Effect of steroids on thyroid activity and adrenal morphology in tammar wallabies after removal of the corpus luteum

1. Plasma total thyroxine (TT4) levels and plasma free thyroxine (FT4) index were significantly lower in adult tammar wallabies (Macropus eugenii) from which the corpus luteum had been removed than in sham-operated controls. 2. Progesterone injections given for 14 days after corpus lutectomy significantly elevated the plasma free tri-iodothyronine (FT3) index, but had no effect on other thyroid parameters measured. 3. Estrogen and androstenedione given for 14 days after corpus lutectomy had no significant effect on any of the thyroid parameters measured, although in both groups injected with these steroids, the histological appearance of the thyroid was suggestive of an increased activity. 4. The adrenal weight, adrenal somatic index, adrenal cortex area, zona fasciculata width, and zona reticularis width were significantly larger in estrogen-injected corpus lutectomized wallabies than in oil-injected corpus lutectomized controls.     

Postnatal Action of Growth and Thyroid Hormones on the Retarded Cerebral Myelinogenesis of Snell Dwarf Mice (dw)

Abstract: Snell dwarf mice (dw) showed a lower CNPase activity (59% of the normal controls) only in the cerebrum among different parts of the CNS, and a strikingly reduced level of spontaneous locomotion activity with an indistinct diurnal periodicity in a 24-h record at 40 days of age. Daily administration of bGH and T₄ to the dwarfs during the first 40 days of postnatal life restored CNPase activity to the level of the normal controls, and was accompanied by normalization of the pattern of spontaneous locomotion activity. Daily administration of bGH alone also restored CNPase activity and spontaneous locomotion, but to a lesser extent. The daily administration of thyroid stimulating hormone (TSH) alone, however, failed to restore CNPase activity, in spite of the fact that the thyroid glands of the TSH-treated dwarfs were indistinguishable from the normal controls in organization and appearance. These results indicate that the restoration of both the retarded myelinogenesis and abnormal behavior of the Snell dwarf mice might essentially depend upon GH levels and the synergistic effects of T₄.     

Role of the hypophysis in thyroid regeneration after partial thyroidectomy.

The role of the hypophysis in thyroid regeneration was investigated by measuring the mitotic activity of the thyroid remnant in hemithyroidectomized rats as well as the blood levels of thyroid hormone at various time-intervals after hemithyroidectomy. Mitotic activity underwent a significant increase to reach a peak (a 5- to 8- fold increase) 2 days after hemithyroidectomy. The thyroid hormone level in blood was lower than in controls. Histologically, the thyroid gland showed signs of an elevated rate of functional activity, as indicated by losses of colloid and cell hypertrophy. In a second approach, the mitotic activity of the thyroid remnant was estimated in hypophysectomized and in thyroxine treated rats. Both hypophysectomy and thyroxine injection prevented occurrence of the mitotic peak at 2 days. The regeneration of the thyroid after hemithyroidectomy, as it occurred in the present work, may be explained by a release of thyroid stimulating hormone from the pituitary, brought about by the low level of circulating thyroid hormone, itself resulting from a loss of thyroid tissue.     

Stimulatory Effects of Growth Hormone and Thyroxine on the Concentration of Gangliosides in the Snell Dwarf Cerebrum

The concentration of gangliosides in the Snell dwarf mouse cerebrum was monitored from postnatal day 5 to day 40. In the dwarf cerebrum, the concentration of total gangliosides increased up to postnatal day 20 and then stopped, whereas in the control cerebrum, it continued to increase up to postnatal day 40. At postnatal day 40, the ganglioside level in the dwarf cerebrum was 70% of that in the control cerebrum. Among the ganglioside species, the concentrations of GM4, GM2, GM1, GD1a, GD3, GD1b, GT1b, and GQ1b were significantly lower in the dwarf cerebrum than in the controls at postnatal day 40. The reduced concentrations of ganglioside species GM2, GD1a, GD3, GD1b, and GQ1b were completely restored by administration of bovine growth hormone (GH) during the first 20 days of postnatal life. The reduced concentration of the GM1 and GM4 species were most efficiently restored by administration of bovine GH plus thyroxine (T4) during the second 20 days of postnatal life. These results indicate that the lower ganglioside concentrations in the dwarf cerebrum can be elevated by hormone therapy and that there exist distinct GH and T4 actions on the enzymes participating in ganglioside metabolism.     

Effects of chronic hemodialysis on thyroid function in chronic renal failure

Thyroid function was studied in 54 patients undergoing chronic hemodialysis. Serum thyroxine, triiodothyronine and free thyroxine and the free thyroxine index were significantly lower than normal. The levels of both serum thyroxine and the free thyroxine index tended to fall progressively the longer the patients were on hemodialysis. These findings, in association with low serum TSH levels and normal increase in radioactive iodine uptake by the thyroid after TSH injection, suggest that a defect in pituitary secretion of TSH may be responsible. Although some patients experienced symptomatic improvement after treatment with L-thyroxine the efficacy of this form of treatment in patients on chronic hemodialysis has not yet been established.     

Low-protein diet changes thyroid function in lactating rats

Lactating rats were fed with free access to an 8% protein-restricted diet (PR); the control group was fed a 23% protein diet (C). An energy-restricted (pair-fed) group was given the same food as the animals in the control group, but the amounts of food consumed by both PF and PR were about the same. The body weight and serum albumin concentration of PR and PF dams were significantly (P < 0. 05) lower than that of the controls. The PR group had a significant increase in serum-free triiodothyronine (FT3) concentration, 24-hr mammary gland and milk radioiodine (I131) uptake (67%, 278%, and 200%, respectively) as compared with the controls. On the other hand, those animals had a significantly lower serum-free thyroxine (FT4) concentration and 2- and 24-hr thyroid I131 uptake (67%, 64%, and 74%, respectively). Protein malnutrition during lactation did not alter thyroid or liver 5'-deiodinase activity significantly. However, PF dams had a significantly lower (25%) thyroid 5'-deiodinase activity. These data suggest that protein-restricted lactating dams had an adaptive change in the thyroid function, which could be important to increase the transference of iodine or triiodothyronine through the milk to their pups and prevent sequelae of neonatal hypothyroidism.     

Cold-induced changes in thyroid function in a poikilothermic mammal, the naked mole-rat

Cold acclimation induces very divergent responses in thyroid function in reptiles and mammals reflective of their different thermoregulatory modes. Naked mole-rats, unlike other small mammals, are unable to effectively employ endothermy and are operatively poikilotherms. We therefore investigated changes in their thyroid status with chronic cold exposure. Under simulated burrow conditions, free thyroxine (T(4); 0.39 +/- 0.09 ng/dl) and thyroid stimulating hormone (TSH; 1.12 +/- 0.56 microIU/ml) levels fell within the reptilian range, one order of magnitude lower than mammalian levels. However, cold induced typical mammalian responses: free T(4) levels (0.55 +/- 0.09 ng/dl) and thyroid follicular cell height were significantly greater. Although TSH levels (1.28 +/- 0.83 microIU/ml) were not significantly elevated, thyrotrophs exhibited ultrastructural signs of increased secretory activity. Low thyroid hormone concentrations may contribute substantially to the unusual thermoregulatory mode exhibited by naked mole-rats.     

Mechanisms of stress resistance in Snell dwarf mouse fibroblasts: Enhanced antioxidant and DNA base excision repair capacity,but no differences in mitochondrial metabolism

Dermal fibroblasts from long-lived Snell dwarf mice can withstand a variety of oxidative and non-oxidative stressors compared to normal littermate controls. Here, we report differences in the levels and activities of intracellular antioxidant and DNA repair enzymes between normal and Snell dwarf mice fibroblasts cultured under a variety of conditions, including: 3% and 20% ambient O₂; the presence and absence of serum; and the addition of an exogenous oxidative stress. The only significant difference between normal and dwarf cells cultured in complete medium, at 20% O₂, was an approximately 40% elevation of glutathione peroxidase (GPx) activity in the mutant cells. Serum deprivation elicited increases in GPx in both genotypes, but these activities remained higher in dwarf mouse cells. Dwarf mouse cells deprived of serum and challenged with exposure to paraquat or hydrogen peroxide showed a generally greater upregulation of catalase and DNA base excision repair enzymes. As these toxins can interact with mitochondria to increase mitochondrial ROS production, we explored whether there were differences in mitochondrial metabolism between normal and dwarf mouse cells. However, neither mitochondrial content nor the apparent mitochondrial membrane potential differed between genotypes. Overall, the results suggest that superior hydrogen peroxide metabolism and a marginally greater DNA base excision repair capacity contribute to the stress resistance phenotype of Snell dwarf mouse fibroblasts.     

Anticonvulsants and thyroid function.

Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3.     

Factors Contributing to the Poor Myelination in the Brain of the Snell Dwarf Mouse

Abstract: Conventional histological examination of the pituitary does not distinguish Snell dwarf mutants (dw/dw) from their normal littermates (+/?) in the neonatal stage. However, immunohistochemical examination of pituitaries of litters born to heterozygous Snell parents revealed that in approximately 25% of the glands examined, the number of positive cells was very low in the neonatal stage. We attempted to delineate the events resulting in the poor myelination in the brain of the Snell dwarf mouse, and to devise an immunohistochemical method for identifying the mutant neonate. Differences in the brain weights of the dw/dw and +/? mice first became apparent on the 10th day of age, and from this time on no further increase in the weight of the dwarf mouse brain was recorded. Increase in CNPase activity was found to be suppressed in the cerebrum and brain stem throughout the developmental stage, but not in the other parts of the brain. The yield of isolated myelin decreased by 58% in the mutant mouse, but CNPase activity was equivalent to that of control myelin. Differences in DNA content per cerebrum from the dw/dw and +/? mice first became apparent on the 10th day of age. Henceforth, the dw/dw mice showed no further increase, although the +/? mice continued to increase. [³H]Thymidine incorporation into the DNA fraction in vivo on the 7th day of age, when glial cell proliferation in the cerebrum is most active, was suppressed to about 50% of the control level in all parts of the dwarf brain. These findings indicate that the poor myelination found in the mutant cerebrum is a hypomyelination due to reduced oligodendroglial proliferation caused by lack of circulating growth hormone.     

Retarded cerebral growth of hormone-deficient mice.

1. Both the Snell dwarf mouse (dw) and the growth hormone-deficient Little mouse (lit) exhibit a microcephalic cerebrum with hypomyelination, retarded neuronal growth, and underdevelopment of axons and dendrites. 2. The hypomyelination is due to arrested glial proliferation, suggesting that the action of growth hormone on the proliferation and maturation of both glial and neuronal cells is a necessary precondition of myelin formation, apart from the complementary or synergistic actions of thyroxine. 3. In contrast, the cerebral hypomyelination present in the inherited hypothyroid mouse (hyt) is not related to arrested glial proliferation, demonstrating that thyroid hormones can act independently on myelinogenesis.     

X-ray microanalysis of cardiocytes in the Snell dwarf mouse

X-ray microanalysis has been used to determine elemental content in the nucleus, myofibrillar cytoplasm and mitochondrially enriched cytoplasm of cardiocytes in Snell dwarf mice in comparison with phenotypically normal mice from the same strain. It was found that there was significantly lower chlorine concentration in all three subcellular locations and significantly lower sodium concentration in the nucleus of dwarf mouse cardiocytes. In both normal and dwarf mice, statistically significant subcellular compartmentalization was found for phosphorus, sulfur, and potassium.     

Selenium concentrations in the human thyroid gland

Recently, we found that prediagnostic serum selenium concentration was significantly lower for cases developing thyroid cancer (n=43) than for controls. We assumed that redistribution of serum selenium into the affected tissue took place in the prediagnostic period. The present study was carried out to determine the physiological concentration of selenium in the thyroid, since very few data are available in the literature. The concentrations of selenium in the thyroid (n=45) and liver samples from Norwegians who had died because of acute illness or accidents were determined by hydride generation atomic absorption spectrometry. The mean selenium concentration was found to be 0.72±0.44 μg/g in the thyroid and 0.45±0.11 μg/g in the liver tissue. The surprisingly high concentration of selenium in apparently normal thyroids indicates that selenium has important functions in this organ. The remarkably broad range, together with the observation that no significant correlation exists between thyroid and liver concentrations, suggest that factors other than the selenium status are important determinants for the selenium concentration in the thyroid gland. This observation is consistent with our hypothesis that in carcinogenesis, prediagnostic processes influence the serum-/thyroid-ratio of selenium.     

Selenium concentrations in the human thyroid gland.

Recently, we found that prediagnostic serum selenium concentration was significantly lower for cases developing thyroid cancer (n = 43) than for controls. We assumed that redistribution of serum selenium into the affected tissue took place in the prediagnostic period. The present study was carried out to determine the physiological concentration of selenium in the thyroid, since very few data are available in the literature. The concentrations of selenium in the thyroid (n = 45) and liver samples from Norwegians who had died because of acute illness or accidents were determined by hydride generation atomic absorption spectrometry. The mean selenium concentration was found to be 0.72 +/- 0.44 microgram/g in the thyroid and 0.45 +/- 0.11 microgram/g in the liver tissue. The surprisingly high concentration of selenium in apparently normal thyroids indicates that selenium has important functions in this organ. The remarkably broad range, together with the observation that no significant correlation exists between thyroid and liver concentrations, suggest that factors other than the selenium status are important determinants for the selenium concentration in the thyroid gland. This observation is consistent with our hypothesis that in carcinogenesis, prediagnostic processes influence the serum-/thyroid-ratio of selenium.     

Hormonal regulation of thermogenesis in goslings. Possible role of the thyroid gland.

The experiments performed on 90 male goslings showed that 6 h cold exposure (5 +/- 1 degree C) of the specimens 3, 10 and 21-day-old increases considerably 131I uptake by their thyroid gland. After single subcutaneous injection of thyroxine (100 mug/kg) no significant alterations of the metabolic rate, during 4 h measurements, in comparison with the pre-injection value were observed. Since, in control birds about 17% decrease of the metabolic rate within the same time occurred, as the effect of fasting, it was concluded that thyroxine does have the calorigenic effect. The metabolic rate of the goslings 5 to 7-day-old treated with thyroxine for four consecutive days (100 mug/kg daily) and the control ones was very similar. In the older goslings (22--24 days) thyroxine treatment significantly elevated the metabolic rate. Direct (extrathyroid) effect of TSH on heat production, did not occur in goslings.     

Reduced levels of thyroid hormones, insulin, and glucose, and lower body core temperature in the growth hormone receptor/binding protein knockout mouse

The mechanisms that are responsible for the extension of lifespan in the mouse with targeted disruption (knockout [KO]) of the growth hormone (GH) receptor/binding protein (GHR-KO) are unknown. However, in the long-living Ames dwarf mouse, blood glucose and body core temperature (Tco) are consistently lower than in normal mice. In addition, insulin levels are reduced and corticosterone levels are elevated in male dwarfs. These functional alterations, similar to those seen in animals under caloric restriction, have not been proven to be causally related to the extension of lifespan, but they do provide some insight into what traits may be necessary for long life. Therefore, to investigate which of these parameters are similarly affected in two genetically unrelated, yet similarly long-living mouse models, we measured Tco, thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), and insulin, in addition to morning and afternoon levels of glucose and corticosterone, in young adult male and/or female GHR-KO mice and their normal siblings. Tco in GHR-KO mice was numerically reduced throughout the 24-hr period; however, these differences were only significant 4 hr prior to lights-off (14:00 hr), immediately after lights-off (18:00 hr), and during the 3 hr preceding lights on (03:00 to 06:00 hr). GHR-KO mice had significantly reduced levels of T3 and T4, while the ratio of these hormones was similar to that in normal mice. Insulin levels in GHR-KO mice were lower than in normal mice; levels in male GHR-KO mice were below the detectable limits of the assay used. Glucose levels in GHR-KO mice (male and females) were lower than in normal mice in measurements taken in both morning and afternoon; however, these differences arose from consistent reductions in males, as morning glucose levels in GHR-KO females were similar to those of normal mice. Corticosterone levels measured in blood plasma collected under basal (nonstressed) conditions showed sex-related alterations. Basal corticosterone levels in female GHR-KO mice were similar to normal females, while those in male GHR-KO mice were higher than in normal males in the afternoon. Corticosterone levels in stressed GHR-KO females were similar to those measured in stressed normal females. These data show that the long-living GHR-KO mouse shares a reduction in glucose, insulin, thyroid hormones, and Tco with the Ames dwarf mouse. Reductions in these parameters may be important to the underlying mechanisms of delayed aging in these animals.     

Reciprocal interaction between seasonal testis and thyroid activity in Zembra Island wild rabbits (Oryctolagus cuniculus): effects of castration, thyroidectomy, temperature, and photoperiod

The reproductive cycle of wild rabbits (Oryctolagus cuniculus) living in Zembra Island (North Tunisia) is dependent on an external factor, the photoperiod: the gonads are inhibited by long days and stimulated by short days or melatonin implants. Here we studied the role of an internal factor, thyroid hormones and the possible thyroid-gonadal interrelationships, in animals captured on Zembra Island and maintained in natural conditions of photoperiod and temperature. We determined the seasonal profile of the thyroid and testis cycles and investigated the effects of castration and thyroidectomy on the seasonal testosterone and thyroxine cycles. Plasma thyroxine and testosterone levels followed similar, parallel seasonal patterns, with a peak in autumn (October) and low values from January to August. In thyroidectomized animals, plasma testosterone levels, although significantly higher than those in controls (P < 0.001), remained low throughout the 13 mo of the experiment, and no testicular reactivation was observed in the fall. In castrated animals, despite the increase in thyroxine concentration in the 3 mo following castration (P < 0.01), plasma thyroxine levels remained low during the 2 yr of the study. We then investigated the combined effects of long days (16L:8D) and moderately high temperature (25 degrees C) on these two endocrine axes. In constant gonado-inhibiting conditions (16L:8D), whether the temperature was kept constantly high or allowed to fluctuate naturally, no reactivation of the thyroid and testicular axes was observed in the fall. In control animals, the peaks of testosterone and thyroxine concentrations observed in September were larger (P < 0.001) than those in animals subjected to the same natural photoperiod conditions but with constantly high temperature. The lower level of autumnal testis stimulation (P < 0.001) in animals maintained in conditions of constant high temperature (25 degrees C) may be attributed to the low thyroxine levels induced by high temperature. These results clearly confirm that the thyroid and testicular cycles display similar seasonal variations and show that the thyroid and gonadal axes are strictly interdependent. This study provides the first demonstration, for a given species, that the seasonal reactivation of gonad activity is controlled by the thyroid, and thyroid activity is controlled by the gonads.     

Effects of anti-thyrotropin-releasing hormone anti-serum treatment during the neonatal period on the development of rat thyroid function

Effects of anti-thyrotropin-releasing hormone (TRH) anti-serum treatment during the neonatal period on the development of rat thyroid function were studied. On postnatal days 2 and 4, rats were administered anti-TRH anti-serum ip, and they were serially decapitated at the 4th, 8th and 12th week after birth. TRH, thyrotropin (TSH), thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by radioimmunoassay. Immunoreactive TRH (ir-TRH) in the hypothalamus did not change significantly after anti-TRH anti-serum treatment, and plasma ir-TRH tended to decrease. The plasma ir-TRH and TSH responses to cold were significantly inhibited. The plasma TSH response to TRH was also significantly inhibited. The plasma basal TSH levels were significantly lower than in controls. The plasma T4 and T3 levels were found to be lower than those in the controls. Findings suggested that treatment with anti-TRH anti-serum during the neonatal period disturbed the development of rat thyroid function, inhibiting TRH release and altering thyrotroph sensitivity to TRH.     

Effect of thyroid hormone and sex status on epidermal growth factor concentrations in the submandibular gland of a congenitally hypothyroid mouse model

Studies were performed to explore the role of thyroid hormone and sex status on epidermal growth factor concentrations in the submandibular gland of a congenitally hypothyroid mouse model designated hyt/hyt. The animals were studied at 20, 30 and 40 days of postnatal age. The euthyroid animals were homozygous or heterozygous for the hypothyroid gene. The homozygous euthyroid animals displayed a pattern of submandibular gland epidermal growth factor concentrations similar to those previously described in other mouse species and showed the expected sex differences. The hypothyroid animals had measurable but very low submandibular gland epidermal growth factor concentrations without sexual dimorphism. Serum thyroxine concentrations in the heterozygotes were comparable to those in the homozygous euthyroid animals, yet the animals had a delayed increase in epidermal growth factor concentrations combined with a later expression of female-male differences. The timing of the sex differences in submandibular gland epidermal growth factor concentrations followed a pattern similar to that seen for the timing of the first litter in these three genetically distinct groups. This infers the timing of the onset of puberty and suggests a role of androgens in the changes seen in epidermal growth factor concentrations. We conclude that thyroid hormone and sex status in this mouse model influence the pattern and concentrations of submandibular gland epidermal growth factor concentrations.