.     

beta-Neoendorphin inhibits thyrotrophin secretion in rats

The effects of beta-neoendorphin on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. beta-neoendorphin (500 micrograms/kg) was injected iv, and the rats were decapitated serially. TRH, TSH, thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by means of a specific radioimmunoassay for each. Hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after beta-neoendorphin injection, and plasma concentrations tended to decrease, but not significantly so. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min. Plasma T4 and T3 levels did not change after the injection. Plasma ir-TRH and TSH responses to cold were significantly inhibited by beta-neoendorphin, but the plasma TSH response to TRH was not. Naloxone partially prevented the inhibitory effect of beta-neoendorphin on TSH release. In the haloperidol- or 5-hydroxytryptophan-pretreated group, the inhibitory effect of beta-neoendorphin on TSH release was prevented, but not in the L-dopa- or para-chlorophenylalanine-pretreated group. These drugs alone did not affect plasma TSH levels at the dose used. These findings suggest that beta-neoendorphin acts on the hypothalamus by inhibiting TRH release, which may be modified by amines of the central nervous system.     

Dynorphin (1-13) effects on thyrotrophin-releasing hormone and thyrotrophin secretion in rats

The effects of dynorphin (1-13) on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. Dynorphin (500 micrograms/kg) was injected iv, and the rats were serially decapitated. TRH and TSH, thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by radioimmunoassay. The hypothalamic immunoreactive TRH did not change significantly after dynorphin injection. Basal plasma TSH levels significantly decreased in a dose-related manner with a nadir at 40 min after dynorphin injection. The effect of dynorphin on TSH release was partially prevented by naloxone. The plasma TSH response to cold was significantly inhibited by dynorphin. The plasma TSH response to TRH did not differ from that of the control. In the L-DOPA or 5-hydrotryptophan-pretreated group, the inhibitory effect of dynorphin on TSH release was prevented, but not in the haloperidol-or para-chlorophenylalanine-pretreated group. These drugs alone did not affect plasma TSH levels. The plasma T4 and T3 levels did not change significantly after dynorphin injection. The findings suggest that dynorphin acts on the hypothalamus by inhibiting TRH release, which may be modified by amines of the central nervous system.     

Comparison of maternal to fetal transfer of 3,5,3'-triiodothyronine versus thyroxine in rats, as assessed from 3,5,3'-triiodothyronine levels in fetal tissues

Thyroxine (T4) is transferred from the mother to the hypothyroid rat fetus late in gestation, mitigating T4 and T3 deficiency in fetal tissues, the brain included. We have now compared the effects of maternal infusion with T3. Normal and thyroidectomized rats were started on methimazole (MMI) on the 14th day of gestation, given alone, or together with a constant infusion of 0.45 micrograms (0.69 nmol) T3 or of 1.8 microgram (2.3 nmol) T4/100 g per day. Maternal and fetal samples were obtained at the 21st day of gestation. The doses of T3 and T4 were biologically equivalent for the dams, as assessed from maternal plasma and tissue T3, and plasma TSH levels. MMI blocked the fetal thyroid; T4 and T3 levels were low in all fetal tissues, and fetal plasma TSH was high. Maternal infusion with T4 mitigated both T4 and T3 deficiency in all fetal tissues, the brain included, and decreased fetal plasma TSH. In contrast, infusion of T3 normalized fetal plasma T3 and increased the T3 levels in several tissues, but not in the brain. Neither did it decrease the high fetal plasma TSH levels. The results show that when the fetus is hypothyroid, T3 crosses the rat placenta at the end of gestation, but does not affect all tissues to the same degree. In contrast to the effects of maternal T4, maternal T3 does not alleviate the T3 deficiency of the brain or, presumably, of the thyrotrope. Thus, end-points of thyroid hormone action related to TSH release should not be used to measure transfer of maternal T3 to the fetal compartment. Moreover, T4 should be given, and not T3 to protect the hypothyroid fetal brain.     

Effect of Moderate Doses of Ethanol and Phenobarbital on Pituitary and Thyroid Hormones and Testosterone

Effects of ingestion of .8 g/kg of body weight of ethanol or 100 mg of phenobarbital on seven consecutive nights on plasma LH, TSH, prolactin, T₃, T₄, and testosterone levels were studied in five healthy young men. Ethanol increased plasma TSH levels during sleep whereas phenobarbital decreased plasma TSH levels during sleep and awake periods. Neither ethanol nor phenobarbital had significant effects on plasma prolactin, total T3, T4, or testosterone levels.     

Thyroxine-induced expression of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase

Suppression of TSH release from the hypothyroid thyrotrophs is one of the most rapid effects of 3,3',5'-triiodothyronine (T(3)) or thyroxine (T(4)). It is initiated within an hour, precedes the decrease in TSHβ mRNA inhibition and is blocked by inhibitors of mRNA or protein synthesis. TSH elevation in primary hypothyroidism requires both the loss of feedback inhibition by thyroid hormone in the thyrotrophs and the positive effects of TRH. Another event in this feedback regulation may be the thyroid hormone-mediated induction of the TRH-inactivating pyroglutamyl peptidase II (PPII) in the hypothalamic tanycytes. This study compared the chronology of the acute effects of T(3) or T(4) on TSH suppression, TRH mRNA in the hypothalamic paraventricular nucleus (PVN), and the induction of tanycyte PPII. In wild-type mice, T(3) or T(4) caused a 50% decrease in serum TSH in hypothyroid mice by 5 h. There was no change in TRH mRNA in PVN over this interval, but there was a significant increase in PPII mRNA in the tanycytes. In mice with genetic inactivation of the type 2 iodothyronine deiodinase, T(3) decreased serum TSH and increased PPII mRNA levels, while T(4)-treatment was ineffective. We conclude that the rapid suppression of TSH in the hypothyroid mouse by T(3) occurs prior to a decrease in TRH mRNA though TRH inactivation may be occurring in the median eminence through the rapid induction of tanycyte PPII. The effect of T(4), but not T(3), requires the type 2 iodothyronine deiodinase.     

Preferential release of tri-iodothyronine following stimulation by thyrotrophin or thyrotrophin-releasing hormone in sheep of different ages.

The influence of TRH and TSH injections on plasma concentrations of tri-iodothyronine (T3) and thyroxine (T4) was investigated in neonatal (injection within 0.5 h after delivery) and growing lambs and in normal, pregnant and lactating adult ewes (all 2 years old and originating from Suffolk, Milksheep and Texal crossbreeds). Neonatal lambs had higher levels of T3, T4 and GH compared with all other groups, whereas prolactin and TSH were higher in lactating ewes. In all animals, injections of TRH increased plasma concentrations of prolactin and TSH after 15 min but not of GH at any time. Small increases in T3 and T4 were observed in neonatal lambs, without any effect on the T3 and T4 ratio, after prolactin administration, whereas prolactin did not influence plasma concentrations of T3 or T4 in all other experimental groups. Similar results for thyroid hormones were obtained after TRH or TSH injections. It was therefore concluded that the effects observed after TRH challenge were mediated by the release of TSH. With the possible exception of neonatal lambs, plasma concentrations of T3 after administration of TRH or TSH were always increased before those of T4; the increase in T3 occurred within 0.5-1 h compared with 2-4 h for T4 in all experimental groups. This resulted in an increased ratio of plasma T3 to T4 up to 4 h after injection. It is concluded that, in sheep, TRH and TSH preferentially release T3 from the thyroid gland probably by a stimulatory effect of TSH on the intrathyroidal conversion of T3 to T4.     

Maternal, infant, and delivery factors associated with neonatal thyroid hormone status.

BACKGROUND: Thyroid function is dynamic during the perinatal period with many factors potentially influencing maternal, fetal and neonatal TSH and thyroid hormone levels. We sought to identify the impact of numerous maternal, fetal and delivery attributes on thyroid parameters in newborns. METHODS: This was a cross sectional study of 300 newborns. Detailed information was obtained from medical records and multiple characteristics from the record were tested as predictors of cord blood serum total T4, free T4 and TSH and infant T4 levels from the Maryland newborn screening program. MAIN OUTCOME: Outcomes are levels of thyroid stimulating hormone (TSH), thyroxine (T(4)), and free T(4) in newborn cord serum and total T(4) in postnatal heelstick bloodspot samples. RESULTS: Multivariate models identified a number of variables that are independently associated with thyroid hormone levels: higher birth order (lower cord TSH); older maternal age (lower cord total T(4)); pregnancy-induced hypertension and/or preeclampsia (lower cord total T(4) and free T(4)); gestational diabetes (higher cord free T(4)); sexually transmitted disease during pregnancy (lower cord TSH); alcohol use during pregnancy (lower cord TSH); thyroid condition/medications (higher bloodspot total T(4), both neonatal and subsequent); Asian ancestry (higher cord TSH); male sex (higher TSH and lower neonatal bloodspot total T(4)); and C-section (lower cord TSH). Gestational age was independently associated with lower cord TSH, higher cord total T(4), and higher neonatal and subsequent bloodspot total T(4). CONCLUSIONS: Fetal and newborn thyroid hormone levels during the perinatal period are dynamic and influenced by several biological and delivery related factors. Efforts to identify fetal thyroid disruptors in late gestation must carefully consider these factors.     

肺心病患者血清甲状腺素含量变化及其临床意义

目的探讨75例无甲状腺疾病的肺心病患者血清三碘甲状腺原氨酸(T3)、血清甲状腺素(T4)和血清促甲状腺激素(TSH)的含量变化及其关系.方法检测75例肺心病患者血清T3、T4和TSH含量,另选80例健康体检者作为正常对照组.结果肺心病患者血清T3降低,与正常对照组比较,P＜0.01,血清T4与正常对照组比较P＞0.05.有肺性脑病、消化道出血严重并发症时,低T3血症尤为显著,P＜0.01.且多伴有低T4血症,P＜0.05.血清T4血症越低,病死率越高.结论血清T3、T4含量可作为判断肺心病轻重和预后指标之一.     

Effect of acute hypercalcemia on thyrotropin (TSH) and triiodothyronine responses to TSH-releasing hormone in man

In chronic hypercalcemia, basal TSH has been found to be low, with normal serum circulating concentrations of T3 and T4. This observation suggested a potentiation by hypercalcemia of the thyroid secretory response to TSH. The present study was undertaken to assess the possible influence of hypercalcemia on the T3 secretory response to TSH. Since T3 secretion was studied after stimulation of endogenous TSH by TRH, it was first necessary to find a protocol enabling us to study the effect of calcium on T3 release without affecting TSH secretion. Eighteen subjects underwent two TRH tests, with and without simultaneous calcium infusion, at 2-week interval and in a randomized order. In group A (five subjects) calcium infusion started 1 min after TRH, in group B (five subjects) 10 min after TRH, and in group C (eight subjects) 20 min after TRH. In groups A and B, TSH secretion was markedly blunted by hypercalcemia. In contrast, when calcium infusion was started 20 min after TRH (group C), the TSH secretion profile was no longer different from that in the control study. However, in this situation the increments of T3 and free T3 120 and 180 min after TRH were significantly higher when the subjects were rendered hypercalcemic than in the control study. These findings suggest that calcium might act at two different levels, to enhance the thyroid secretory response to TSH and decrease TSH secretion by acting directly on the pituitary gland. Both effects would produce the association of low serum TSH and normal levels of T3 and T4 observed in chronic hypercalcemia.     

Comparison of the effects of pulsatile and continuous TRH infusion on TSH release in men

Pulsatile secretion of hypothalamic releasing factors modulates the release of pituitary hormones. To compare the effects of pulsatile and continuous administration of TRH on TSH secretion, we studied six healthy euthyroid 20- to 38-year-old men by obtaining blood samples every 20 minutes for 12 hours (8 AM to 8 PM) during five days of study. TRH was administered according to the following schedule: day 1 (no TRH, control); day 2 and subsequent day 3 (20 micrograms IV bolus of TRH every 96 minutes); 6 to 17 days rest; then consecutive days 4 and 5 (continuous infusion of 20 micrograms TRH/96 minutes) for 12 hours on and 12 hours off. The highest mean serum TSH levels occurred on the first day of pulsatile TRH. Serum TSH on pulsatile days 1 and 2 and continuous day 1 was significantly greater than on the control day. Similarly, the mean TSH on each day of pulsatile TRH was greater than the mean TSH on the corresponding days of continuous TRH administration. The highest serum T4 and T3 levels were observed on pulsatile day 2, suggesting that the decrease in serum TSH on this day was due to thyroid hormone negative feedback at the pituitary. The mean T4 and T3 values on continuous day 1 and 2 did not differ significantly, suggesting that other factors, including "down-regulation" of the pituitary TRH receptors by the continuous TRH infusion may be involved in the further decline of TSH levels on continuous day 2. We conclude that pulsatile TRH infusion releases more TSH, T3, and T4 than the corresponding amount of TRH administered continuously.(ABSTRACT TRUNCATED AT 250 WORDS)     

Grades of subclinical hypothyroidism in asymptomatic autoimmune thyroiditis revealed by the thyrotropin-releasing hormone test

Serum levels of T4 T3, and TSH and peak TSH after TRH administration were determined in 60 female subjects affected with asymptomatic autoimmune thyroiditis (AAT), in 27 normal subjects, and in 8 myxoedematous patients used as controls. The AAT subjects were divided into 3 groups on the basis of their basal and peak TSH values. In the first group (grade I AAT), these parameters were similar to those of the normal controls; in the second (grade II AAT), basal TSH remained normal but peak TSH was significantly increased; and in the third (grade III AAT), both parameters were significantly increased. Serum T4 levels decreased progressively from group 1 to group 3, but all T4 values were within the normal range. T3 levels were similar in all groups. Peak and basal TSH values were highly correlated, except in grade II AAT. There seems to exist a graded process of subclinical hypothyroidism in AAT; a progressive pituitary TSH reserve is modulated by a progressive decrease in T4 levels still within the normal range.     

Effect of acute exposure to cold on the activity of the hypothalamic-pituitary-thyroid system.

The effects of a sudden but sustained exposure to cold (1 to 6C) on serum TSH, thyroxine (T4) and triiodothyronine (T3) (all measured by radioimmunoassay), pituitary TSH concentration, pituitary TSH secretory responsiveness to hypothalamic extract or synthetic thyrotropin-releasing hormone (TRH) in vitro as well as in vivo, and the changes of the thyrotropin-releasing activity in three TRF-rich hypothalamic areas were determined. In normal animals, serum TSH underwent a series of oscillations, first rising then returning to the basal levels, then rising again, whereas serum T4 and T3 increased within 2 h of cold exposure and remained elevated. Pituitary TSH concentration and the in vitro pituitary responsiveness declined after an initial elevation, whereas the in vivo responsiveness to TRH was diminished throughout the whole exposure to cold. Thyroid-blocked animals with steady, low levels of serum T4 and T3 showed a step by step increase of serum TSH levels and no changes in the other parameters. It is therefore assumed that the decrease of TSH secretion following the initial rise is due to a feedback inhibition by the increased levels of thyroid hormones as is the decreased pituitary responsiveness of TRH in vivo. The pituitary responsiveness in vitro seems to be determined by TSH pituitary concentrations, the changes of which are probably also secondary to the changes of the thyroid hormone levels. The mechanism of the second rise of serum TSH levels is not clear. Thyrotropin-releasing factor (TRF) activity was higher after 2 and 24 h of cold exposure in the median eminence and after 8 h in the anterior hypothalamus-preoptic area, but lower after 8 and 24 h in the dorsomedial hypothalamus. Since the changes of TRF activity in the median eminence coincided with the elevated serum TSH, they are assumed to reflect increased TRF production and secretion. The significance of the TRF changes in the other two areas is not clear.     

Effect of dexamethasone on prolactin and TSH responses to TRH and metoclopramide in man.

We studied the effects of administration of dexamethasone, 2 mg orally every 6 h, for 5 days on the thyrotropin-releasing hormone (TRH)-induced release of prolactin (PRL), thyrotropin (TSH), triiodothyronine (T3) and thyroxine (T4) in 9 normal men and on the metoclopramide-induced release of PRL in 7 normal men. Dexamethasone suppressed the baseline serum levels of PRL, TSH and T3. The administration of dexamethasone blunted the PRL and TSH response to TRH; the blunted TSH response resulted in a decreased T3 and T4 response to TRH after dexamethasone. Following dexamethasone administration, the PRL response to metoclopramide, a dopamine antagonist which acts at the hypothalamicpituitary level to stimulate PRL secretion, was blunted in 7 normal men. The data suggest that short-term administration of pharmacological doses of glucocorticoids suppress the secretion of PRL and TSH by a direct effect on the anterior pituitary gland.