rT3 Concentrations Research Articles

Melatonin and the pituitary-thyroid axis status in blind adults: a possible resetting after puberty.

Increased levels of free thyroid hormones have been previously described in prepubertal blind subjects and have been thought to be a consequence of a partial target organ refractoriness due to the early and prolonged lack of light perception. The aim of this study was to clarify whether this abnormality is permanent or transient and the interrelationships between melatonin and thyroid hormone secretion. Total and free thyroid hormones, TSH, thyroxine-binding globulin (TBG), reverse triiodothyronine (rT3) and melatonin were measured in plasma samples obtained at 0800 h (two hours after lights-on) in a group of 11 totally (group 1) and 16 partially (group 2) blind adult patients and in 10 age-matched healthy subjects. Both totally and partially blind patients showed melatonin levels higher than in controls (330 +/- 106 pmol/l, group 1 and 361 +/- 159 pmol/l, group 2, respectively; controls: 53 +/- 12 pmol/l, P < 0.001 vs both groups), but fT4, fT3, T4, T3 TSH, rT3 and TBG concentrations showed no significant differences from controls. A possible resetting of pituitary-thyroid axis regulation can occur in blindness after puberty; variations of melatonin secretion could play a role in this. The inhibitory effect of melatonin on thyroid gland function found in animals does not seem to occur in humans. Elevated melatonin levels, both in patients with total blindness and in those with light perception only, suggest that more complex mechanisms other than light signalling are involved in the changes of melatonin secretion in blindness.

Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men.

Both hyper- and hypothyroidism have been reported during prolonged recombinant human interferon-alpha (rhIFN alpha) therapy. To assess the short term effects of IFN alpha therapy on thyroid hormone metabolism, we measured thyroid hormone concentrations in eight healthy volunteers for 24 h after sc administration of rhIFN alpha and, on another occasion, after sc administration of saline (control study). There were no effects of rhIFN alpha on plasma T4 and free T4 or on thyroid hormone binding index. However, rhIFN alpha induced a significant decrease in the plasma concentrations of TSH (P < 0.03) and T3 (P < 0.02) compared with those in the control study, associated with an increase in rT3 concentrations (P < 0.02). IFN alpha induced a moderate increase in interleukin-6 (IL-6) concentrations (P < 0.02 vs. control study), whereas IL-1 and tumor necrosis factor concentrations remained below the detection limit in all subjects. It is concluded that IFN alpha administration induces major changes in thyroid hormone metabolism, possibly mediated in part by IL-6. The acute effects of rhIFN alpha mimic the euthyroid sick syndrome and appear to be different from the effects of chronic rhIFN alpha treatment on thyroid hormone metabolism.

Amniotic and allantoic fluid concentrations of thyroxine, 3,3',5'-tri-iodothyronine, 3,3'-di-iodothyronine and 3',5'-di-iodothyronine in the pig during the period of gestation.

Thyroxine (T4), 3,3',5'-tri-iodothyronine (reverse T3; rT3) and di-iodothyronines (3,3'-T2 and 3',5'-T2) were measured in pig amniotic fluid (AF) and allantoic fluid (Al) between 32 and 113 days of normal pregnancy. Low but measurable quantities of T4 in AF and Al (2.1 +/- 0.3 and 3.2 +/- 0.5 nmol/l respectively) were found before the onset of fetal thyroid gland function, which indicates the maternal source of T4. The presence of rT3 (55.8 +/- 4.1 pmol/l in AF and 49.8 +/- 5.3 pmol/l in Al), 3,3'-T2 (45.5 +/- 0.6 pmol/l in AF and 49.2 +/- 9.2 pmol/l in Al) and 3',5'-T2 (20.8 +/- 2.6 pmol/l in AF and 24.0 +/- 2.2 pmol/l in Al) may be attributed to the monodeiodinase system already active in fetal pig tissues in early pregnancy, as demonstrated previously. T3 concentration was undetectable in both AF and Al. An approximately twofold increase in the levels of T4, rT3 and T2s in AF and Al at mid-gestation was observed. T4 and rT3 in AF showed a positive correlation with protein concentrations. AF rT3 concentration (but not T4) correlated with rT3 in the cord and maternal serum. The 3,3'-T2 and 3',5'-T2 in AF and Al showed parallel changes to rT3, while the rT3/3,3'-T2 and rT3/3',5'-T2 molar ratios remained constant. T4 concentrations in AF and Al were markedly lower than in corresponding maternal and fetal serum; the rT3 concentration in Al was equal to that in AF and two to four times lower than in fetal serum. In spite of differences between serum hormone patterns in the pig and human near term, iodothyronine concentrations in AF showed some similarities, mainly the following: undetectable T3, a strong correlation between rT3, T4 and AF total protein and the presence of 3,3'-T2 and 3',5'-T2 in measurable levels. Comparative data for Al, except the ones in the present study in the pig, are not available.

Influence of nutrition, thyroid hormones, and rectal temperature on in-hospital mortality of elderly patients with acute illness

The present study was undertaken to investigate the interrelation of nutrition, core temperature, and thyroid function and their influence on survival of patients aged > or = 70 y admitted to the hospital with acute conditions. Sixty-seven patients entered the study. Nutritional state, thyroid function, rectal temperature, and the APACHE II score were recorded at admission. The patients were followed until death or hospital discharge. Patients with a serum albumin concentration < 35 g/L showed a lower triiodothyronine (T3) concentration, a higher reverse triiodothyronine (rT3) concentration, and a higher death rate. Prior weight loss (> or = 10%) did not influence thyroid status but increased the mortality rate. Eleven patients were hypothermic (< 36.5 degrees C) and had a higher mortality, lower total T3 concentration, and higher rT3 concentration than the normothermic or hyperthermic subjects. Serum albumin, body weight, and total T3 concentration were higher in survivors (n = 51) than in nonsurvivors (n = 16). Ongoing weight loss and hypoalbuminemia at admission are highly prevalent in elderly people with acute disease, and influence their clinical outcome. Mild hypothermia was a good predictor of death. Hypoalbuminemia and hypothermia were associated with low T3 and high rT3 values.

Unchanged 5′-Deiodinating Activity During the Induction of a Nonthyroidal Illness

We investigated the formation of a "nonthyroidal illness" (NTI) in pigs undergoing ventricular fibrillation (VF) and resuscitation. Seven minutes after VF twenty-one pigs received either Epinephrine (E: 45 micrograms/kg B.W.; n = 7), Norepinephrine (NE: 45 micrograms/kg B.W.; n = 7), or Vasopressin (VP: 0.8 U/kg B.W.; n = 7). We determined the serum concentrations (sc) of total T4 (TT4), FT4, total T3 (TT3) and rT3 120 min before, during (t0), and 5, 15, 60 and 120 min after VF. At the end of the observation period we figured out the in-vitro T3-generation (kM, Vmax), the in-vitro rT3-generation, the in-vitro rT3-decomposition (kM, Vmax) and the content of cytosolic sulfhydryls (total sulfhydryls, non-protein bound sulfhydryls) in liver and kidney specimen. Animals not undergoing VF served as controls (C) for parameters measured in the intracellular compartment. TT4- and TT3-sc decreased to 3.3 +/- 0.6 micrograms/dl (p < 0.05, vs. t0) and 15.2 +/- 4.1 ng/dl (p < 0.05, vs t0), resp. FT4-sc remained stable for five minutes (2.63 +/- 0.41 ng/dl) before declining to 1.8 +/- 0.39 ng/dl (p < 0.05, vs. t0). The rT3-sc raised finally to 46.9 +/- 7.3 ng/dl (p < 0.05, vs t0). Iodothyronine sc did not exhibit differences between E-, NE- and VP-treatment. Neither in-vitro T3-generation, nor in-vitro rT3-generation, nor in-vitro rT3-decomposition nor intracellular sulfhydryl content were affected by the events of VF and resuscitation as compared to the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of food deprivation on baseline iodothyronine and cortisol concentrations in healthy, adult horses

SUMMARY Six healthy, adult horses, with normal (mean ± sem) baseline serum concentrations of total triiodothyronine (T3,1.02 ± 0.16 nmol/L), free T3 (FT3,2.05 ± 0.33 pmol/L), total thyroxine (T4, 19.87 ± 1.74 nmol/L), free T4 (FT4, 11.55 ± 0.70 pmol/L), total reverse T3 (rT3, 0.68 ± 0.06 nmol/L), and cortisol (152.75 ± 17.50 nmol/L), were judged to be euthyroid on the basis of response to a standardized thyroid-stimulating hormone response test. Serum concentrations of T3, FT3, T4, FT4, rT3, and cortisol were determined immediately before and every 24 hours during a 4-day period of food deprivation, when water was available ad libitum. Similar variables were measured 72 hours after refeeding. Decreases (to percentage of baseline, prefood deprivation value) in circulating T3 (42%), T4 (38%), FT3 (30%), and FT4 (24%) concentrations were maximal after 2, 4, 2, and 4 days of food deprivation, respectively (P &lt; 0.05). Increases (compared with baseline, prefood deprivation value) in rT3 (31%) and cortisol (41%) concentrations were maximal after 1 and 2 days of food deprivation, respectively (P &lt; 0.05). Refeeding resulted in increase in serum T4 and FT4, and decrease in rT3 and cortisol concentrations toward baseline values, after 72 hours (P &lt; 0.05). Re-feeding did not effect a return of T3 or FT3 concentration to baseline values after 72 hours (P &lt; 0.05). Food deprivation appears to cause changes in serum concentrations of T3, FT3, T4, FT4, rT3, and cortisol in horses that are similar to those in human beings. This effect of food deprivation should be considered when results of serum thyroid hormone and cortisol assays are interpreted in the face of clinical disease. These results further emphasize the invalidity of making a clinical diagnosis of hypothyroidism on the basis of baseline, serum thyroid hormone concentrations in horses, especially if the horses have been anorectic or inappetent.

Effect of dexamethasone administration on serum thyroid hormone concentrations in clinically normal horses

Summary The effect that 5 consecutive days of treatment with dexamethasone (0.04 mg/kg of body weight, IM, q 24 h) would have on baseline concentrations of triiodothyronine (T3), thyroxine (T4), reverse T3 (rT3), free T3 (FT3), and free T4 (FT4), and on response to thyroid-stimulating hormone (tsh) administration was determined in 12 clinically normal horses. Results of tsh response tests indicated that the horses could be placed into 2 groups: in 6 horses (group A), T4 concentration after administration of tsh was more than twice the baseline concentration; in the other 6 horses (group B), T4 concentration 6 hours after administration of tsh was less than twice the baseline concentration. Baseline serum concentrations of T3, T4, rT3, FT3, and FT4, were not significantly different between group-A and group-B horses. In both groups of horses, serum T3, T4, rT3, and FT4, concentrations were significantly increased 6 hours following tsh administration, compared with baseline concentrations. Treatment with dexamethasone resulted in significant (P &lt; 0.05) increases in baseline concentrations of rT3 and FT3 in group-A horses and baseline concentrations of rT3 in group-B horses. The response to tsh administration following dexamethasone treatment appeared to be blunted with significant (P &lt; 0.05) increases only in T3, T4, and FT4, concentrations in group-A horses and FT4, concentration in group-B horses. The magnitude of change in serum FT3 concentration in response to tsh administration was significantly less (P = 0.05) following dexamethasone treatment, compared with magnitude of change prior to dexamethasone treatment. Results suggested that tsh response testing may not be as valuable as once thought for diagnosing hypothyroidism in horses or for differentiating thyroidal from nonthyroidal illness.

Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.

Thyroid function during a prolonged stay in Antarctica.

Adaptation of the thyroid gland to the Antarctic environment was studied in nine healthy euthyroid tropical men of the Sixth Indian Antarctic Expedition during 1 year of their residence at polar latitudes. Circulatory concentrations of thyroid hormones, total T4 (TT4), total T3 (TT3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3), thyroxine binding globulin (TBG), T3 uptake and thyroid stimulating hormone (TSH) were estimated in New Delhi and during the first week of each month of the stay in Antarctica. At the end of the Austral summer in March, the TT3 concentrations were found to be significantly lower (P < 0.01) compared to values recorded in New Delhi and showed a significant increase (P < 0.05) during the Austral winter in August. The mean TT3 concentrations from May to December were found to be significantly higher than the March or April values. Plasma TT4 and rT3 concentrations tended to decline in March but remained unaltered during the entire period in Antarctica. The FT4, FT3, TBG and T3 uptake did not show any appreciable change. Though, the TT3:TT4 ratio tended to decline in March and April suggesting decreased peripheral conversion of T4 to T3 as the possible mechanism for a decline in TT3 in March. physical exertion and prolonged exposure to extreme cold appeared to be the major contributory factors. The TSH concentration in March, April, November and December were found to be significantly higher than the New Delhi values. The morning as well as evening cortisol concentrations during the Austral winter were higher than the March values suggesting that cortisol rhythmicity was well maintained in Antarctica, albeit at a higher level. These observations indicated that the subtle changes in thyroid hormones during a prolonged stay at polar latitudes are related not only to the extreme cold but also to other factors such as physical activity, polar days and polar nights.

Interleukin 6 effects on the pituitary–thyroid axis in the rat

It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), may have a role in the pathogenesis of the changes of serum thyroid hormone concentrations that are encountered in patients with non-thyroidal illness (NTI). Many of the IL-1 and TNF-alpha effects are believed to be mediated by the induction of IL-6 synthesis, which might, therefore, represent an important mediator of thyroid hormone changes in NTI. To address this problem, male Wistar rats were injected subcutaneously with 2.5 micrograms of recombinant human IL-6 (rhIL-6, in 500 microliters of saline solution), with 2.5 micrograms of rhIL-6 preincubated with 100 microliters of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T4) from 82 +/- 4 nmol/l (mean +/- SEM) to a nadir of 33 +/- 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T3) from 1.6 +/- 0.1 to 0.8 +/- 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T4 and T3 concentrations also was observed in the control group, but the lowest values (T4, 66 +/- 3 nmol/l; T3, 1.2 +/- 0.1 nmol/l) were significantly higher (p < 0.0001) than in IL-6-treated rats. The IL-6-induced changes could be prevented by preincubation of rhIL-6 with its neutralizing antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective study of the effects of amiodarone on thyroid function in chagasic patients in an area of iodine deficiency

In order to evaluate the development of thyroid dysfunction during chronic amiodarone treatment in an area deficient in iodine and endemic for Chagas' disease, a group of 24 patients was prospectively studied. Clinical examination and measurement of serum T4, T3, rT3, TSH and antithyroglobulin antibodies were performed before and at 3 and 9 months of use of amiodarone. A TSH response 30 minutes after IV injection of 200 micrograms of TRH was also compared to TSH basal levels before and during amiodarone treatment. Thyroid radioactive uptake and scan were obtained before and nine months after amiodarone was started. Elevated rT3 concentrations were unexpectedly found in two thirds of the patients before treatment. Thyroid dysfunction developed during amiodarone administration in 20.8% of the patients; 12.5% became hyperthyroid and 8.3%, hypothyroid (with negative antithyroglobulin antibodies). Positive RAI uptake was seen in one patient with hyperthyroidism and diffuse goiter. Since T3 levels were not found to increase, the diagnosis of amiodarone-related hyperthyroidism was better evidenced by the reduced or blocked TSH response to TRH. Elevated TSH concentration was the best evidence of amiodarone-induced hypothyroidism. Increase in TSH levels since the beginning of amiodarone therapy may predispose to the growth of a goiter. In conclusion, amiodarone treatment in an iodine deficient area as above should be judiciously decided and thyroid function carefully monitored before and during the use of the drug.

Thyroid hormones and thyrotropin variations during long term overfeeding in identical twins.

The aim of this study was to evaluate variations in plasma thyroid hormones and TSH during a standardized long term overfeeding protocol (4.2 megajoules/day [corrected] during a 100-day period) in 24 lean adults (12 pairs of monozygotic twins) and to assess their relationships with body composition and resting metabolic rate (RMR) changes. Compared to preoverfeeding values, basal plasma T3 concentrations were increased on day 25, but not later; basal plasma T4 and free T4 (FT4) concentrations were unchanged; basal plasma rT3 concentrations were persistently decreased throughout the entire protocol; and the TSH response to TRH stimulation was persistently enhanced. The TSH response to TRH before overfeeding was positively correlated with the changes in RMR with overfeeding (r = -0.53; P < 0.01). No association was found between changes in basal plasma T3 concentrations and changes in RMR. However, changes in basal T3 were positively related to changes in body weight (r = 0.46; P < 0.05). A significant within-pair similarity was found for changes in T4 and FT4 with overfeeding (P < 0.05). We conclude that 1) during overfeeding, the early increase in T3 concentrations is a transitory phenomenon, whereas the decrease in rT3 concentrations and the increased TSH response to TRH are more sustained; 2) the TSH responsiveness to TRH stimulation could be a predictor of the changes in RMR during times of increased energy intake; 3) there is no evidence for a direct role of T3 in the adaptation of resting energy expenditure during a long term overfeeding protocol; and 4) the genotype could be involved in the changes in T4 and FT4 during a prolonged positive energy balance period.

Hypothalamic-pituitary-thyroid (HPT) axis in chronic alcoholism. I. HPT axis in chronic alcoholics during withdrawal and after 3 weeks of abstinence.

Thyroxine (T4), free T4 (fT4), triiodothyronine (T3), free T3 (fT3), reverse T3 (rT3), thyrotropin (TSH), thyroxine binding globulin (TBG), and T3 uptake were measured in 14 chronic alcoholics during withdrawal and after 21 days of abstinence. Results were compared with those of 16 healthy volunteers. During withdrawal, the fT4 and fT3 concentrations were subnormal, whereas the respective protein-bound fractions were normal. T4, T3, and TBG increased during the abstinence period, T3 and TBG being significantly higher than in normals at the second measuring time. T3 uptake values fell, but remained well within the normal range at both measuring times. During abstinence, the fT3 levels remained significantly lower than in healthy subjects. rT3 concentrations decreased, but not significantly. The TSH values were normal throughout. These results showed numerous abnormalities in the hypothalamic-pituitary-thyroid axis in alcoholics, the reasons for which are as yet unclear. The following possible interpretations are suggested: 1. The abnormally low serum fT3 and fT4 levels during withdrawal might reflect an increase in tissue uptake. 2. The increases in T4--and partly those in T3--during abstinence seem to reflect increased binding by TBG, the level of which rose markedly for reasons as yet unknown. 3. If increases in TBG during abstinence are taken into account, the decreases in rT3 concentrations may reach the level of statistical significance. These falls in rT3 concentrations may reflect an increase in rT3 metabolization (deiodination) in various tissues, including the CNS, leading to a reduction in serum rT3 bioavailability. 4. Factors such as liver disease, protein caloric malnutrition, and "psychological stress" do not fully explain all these abnormalities. A direct effect of ethanol on intracellular thyroid hormone metabolism and/or function seems conceivable.

Transient hypothyroxinemia in neonates with birth asphyxia delivered by emergency cesarean section.

The aim of this study was to evaluate the effects of prenatal asphyxia on perinatal thyroid function by measuring the levels of serum T4, FT4, T3, rT3, TSH and TBG in twenty-seven asphyxiated full-term infants delivered by emergency cesarean section, at birth and on the 5th day of age. All the babies had a one-minute Apgar score of less than 6 and body weight from 3 to 4.6 kg. The control group consisted of 30 healthy neonates which were delivered by elective cesarean section. The mean values of T4 and FT4 observed in the cord blood of the asphyxiated neonates were significantly lower compared to the matched controls, while there were no differences in concentrations of T3, rT3, TSH and TBG. At five days of life, serum concentrations of T4 and FT4 became normal. These results demonstrate the existence of transient hypothyroxinemia at birth in hypoxic babies delivered by emergency cesarean section.

The postnatal serum 3,5,3'-triiodothyronine (T3) surge in the rat is largely independent of extrathyroidal 5'-deiodination of thyroxine to T3.

In the rat, selenium deficiency causes a near-complete loss of the selenoenzyme type I 5'-deiodinase (5'D-I), resulting in a marked decrease in hepatic T4 to T3 conversion. In adult rats, serum T4 concentrations are consistently increased, whereas serum T3 and rT3 concentrations are unaffected or slightly decreased and increased, respectively. In rat fetuses near term, serum T4 and rT3 concentrations are not affected by selenium deficiency. We have now studied the effect of selenium deficiency on thyroid function in the neonatal rat. Weanling female rats were fed either a selenium-supplemented or a selenium-deficient diet for 4 weeks before mating and then throughout gestation and lactation. Neonatal rats were killed at 7, 14, 21, and 28 days. Selenium deficiency was confirmed by a more than 89% decrease in liver 5'D-I activity in mothers and pups. Selenium deficiency resulted in significant increases in serum T4 concentrations in 3- and 4-week-old pups. In contrast, selenium deficiency led to a striking increase in serum rT3 concentrations. The normal postnatal serum T3 surge was not affected by selenium deficiency at any age. In 2- and 4-week-old selenium-deficient pups obtained from a second litter from the same mothers, liver 5'D-I activity was markedly decreased, but thyroid 5'D-I activity was not affected. The increased serum rT3 and, less so, T4 concentrations observed in selenium-deficient pups were associated with a significant decrease in brain 5'D-II activity in 14- and 28-day-old pups and in brown adipose tissue 5'D-II activity in 14-day-old pups. In conclusion, the present study demonstrates that the increase in serum T4 concentrations consistently observed in selenium-deficient adult rats occurs only after the second week of life. The normal physiological postnatal 12-fold increase in serum T3 concentrations observed in selenium-deficient pups despite the marked decreases in liver 5'D-I and brain and brown adipose tissue 5'D-II activities suggests that T4 to T3 conversion by peripheral tissues may not be a major source of T3 in the neonate. In contrast, the thyroid gland, whose 5'D-I activity is not affected by selenium deficiency, is probably the principal source of circulating T3 in the neonate. Finally, the early and marked increase in serum rT3 concentrations observed in selenium-deficient pups suggests that liver 5'D-I is important in rT3 deiodination.

NORMAL SERUM T3 POSTNATAL SURGE AND INCREASED REVERSE T3 LEVELS IN SELENIUM-DEFICIENT RAT PUPS

In adult rats, selenium (Se) deficiency markedly decreases liver type I outer-ring 5′ deiodinase (5′D-I, a selenoenzyme convening T4 into T3), resulting in a 40% increase in serum T4 concentrations. Serum T3 and reverse T3 (rT3) concentrations are unchanged or marginally decreased or increased, respectively. In rat fetuses, serum T4 and rT3 concentrations are not affected by selenium deficiency. We studied the effect of Se deficiency on thyroid function in the rat neonate. 28 weanling female rats were fed a Se replete (Se+) or Se deficient (Se−) diet for 4 wk prior to mating and throughout gestation. 2-3 pups from each litter were sacrificed 7, 14 and 21 days after delivery. Serum T4, T3, rT3 and TSH concentrations and liver 5′D-I activity, to assess Se deficiency, were measured.*P<0.001 compared to corresponding Se+group Mean(SE).In Se- pups, the decrease in 5′D-I activity was >89% confirming Se deficiency (P<0.001). In contrast to adult rats, Se deficiency causes no increase in serum T4 in 1 and 2 wk old pups and only a 20% increase in 3 wk old pups, but results in a 60-250% increase in serum rT3.Conclusion: 1) In the rat neonate, the 500 to 600% surge in serum T3 levels observed physiologically after birth is independent of liver 5′D-I activity, strongly suggesting that T4 to T3 conversion by peripheral tissues is not a major source of T3 in the neonate; 2) In contrast, serum rT3 levels increase markedly in Se- pups as early as the 7th postnatal day, suggesting that liver 5′D-I is important in rT3 metabolism.

Effect of fetal thyroid hormone (RT3) on sarcoma cells in culture.

Fetal thyroid hormone (RT3) is considered metabolically inactive and is present in high concentration in fetuses and in some patients with end-stage malignant disease. In a virus-induced erythroleukemia cell model, RT3 was found to stimulate the growth of the erythroleukemia cells in culture. The focus of this research was to test the effect of RT3, at several concentrations, on the growth of naturally occurring human sarcomas in cell culture. Cloned cell lines of Ewing sarcoma, rhabdomyosarcoma, and osteogenic sarcoma were grown in multiple flasks of serum-free medium containing varying concentrations of RT3, ranging from 10(-8)-10(-5) M. Cells grown in serum-free medium containing no RT3 were used as a control. RT3 significantly increased the growth (total protein) of the rhabdomyosarcoma cell line in culture at concentrations between 10(-8) and 10(-6) M, with the maximum effect at 10(-7) M. The growth of one cell line of Ewing sarcoma was not affected by RT3 for any of the concentrations tested. The growth of two Ewing sarcomas and one osteogenic sarcoma was significantly stimulated by RT3 but only at the highest concentration of 10(-5) M. The growth of the other osteogenic sarcoma cell line was significantly increased at concentrations of 10(-6) and 10(-7) M. The stimulatory effect of RT3 on several sarcoma cell lines in culture suggests the presence of a specific receptor in the neoplastic cells and the possibility that RT3 may be useful as a model for new chemotherapeutic agents.

Effect of the antioxidant TK 12627 (Irganox) on monodeiodination and on the levels of messenger ribonucleic acid of 5′-deiodinase type I and spot 14

Until now, most potent inhibitors of monodeiodination are iodinated, propylthiouracil being an exception. We report here studies on a new non-iodinated substance, triethylene glycol bis-3-(3-tert-butyl-4-hydroxy-5-methyl-phenyl) propionate (TK 12627 or Irganox), which is used as a very efficient antioxidant in the chemistry of plastics. The studies were performed with 23 hypothyroid rats that received Irganox in their daily food (8 mg.day-1 x (100 g body wt)-1) for 3 weeks. Thyroxine (T4) metabolism was studied by implanting minipumps delivering 2.3 nmol T4.day-1 x (100 g body wt)-1 for 1 week. On day 1 before sacrifice, another minipump containing [125I]-3,5,3'-triiodothyronine (T3, 2.6 microCi/day) and [131I]-3,3',5'-triiodothyronine (rT3, 2.1 microCi/day) was implanted. The results showed that with Irganox treatment serum T4 concentrations were higher (p < 0.05). Serum T3 concentrations markedly decreased (1.07 +/- 0.07 vs 0.65 +/- 0.04 nmol/l), accompanied by a decrease of free T3 concentrations (p < 0.001). Serum rT3 concentrations increased by 50% (p < 0.001). Serum thyrotropin levels were mostly unmeasurable. The plasma clearance rate decreased slightly for T4 (19%, p < 0.05) and remarkably for rT3 (46.7%, p < 0.001). The conversion rate of T4 to rT3 did not change. Deiodinase type I (5'D-I) activity decreased in both liver and kidney tissues by 54% and 52%, respectively, and correlated with T3 (r2 = 0.79 and 0.65, respectively). Brain deiodinase type III (5D-III) was unchanged and type II (5'D-II) was unmeasurable.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of placental thyroxine 5-deiodinase activity decreases amniotic fluid concentration of 3,3',5'-triiodothyronine in rat.

We investigated whether the inhibition of placental T4 5-deiodinase (5-D) activity would decrease the amniotic fluid (AF) concentration of rT3. Iopanoic acid (IOP) was used to inhibit placental T4 5-D activity. From gestation days 14 to 17, a group of rats received IOP (10 mg/100 g bw/day, sc) once daily in experiment (exp) 1, and received it (40 mg/100 g bw/day) four times daily in exp 2. In exp 2, control dams received propylthiouracil (PTU; 2 mg/100 g bw/day) instead of IOP. Methimazole and T4 were also given to all dams in exp 1 and 2. On day 17 of gestation, we collected the liver, placenta, blood, and AF of each animal. In the IOP-treated group in both experiments, the serum T4 concentration was significantly increased. Hepatic T4 5'-deiodinase activity was significantly decreased by either PTU or IOP administration. In both experiments placental T4 5-D activity was significantly decreased in the IOP-treated group. The concentration of rT3 in AF was significantly decreased in the IOP-treated group in exp 2 (1.71 vs. 0.75 nmol/l, P < 0.01) despite a higher serum T4 concentration. There was a significant positive correlation between placental T4 5-D activity and the concentration of rT3 in AF in exp 2 (r = 0.62, P < 0.05). These observations indicate that the inhibition of placental T4 5-D activity decreases the concentration of rT3 in rat AF, and that placental T4 5-D and the T4 concentration in maternal serum plays important roles in maintaining the concentration of rT3 in rat AF.

Effects of oral administration of anti-inflammatory doses of prednisone on thyroid hormone response to thyrotropin-releasing hormone and thyrotropin in clinically normal dogs

SUMMARY Prednisone was given orally to 12 dogs daily for 35 days at an anti-inflammatory dosage (1.1 mg/kg of body weight in divided dose, q 12 h) to study its effect on thyroxine (T4) and triiodothyronine (T3) metabolism. Six of these dogs were surgically thyroidectomized (THX-Pred) and maintained in euthyroid status by daily SC injections of T4 to study peripheral metabolism while receiving prednisone; 6 dogs with intact thyroid gland (Pred) were given prednisone; and 6 additional dogs were given gelatin capsule vehicle as a control group (Ctrl). Baseline T4 concentration after 4 weeks of treatment was not significantly different in dogs of the THX-Pred or Pred group (mean ± SEM, 2.58 ± 0.28 or 3.38 ± 0.58 μg/dl, respectively) vs dogs of the Ctrl group (2.12 ± 0.30 μg/dl). A supranormal response of T4 to thyrotropin was observed in dogs of the Pred group, but the T4 response to thyrotropinreleasing hormone was normal. Baseline T3 concentration in dogs of both steroid-treated groups was significantly (P&lt; 0.05) lower after 2 and 4 weeks of prednisone administration vs pretreatment values, but normalized 2 weeks after prednisone was stopped. Free T3 (FT3) and T4 (FT4) fractions and absolute FT3 and FT4 concentrations were not altered by prednisone administration. Reverse T3 (rT3) concentration in vehicle-treated Ctrl dogs (26.6 ± 3.5 ng/dl) was not different from rT3 concentration in dogs of the THX-Pred (25.7 ± 4.3 ng/dl) and Pred (28.9 ± 3.8 ng/dl) groups after 4 weeks of medication. These data indicate that daily oral administration of such anti-inflammatory dose of prednisone for 1 month reduces baseline serum T3 concentration, does not alter serum T4 concentration, and enhances thyroidal sensitivity to thyrotropin.