Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation

The occurrence of central hypothyroidism in previously euthyroid children during GH therapy has been reported with widely varying incidence. We monitored the acute effects on the hypothalamic-pituitary-thyroid axis in 15 euthyroid children with classic GH deficiency during the first year of GH therapy. All were initially euthyroid, as assessed by normal baseline TSH, T4, free T4, and T3 levels and negative antithyroid antibodies. A thyroid profile (T4, free T4 index, T3, rT3, and TSH) was performed at baseline and 1, 3, 6, 9, and 12-15 months after GH therapy began; a TRH stimulation test was performed at baseline and after 1, 3, and 9 months of therapy. By 1 month, there were significant decreases in T4, free T4 index, and rT3, and significant increases in T3 and the T3/T4 ratio. The changes from baseline values were greatest at 1 month, were almost universal for all thyroid values, and showed a gradual return to baseline from 3-12 months. There were no clinical signs of hypothyroidism and no change in baseline or TRH-stimulated TSH levels or in cholesterol levels, and all patients grew at velocities expected for the treatment schedule. There is little evidence for the development of clinically significant hypothyroidism in the great majority of initially euthyroid patients after GH therapy is begun. T4 supplementation is seldom needed in such patients.     

Studies on obesity. III. effect of triiodothyronine (T3) on thyroglobulin autoantibodies in euthyroid obese subjects

Effect of T3 therapy on tanned red cell agglutinating thyroglobulin (TRC-TG) antibodies in 10 obese subjects without apparent thyroid disease was investigated. Six other obese subjects without thyroid dysfunction and of approximately the same mean age who also had circulating TRC-TG antibodies served as control subjects and were untreated. In vitro thyroid tests (TSH, total and free T4) performed before T3 therapy, as well as clinical examination, showed thyroid function to be normal in all subjects, and there was no evidence of thyroiditis. TRC-TG antibodies were present in low to moderate titers of 40-1280 in control subjects as well as in subjects selected for T3 treatment. Therapy with T3 was started at 50 mug/day and gradually increased to a maximum of 250 mug/day, depending on clinical needs. T3-treated as well as untreated obese control subjects were all maintained on a high protein, low fat, low carbohydrate diet. Duration of T3 therapy varied from 2-8 mo, and in all but one T3-treated subject, TRC-TG antibodies completely disappeared. In the one exceptional case, TRC-TG antibody titer decreased from 1280 to 80 after 7 mo of therapy. In non-T3-treated obese control subjects, antibody titers remained at the same levels throughout the observation period, thereby indicating a lack of spontaneous regression of circulating immune response. Therapy with T3, by inhibiting TSH, may have caused regression of inapparent immunologic thyroid lesion, thus leading to the disappearance of circulating TRC antibodies; alternatively, T3 specifically may have accelerated catabolism of thyroid antibodies. The latter possibility is favored in the absence of clinical and laboratory evidence of thyroiditis in T3-treated subjects.     

Role of protein degradation in the growth of livers after a nutritional shift

Four patients with idiopathic pituitary dwarfism were shown to have growth hormone (GH), adrenocorticotropin (ACTH), and luteinizing hormone (LH) deficiencies. Basal levels of thyrotropin (TSH) were within normal range in three patients and slightly elevated in one. Exaggerated and delayed responses were obtained after TSH-releasing hormone (TRH) stimulation. Serum thyroxine (T4) values were low (2.3 +/- 0.4 mug/100 ml), while triiodothyronine (T3) levels were in the normal range (1.22 +/- 0.25 ng/ml), both rising substantially after exogenous TSH and consecutive TRH administration. Their hypothyroid state was, therefore, probably due to TRH deficiency. To examine the dose of L-T4 necessary to produce inhibition of the TSH response to TRH, 50 mug/m2/day of L-T4 was administered to these patients. At the end of 4 weeks of replacement, serum T4 rose to 5.2 +/- 0.5 mug/100 ml, whereas T3 was unchanged from the previous levels, after which TSH responses to TRH were completely suppressed in all patients. As a control group, six patients with primary hypothyroidism received gradually increasing doses of L-T4 for 4-week periods, and TSH response to TRH was tested at the end of each dosage of L-T4, until complete inhibition of TSH release was obtained. The primary hypothyroid patients required approximately 150 mug/m2/day of L-T4 for suppression of TSH response to TRH. At this dosage, serum T4 and T3 levels were 8.5 +/- 0.9 mug/100 ml and 2.34 +/- 0.5 ng/ml respectively, which were significantly higher than those levels in the pituitary dwarfs (P less than 0.001 for T4 and P less than 0.01 for T3). These observations indicate that the set point of TSH release in feedback inhibition by throxine is low in idiopathic hypopituitarism with TRH deficiency, and TRH seems to control the pituitary sensitivity to feedback regulation of thyroid hormones.     

Ehanced biliary thyroxine excretion in rats treated with pregnenolone-16alpha-carbonitrile

Normal rats were treated with pregnenolone- 16alpha - carbonitrile (PCN) 10 mg/100 g by stomach tube twice daily for 3 days. In these animals the biliary excretion of intravenously injected 125I-thyroxine (T4) was enhanced and the bile: plasma 125I ratio (B/P ratio) and the biliary clearance rate of plasma 125I-T4 was increased. Normal rats were treated with PCN for 3 days and homozygous Gunn rats for 13 days. In both groups PCN enhanced the bile flow and elevated the B/P ratios and the biliary clearance rate of plasma T4 following ip injection of 125I-T4 17 h previously. PCN-treatment had no effect on the fractions of biliary 125I present as T4-glucuronide, T4 and I- in either the normal or Gunn rats. Treatment with PCN for 10 days produced goitres in normal and Gunn rats and in normal rats elevated the serum TSH (bioassay) levels and the 17 h thyroid 131I uptake as well as the serum PB125I concentrations, without affecting stable PBI concentrations. These data indicated increased pituitary TSH release in response to increased peripheral metabolism of thyroid hormone; enhanced hormonal release from the thyroid kept pace with the accelerated peripheral loss.     

Thyroid hormones in diabetic ketoacidosis before and after therapy

Fifteen IDDM patients were evaluated for thyroid hormone abnormalities before and after control of diabetes mellitus/ketoacidosis. Blood sugar mean +/- SEM mg/dl on admission was 430 +/- 20.3 and after therapy fasting and post prandial blood sugar values were 120 +/- 14.5 and 150 +/- 20.2 respectively. GHb mean +/- SEM % on admission was 15.2 +/- 0.36. Serum T3 mean +/- SEM ng/dl of 0.36 +/- 0.04 was in hypothyroid range and rT3 mean +/- SEM ng/ml 0.40 +/- 0.6 was significantly raised (P < 0.001) before therapy. After metabolic control both T3 and rT3 became normal. T4 concentration mean +/- SEM meg/dl of 5.5 +/- 0.7 was well within normal range before therapy and rose to mean +/- SEM mcg/dl 8.8 +/- 0.5 after therapy (P < 0.01). TSH response to TRH was blunted in uncontrolled state. It is concluded that peripheral changes in T3, T4 and rT3 (low T3, high rT3 and low or normal T4) occurred in uncontrolled diabetic state during ketoacidosis. TSH response to TRH was blunted due to suppression of hypothalamic pituitary thyroid axis which takes more than a week for complete recovery.     

Thyroglobulin assay in the follow-up of patients with differentiated thyroid carcinomas: comparison of its value in patients with or without normal residual tissue

The usefulness of serum thyroglobulin (Tg) assay in the follow-up of differentiated thyroid carcinomas has been evaluated in 109 subjects divided into two groups. Group 1 included 64 patients who had undergone total thyroid ablation. In 40 of the 41 patients in complete remission serum Tg was undetectable during replacement therapy (TSH below 5 microunits/ml). In 18 out of the 40 patients serum TG was detectable following endogenous TSH stimulation. As 83% of these patients had ectopic uptake prior to the last radioiodine treatment, this release of Tg under TSH stimulation suggests the persistence of occult neoplastic tissue. Of the other 23 patients, 20 had bone or lung metastases and 3 patients had lymph node recurrences: in all these patients, serum Tg was detectable during replacement therapy and increased after TSH stimulation. Group 2 included 45 patients in whom normal residual thyroid tissue was present at the time of the investigation. Of these, 35 patients were in apparent remission and 19 of them had detectable Tg level within the normal range. The other 10 patients had detectable metastases and in 4 of these the Tg level was also within the normal range. Thus, no conclusion can be drawn from a normal Tg level in the presence of residual thyroid tissue. Bovine TSH stimulation did not improve significantly the diagnostic value of Tg assay in this group of patients.     

Pituitary and peripheral thyroid hormone responses to thyrotropin-releasing hormone during sustained sleep deprivation in freely moving rats

Sleep deprivation is associated with poor cognitive ability and impaired physical health, but the ways in which the brain and body become compromised are not understood. In sleep-deprived rats, plasma total T4 and T3 concentrations decline progressively to 78% and 47% below baseline values, respectively, brown adipose tissue 5'-deiodinase type II activity increases 100-fold, and serum TSH values are unknown. The progressive decline in plasma thyroid hormones is associated with a deep negative energy balance despite normal or increased food intake and malnutrition-like symptoms that eventuate in hypothermia and lethal systemic infections. The purpose of the present experiment was to evaluate the probable causes of the low plasma total T4 during sleep deprivation by measuring the free hormone concentration to minimize binding irregularities and by challenging the pituitary-thyroid axis with iv TRH to determine both 1) the pituitary release of TSH and 2) the thyroidal response of free T4 (FT4) and free T3 (FT3) release to the TSH increment. Sleep-deprived rats were awake 91% of the total time compared with 63% of the total time in yoked control rats and 50% of the total time during the baseline period. Cage control comparison rats were permitted to sleep normally. Sustained sleep deprivation resulted in a decline from baseline in plasma FT4 of 73 +/- 6% and FT3 of 45 +/- 12%, which were similar to the declines in total hormone concentrations observed previously; nonstimulated TSH was unchanged. In the yoked and cage control groups, FT4 also declined, but much less than that of the sleep-deprived group. The relative changes in free compared with total hormone concentrations over the study were also less parallel than those in the sleep-deprived group. The plasma TSH response to TRH was similar in all groups across experimental days. The plasma FT4 and FT3 concentrations in sleep-deprived rats increased after TRH-stimulated TSH release to an extent comparable to control values. Taken together, low basal FT4 and FT3 hormone concentrations and unchanged TSH and thyroidal responses to TRH suggest a pituitary or hypothalamic contribution to the hypothyroxinemia during sleep deprivation.     

Accumulation of zinc in rainbow trout (Oncorhynchus mykiss) after waterborne and dietary exposure

An acromegalic patient with nontoxic autonomous goiter was sequentially treated with octreotide and bromocriptine. Before therapy, serum GH, PRL and insulin-like growth factor-I (IGF-I) levels were increased. Free T3 and free T4 were within the normal range with suppressed TSH levels, whereas 123Iodine-uptake of thyroid was 5.6% after 24 h. During treatment with octreotide and bromocriptine, serum GH, PRL, and IGF-I became normal and free T3 and free T4 were slightly but significantly decreased, but TSH levels remained very low. After thyroidectomy, thyroglobulin, free T3 and free T4 were further decreased, and the TSH levels were recovered to normal. These findings suggested that octreotide and bromocriptine inhibit the release of thyroid hormones from the autonomous thyroid gland directly or indirectly through the decline in IGF-I.     

Effect of thyrotropin-releasing hormone on secretion of thyrotropin, prolactin, thyroxine, and triiodothyronine in pregnant and fetal rhesus monkeys

The effect of thyrotropin-releasing hormone (TRH) on the pituitary-thyroid axis and on prolactin secretion was studied in pregnant Rhesus monkeys during the latter period of gestation and in non-pregnant female controls. The baseline plasma concentrations of TSH, T3, T4, and prolactin (PRL) of pregnant monkeys did not differ from those of non-pregnant monkeys. After administration of TRH, plasma prolactin rose to higher levels in pregnant monkeys than in non-pregnant monkeys whereas there was a similar response of plasma TSH, T4 and T3 in both groups. The baseline plasma TSH was elevated and plasma T3 was decreased in the fetus compared with the mother. Administration of TRH iv to the maternal monkey caused a larger response in the fetal plasma TSH than in that of the mother and was followed by larger increments in plasma T4 and T3 concentrations in the fetuses than in the mothers. The larger increments of plasma TSH and thyroid hormones in the fetus compared with the mother also occurred when TRH was given iv to the fetus. There was a significant rise of plasma prolactin in both mother and fetus after administration of TRH to mother or fetus; the increase of plasma PRL was much higher in the mother than in the fetus. The data show that TRH can cross the primate placenta in either the maternal to fetal or fetal to maternal direction. The fetal thyroid of the Rhesus monkey during the latter period of gestation can release both T4 and T3 in response to TSH.     

Failure of triiodothyronine to inhibit TSH-mediated thyroid hormone release in man

We studied the effect of short-term triiodothyronine administration on thyroid gland responsivity to exogenous thyrotropin in four euthyroid human subjects. Thyroidal iodine release and serum thyroxine during daily im injections of bovine TSH were not significantly inhibited, despite a four-fold elevation in serum T3 concentrations. This negative finding contrasts with earlier positive reports of a regulatory "short-loop" effect of elevated circulating T3 on the thyroid gland. This difference may be due either to the use in previous murine or in vitro studies of non-physiologic, high doses of exogenous T3, or failure to control the withdrawal of the trophic effect of endogenous TSH in man on the subsequent glandular response.     

Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas

The recorded number of patients with central hyperthyroidism due to TSH-secreting pituitary adenoma doubled in the last few years after the introduction of ultrasensitive TSH assays in the assessment of thyroid function; however, information about the results and the criteria for cure after pituitary surgery is scanty. Seventeen patients with a TSH-secreting adenoma, diagnosed on the basis of detectable TSH levels in the face of high free thyroid hormone concentrations and pituitary lesion at neuroimaging, underwent pituitary surgery. Hypersecretion of other pituitary hormones was diagnosed in 5 of 17 patients. Four patients were initially misdiagnosed and treated with thyroid surgery or radioiodine therapy. The majority (86%) of hyperthyroid patients normalized thyroid hormone concentrations and regained euthyroidism, although pituitary imaging, alpha-subunit, and alpha-subunit/TSH molar ratio normalized in only 47%, 54%, and 58% of patients, respectively. Moreover, TSH secretion was normally suppressed by T3 in 40% of the patients. Interestingly, the finding of undetectable TSH levels 7 days after surgery was highly predictive of successful outcome. During long term follow-up, there was one relapse of hyperthyroidism. Early diagnosis of TSH-secreting adenomas permits a high rate of remission of hyperthyroidism after surgery. However, normalization of thyroid function alone does not necessarily reflect complete removal of the tumor, and more comprehensive criteria of cure based on pituitary imaging, hormone measurement, and suppression of TSH during T3 administration should be used. Lastly, all patients need an accurate long term follow-up to monitor the possible recurrence of the adenoma.     

Effect of (-)-N-[(S)-hexahydro-l-methyl-2, 6-dioxo-4-pyrimidinylcarbonyl]-L-histidyl-L-prolinamide (TA-0910), a new TRH analog, on plasma levels of TSH and thyroid hormones in rats

The stimulatory effect of TA-0910 on the secretions of thyroid-stimulating hormone (TSH) and thyroid hormones was investigated in male and female rats. Single intravenous administration of TA-0910 at 8.3 nmol/body acutely elevated the plasma TSH level, with delayed and moderate increases of T3 and T4 in plasma. Similar increments of plasma TSH and thyroid hormones were observed when TRH was injected at the dose of 0.83 nmol/body. Oral administration of TA-0910 at 2.75 mumol/body was equally potent or slightly more potent to secrete TSH than TRH at 0.275 mumol/body. The elevated TSH by TA-0910 decreased to the control level within 2 hr after intravenous injection or within 6 hr after oral administration; on the other hand, the higher levels of the thyroid hormones were retained for up to 4 and 6 hr after intravenous and oral administration, respectively. These findings indicate that TA-0910 and TRH stimulate the secretion of TSH and thyroid hormones by a similar manner and that the TSH-secreting activity of TA-0910 is lower by an order of magnitude compared with that of TRH.     

Hypothyroidism and hyperthyroidism in major depression revisited

BACKGROUND: The aim of our study was to evaluate the prevalence of thyroid abnormalities among depressed outpatients and to examine the response to treatment of those subjects with relatively low or high thyroid hormone levels. METHOD: Outpatients (N = 200) 18 to 65 years of age who met DSM-III-R criteria for major depression were screened for the presence of thyroid abnormalities using a number of thyroid indices. Of these patients, 166 were then treated openly with the antidepressant fluoxetine for 12 weeks. We assessed whether patients with relatively low or high thyroid hormone levels had a different response to treatment compared with other patients. The 17-item Hamilton Rating Scale for Depression (HAM-D-17) was administered during the study to assess changes in depressive symptoms. Thyroid function was assessed by measuring T3, T4, free T4 index (FT4I), T3 uptake (T3U), and serum thyroid-stimulating hormone (TSH) levels. RESULTS: No clinical cases of hyperthyroidism or hypothyroidism were detected. Of the patients examined, 5 (2.6%) had slightly elevated TSH levels (range, 4.7-8.2); none of these had T4 or FT4I levels below the normal range. Subnormal levels of T4 or FT4I were found in 1 subject (0.5%). T3 and T3U levels were below the normal range in a larger number of patients (7.6% and 15.0% respectively), but only 1 of these patients had elevated TSH levels. None of the patients had levels of TSH below the normal range, and only 3 subjects (1.5%) had T4 levels above the normal range. No relationship was found between response rate (assessed as either change in HAM-D-17 score or as remission of depressive symptoms with a HAM-D-17 score < or = 7 for 3 consecutive weeks) and each of the thyroid tests, even after adjusting for baseline severity of depression. CONCLUSION: In depressed outpatients, it appears that hypothyroidism and hyperthyroidism are extremely uncommon and that the presence of subtle thyroid function abnormalities does not have an impact on treatment outcome.     

Ingestion of androgenic-anabolic steroids induces mild thyroidal impairment in male body builders

Self-administration of very high doses of androgenic anabolic steroids is common use in power athletes because of their favorable effect on performance. Since androgenic steroids decrease serum T4-binding globulin (TBG) concentrations dramatically, we were interested in the effects of this procedure on thyroid function: we performed TRH tests (200 micrograms Relefact, i.v.), with blood withdrawal before and for 180 min after injection, for determination, using RIA kits, of serum concentrations of total and free T4, total T3, TSH, and TBG in 13 young (20-29 yr old) male body builders with clinically normal thyroid glands, who were all in the same state of training. Five of these athletes admitted taking androgenic anabolic steroids at an average total dose of 1.2 g/week for at least 6 weeks before the tests. TBG, total T4, and total T3 were significantly (P < 0.001) decreased, whereas basal TSH and free T4 were not significantly different from the values of the other 8 without androgenic steroids. The maximum TSH increase after TRH administration (mean +/- SE, 16 -/+ 6 vs. 9 -/+ 4 mU/L; P < 0.05) was relatively increased, whereas the T3 response to TRH (0.61 -/+ 0.10 vs. 1.13 -/+ 0.13 nmol/L; P < 0.05) was relatively decreased in the group receiving androgens. The 5 patients taking androgens had significantly greater weight (114 vs. 90 kg; P < 0.01) and higher total cholesterol levels (6.3 -/+ 1.3 vs. 3.8 -/+ 0.3 mmol/L; P < 0.05) together with very low high density lipoprotein cholesterol levels (0.20 -/+ 0.03 vs. 1.03 -/+ 0.10; P < 0.001) than the controls. PRL levels were normal and similar in both groups. We conclude from our results that high dose androgenic anabolic steroid administration leads to a relative impairment (within the normal range) of thyroid function. Whether this is due to a direct thyroid hormone release (or synthesis?)-blocking effect of these steroids needs further investigation.     

Thyroid profile in normal pregnancy

The aim of this study was to update the thyroid hormone profile in normal pregnant women with adequate iodine nutrition, to analyze the physiological changes that occur during pregnancy and to know the role that TBG and bHCG exert on these changes. One hundred six pregnant women without goiter, former thyroid diseases or positive antimicrosomal antibodies were studied. Fifty three of them were prospectively followed during the gestational period. Thirty age matched non pregnant women were studied as a control group. Serum T3t, T4t, T41, conventional and IRMA TSH, rT3, TBG, bHCG, antimicrosomal antibodies and urinary iodine content were measured. Median urinary iodine content was 18.9 ug/ml in pregnant women, discarding iodine deficiency, the main observed changes occurred between weeks 6 and 14 with significant elevations of T3t, T4t, T41, rT3, TBG and bHCG and TSH decrease. There was a positive correlation between TBG and T3t and T4t indicating a causal relationship. There was a negative correlation between T41 and TSH and between TSH and bHCG and a positive correlation between T41 and bHCG, suggesting a thyroid stimulator effect of bHCG which would raise T41 and thus inhibit TSH secretion.     

Transient hypothyroidism after iodine-131 therapy for Grave's disease

We studied 355 patients with Grave's disease to characterize transient hypothyroidism and its prognostic value following 131I therapy. METHODS: The patients received therapeutic 131I treatment as follows: 333 received a dose < 10 mCi (6.6 +/- 1.9 mCi) and 22 received a dose > 10 mCi (12.8 +/- 2.9 mCi). Diagnosis of transient hypothyroidism was based on low T4, regardless of TSH within the first year after 131I followed by recovery of T4 and normal TSH. RESULTS: After administration of < 10 mCi 131I, 40 patients developed transient hypothyroidism during the first year; transient hypothyroidism was symptomatic in 15. There was no transient hypothyroidism after high doses (> 10 mCi) of 131I. Iodine-131 uptake > 70% at 2 hr before treatment was a risk factor for developing transient hypothyroidism (Odds ratio 2.8, 95% confidence interval 0.9-9.4). At diagnosis of transient hypothyroidism, basal TSH levels were high (51%), normal (35%) or low (14%); therefore, the transient hypothyroidism was not centralized. If hypothyroidism developed during the first 6 mo after basal TSH > 45 mU/liter ruled out transient hypothyroidism. CONCLUSION: The development of transient hypothyroidism and its hormonal pattern did not influence long-term thyroid function. Since no prognostic factors reliably predicted transient hypothyroidism before 131I or at the time of diagnosis, if hypothyroidism appears within the first months after 131I, the reevaluation of thyroid function later is warranted to avoid unnecessary chronic replacement therapy.     

Inhibition in the senso-motor cortex of cats

The clinical course from birth and serial measurements of serum T3, T4 and TSH in an infant with untreated neonatal thyrotoxicosis are reported. The thyroid hormone levels fell exponentially with time at rates very much slower than those previously reported for the maternally-transmitted thyroid stimulating antibody generally thought to cause the disorder. Steady physiological levels of thyroid hormones were achieved after 110 days (serum T3 = 3.4 NMOL/L, T4 = 118 nmol/l). TSH first rose to a measurable level after about 90 days.     

Thyrotropin-secreting pituitary adenoma

Thyrotropin (TSH)-secreting pituitary adenoma (TSPA) is a rare cause of hyperthyroidism and detailed reports of this entity in Taiwan are uncommon. We report a patient with TSPA with symptoms of hyperthyroidism and describe the presentation, endocrine and histologic findings, and treatment. The patient, a 42-year-old man, presented with a 2-year history of weight loss, palpitation, anxiety, and bad temper. He had increased basal serum thyroxine (T4, 18.3 micrograms/dL) and triiodothyronine (T3, 250 ng/dL) concentrations. The TSH concentration was normal (4.6 microIU/mL) and showed impaired response to stimulation by TSH-releasing hormone. Tests for antithyroid antibodies were negative. Thyroid scintigraphy showed mild thyroid enlargement. The thyroid uptake of radioactive iodine (131I) was high at 2 hours (34%) and 24 hours (63%) after 131I administration. Other serum hormone concentrations were within normal limits. Magnetic resonance imaging of the brain showed a microadenoma in the pituitary region. Octreotide and bromocriptine tests showed 78.4% and 58.3% inhibition of TSH, respectively. The patient underwent trans-sphenoidal pituitary tumor excision, and the symptoms of hyperthyroidism subsided after surgery. Six months after the operation, there was no evidence of recurrence of the tumor or symptoms of hyperthyroidism. Hormonal supplements were also not necessary. In conclusion, TSPA is a rare cause of hyperthyroidism. However, in patients with symptoms of hyperthyroidism and increased basal serum T1 and T3 concentrations, but normal or even elevated serum TSH concentrations, TSPA should be considered in the differential diagnosis.     

Antigen-presenting dendritic cells as regulators of the growth of thyrocytes: a role of interleukin-1beta and interleukin-6

An accumulation of antigen-presenting dendritic cells (DC) in the thyroid gland, followed by thyroid autoimmune reactivity, occurs in normal Wistar rats during iodine deficiency, and spontaneously in diabetic-prone Biobreeding rats. This intrathyroidal DC accumulation coincides with an enhanced growth rate and metabolism of the thyrocytes, suggesting that both phenomena are related. Because DC are known to regulate the hormone synthesis and growth in other endocrine systems (i.e. the pituitary, the ovary, and the testis), we tested the hypothesis that DC, known for their superb accessory cell function in T cell stimulation, act as regulators of thyrocyte proliferation (and hormone secretion). We investigated the effect of (Nycodenz density gradient) purified splenic DC from Wistar rats on the growth rate of and thyroid hormone secretion by Wistar thyroid follicles (collagenase dispersion) in culture. Various numbers of DC and follicles were cocultured during 24 h. The proliferative capacity of thyrocytes was measured by adding tritiated thymidine (3H-TdR) and bromodeoxyuridine, the hormone secretion into the culture fluid was measured by using a conventional T3 RIA. Furthermore, antibodies directed against interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were added to these cocultures to determine the role of these cytokines in a possible DC regulation of thyrocyte growth. Cocultures were also carried out in the presence of antimajor histocompatibility complex-class I (MHC I), anti-MHC II, antiintercellular adhesion molecule-1 (ICAM-1), and antilymphocyte function-associated antigen-1alpha (LFA-1alpha) antibodies to possibly interfere with DC-thyrocyte interactions. The addition of DC to thyroid follicles clearly inhibited their 3H-TdR uptake, particularly at a 10:1 ratio, in comparison to follicle cultures alone, both under basal conditions and after TSH stimulation (75 +/- 7% and 49 +/- 11% reduction, respectively, n = 4). The follicle T3 secretion (after TSH stimulation) was also suppressed by DC in this system, but to a lesser extent (at best at an 1:1 ratio, 25 +/- 7% reduction, n = 4). The DC-induced inhibition of thyroid follicle growth was totally abrogated after addition of anti-IL-1beta antibodies; anti-IL-6 only had effect on the DC inhibition of non-TSH-stimulated thyrocytes, whereas anti-TNF-alpha demonstrated no effect at all. The antibodies to MHC and to adhesion molecules had also no effect on this DC-induced growth inhibition. The effect of the different anti-cytokine and anti-adhesion antibodies on the T3 secretion from thyroid follicles was not investigated. The clear inhibition of thyrocyte growth by splenic DC (classical antigen-presenting cells) again demonstrates the regulatory role of DC in endocrine systems. Proinflammatory cytokines such as IL-1beta and IL-6 are important mediators in this regulation. The here shown dual role of DC represents a link between the immune and endocrine system, which may form the gateway to the understanding of the initiation of thyroid autoimmune reactions and the thyroid autoimmune phenomena seen in iodine deficiency.     

Thyroxine administration to infants of less than 30 weeks gestational age decreases plasma tri-iodothyronine concentrations

OBJECTIVE: To investigate the effect on thyroid hormone metabolism of the administration of thyroxine to very preterm infants. DESIGN AND METHODS: Two hundred infants of less than 30 weeks gestation were enrolled into a randomized, double-blind, placebo-controlled trial. Thyroxine (T4) (at a fixed daily dose of 8 microg/kg birthweight) or placebo was started 12-24h after birth and discontinued 6 weeks later. Plasma concentrations of T4, tri-iodothyronine (T3), reverse T3 (rT3), TSH, and thyroxine-binding globulin were measured weekly during trial medication and 2 weeks thereafter. RESULTS: The T4 and the placebo group each comprised 100 infants. Antenatal, perinatal, and postnatal clinical characteristics were comparable in both groups. T4 and rT3 were significantly increased in the T4 group. TSH concentrations were depressed in the T4 group and T3 was significantly decreased, probably as a result of TSH depression. The T4/T3 and T4/rT3 ratios differed significantly between the two study groups. CONCLUSIONS: Daily T4 administration during the first 6 weeks after birth to infants of less than 30 weeks gestation prevents hypothyroxinemia, but decreases plasma T3 concentrations. Our finding possibly implies that very preterm infants should receive supplements of both T4 and T3.