methimazole and Congenital-Hypothyroidism

Hypothyroidism and hyperthyroidism are associated with maternal and neonatal pregnancy complications. Hypothyroidism should be treated with levothyroxine. Hyperthyroidism requires treatment with propylthiouracil or thiamazole. Subclinical hypothyroidism and thyroid auto-immunity are also associated with maternal and neonatal pregnancy complications. For both subclinical hypothyroidism and thyroid auto-immunity, treatment with levothyroxine has not yet been proven to be effective in preventing complications during pregnancy. For the Dutch population the following reference values for TSH levels during pregnancy may be used: 0.01-4.00 mU/l in the first and second trimesters. Reference values for the third trimester have not reported for this population, but are probably comparable with those of the second trimester.

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Reference Values; Thyroid Function Tests; Thyrotropin; Thyroxine

Topics: Abortion, Spontaneous; Congenital Hypothyroidism; Female; Fetal Death; Humans; Hyperthyroidism; Infant, Newborn; Infant, Newborn, Diseases; Intellectual Disability; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroidectomy; Triiodothyronine

Thyroid hormones play an instrumental role in the development of the central nervous system. During early development, the fetus is dependent on maternal thyroid hormone production due to the dysfunction of its own thyroid gland. Thus, maternal thyroid dysfunction has been shown to elicit significant abnormalities in neural development, neurochemistry, and behavior in offspring. Previous reports have suggested that human maternal hypothyroidism may increase the chances of having children with autism spectrum disorder and attention-deficit/hyperactivity disorder. However, very few studies have evaluated social behaviors in animal models of perinatal hypothyroidism. To evaluate the possibility that hypothyroidism during development influences the expression one of the most commonly observed non-reproductive social behaviors, juvenile play, we used the validated rat model of perinatal hypothyroidism by methimazole administration (MMI; 0.025% in drinking water) from GD12-PD23. Control animals had regular drinking water. During adolescence (PD33-35), we tested subjects for juvenile play behavior by introducing them to a same-sex, unfamiliar (since weaning) littermate for 30min. Play behaviors and other behaviors (sleep, social contact, locomotion) were then scored. MMI-treated subjects played more than twice as much as control animals, and the increase in some behaviors was particularly dramatic in males. Locomotor and other affiliative social behaviors were unaffected. These data suggest that perinatal hypothyroidism may alter the organization of the neural networks regulating play behaviors, but not other social behaviors. Moreover, this implicates perinatal hypothyroidism as a potential etiological factor in the development of neurobehavioral disorders, particularly those characterized by heightened social interactions and impulsivity.

Topics: Animals; Antithyroid Agents; Behavior, Animal; Congenital Hypothyroidism; Female; Male; Methimazole; Motivation; Neurogenesis; Play and Playthings; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Long-Evans; Social Behavior; Thyroid Hormones

The aim of this study was to investigate depression-like behaviors of juvenile rats with congenital and postnatal hypothyroidism.. Twenty-seven newborn rat pups were used. First, 6-month-old Wistar Albino female rats were impregnated. Methimazole (0.025% wt/vol) was given to dam rats from the first day of pregnancy until postnatal 21 days (P21) to generate pups with congenital hypothyroidism (n=8), whereas in the postnatal hypothyroidism group (n=10), methimazole was given from P0 to P21. In the control group (n=9), dam rats were fed ad libitum and normal tap water. Offspring were fed with breast milk from their mothers. The behavioral parameters were measured with the juvenile forced swimming test (JFST). The procedure of JFST consisted of two sessions in two consecutive days: the 15-minute pre-test on day 1 and the 5-minute test on day 2.. Increased immobility and decreased climbing duration were observed in both congenital and postnatal hypothyroidism groups. Decreased swimming duration was detected in the postnatal hypothyroidism group. Both hypothyroidism groups had a lower body weight gain compared with the control group, while the congenital hypothyroidism group had the lowest body weight.. Our results showed that hypothyroidism had negative effects on depression-like behavior as well as on growth and development. Both congenital and postnatal hypothyroidism caused an increase in immobility time in JFST. New studies are required to understand the differing results on depression-like behavior between congenital and postnatal hypothyroidism.

Topics: Analysis of Variance; Animals; Animals, Newborn; Body Weight; Congenital Hypothyroidism; Depression; Female; Hypothyroidism; Male; Methimazole; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Wistar; Swimming; Thyroxine; Time Factors; Triiodothyronine

The timing of thyroxine (T4) replacement treatment in congenital hypothyroidism (CH) has been suggested to be important for optimizing cognitive recovery in humans; however this has not been fully established using modern animal models of CH. Consequently, the current studies investigated the ameliorating effects of postnatal T4 treatment on neuropathology and behavior in CH rats. Rat dams were administered methimazole to produce CH offspring, then brain tissue from male CH pups was analyzed to determine the effects of postnatal (P3, P7, P14 and P21) T4 treatment on hippocampal dendritic branching and the expression of nerve growth factor (NGF). Two operant behavioral procedures were employed to confirm and extend previous findings obtained using this model, and to investigate timelines for instigating T4 treatment on improved behavioral outcomes. T4 treatment initiated at P14 was protective of a reduction in dendritic branching in the hippocampus, and initiated at P7 was protective of a reduction of NGF expression in the fimbria of the hippocampus. Induction of CH did not affect the acquisition of simple operant response rules but had a significant effect on the acquisition of complex operant rules subsequently imposed. Furthermore, T4 treatment initiated at P3 protected learning deficits seen following the imposition of complex operant response rules. These findings indicate T4 treatment initiated at P7 is sufficient for the protection of hippocampal NGF expression and dendritic branching but for the protection of complex behavioral abilities T4 treatment is necessary prior to or approximating P3.

Topics: Animals; Conditioning, Operant; Congenital Hypothyroidism; Dendrites; Disease Models, Animal; Female; Hippocampus; Hormone Replacement Therapy; Male; Methimazole; Nerve Growth Factor; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Rats, Sprague-Dawley; Thyroxine

Hypothyroidism induced by methimazole (MMI), has a negative impact on the postnatal development. Neonatal Granulocyte Macrophage-Colony Stimulating Factor [GM-CSF; 50μg/kg, intramuscular injection at postnatal day (PND) 17] had been tested to ameliorate the effects of MMI [0.05%, (weight per volume; w/v), intraperitoneal injection at PND 15]-induced hypothyroidism in Wistar rats. The hypothyroid conditions due to the administration of MMI produced inhibitory effects on neonatal serum thyroxine (T4), 3,5,3'-triiodothyronine (T3), neutrophil count in bone marrow and blood, cerebellar glutathione (GSH) and acetylcholinesterase (AchE), although it induced stimulatory actions on serum thyrotropin (TSH), growth hormone (GH), insulin growth factor-II (IGF-II), tumor necrosis factor alpha (TNF-α), and cerebellar malondialdehyde (MDA) at PND 19. The treatment with GM-CSF could reverse the depressing and stimulating effects of MMI on these markers except for cerebellar AchE where its enhancement was non-significant (P>0.05) at tested PND. Thus, neonatal GM-CSF may be responsible for suppressing autoimmune responses and preventing hypothyroidism.

Topics: Acetylcholinesterase; Animals; Animals, Newborn; Cerebellum; Congenital Hypothyroidism; Glutathione; Granulocyte-Macrophage Colony-Stimulating Factor; Hormones; Leukocyte Count; Male; Malondialdehyde; Methimazole; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

The EphA5 receptor has recently been known to play an important role in the initiation of the early phase of synaptogenesis, during which irreparable harm would be done to the developing brain in the absence of sufficient thyroid hormone (TH). In the present article, we aimed to analyze the characteristics of EphA5 receptor expression in the brain of congenital hypothyroid rats. The results showed that the levels of the EphA5 receptor were downregulated by TH deficiency in the developing rat brain with remarkable spatial and temporal characteristics. In the hypothyroid rats, the mRNA and protein levels of EphA5 receptor decreased significantly in the hippocampus (27.92-53.26%), cerebral cortex (12.52-47.16%), and cerebellum (8.72-31.69%) compared with those in the normal rats from postnatal day 0 (P0) to P21 (p < 0.01). The expression of EphA5 receptor was highest and declined most as much as 53% in the hippocampus with TH deficiency. At P7, the EphA5 receptor decreased most prominently during all the observed time point.. The EphA5 receptor plays actively in the brain development in congenital hypothyroid rats. Our study highlights the high expression of EphA5 receptor protein in hippocampus and dramatic changes at P7 in condition of TH deficiency, which may provide important basis for further investigations in manipulating congenital hypothyroidism.

Topics: Animals; Antithyroid Agents; Brain; Congenital Hypothyroidism; Disease Models, Animal; Female; Fluorescent Antibody Technique; Gene Expression; Hypothyroidism; Male; Methimazole; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, EphA5; RNA, Messenger; Thyroid Hormones

To determine whether developmental hypothyroidism causes permanent disruption of neuronal development, we first performed a global gene expression profiling study targeting hippocampal CA1 neurons in male rats at the end of maternal exposure to anti-thyroid agents on weaning (postnatal day 20). As a result, genes associated with nervous system development, zinc ion binding, apoptosis and cell adhesion were commonly up- or down-regulated. Genes related to calcium ion binding were up-regulated and those for myelination were often down-regulated. We, then, examined immunohistochemical cellular distribution of Ephrin type A receptor 5 (EphA5) and Tachykinin receptor (Tacr)-3, those selected based on the gene expression profiles, in the hippocampal formation at the adult stage (11-week-old) as well as at the end of exposure. At weaning, both EphA5- and Tacr3-immunoreactive cells with strong intensities appeared in the pyramidal cell layer or stratum oriens of the hippocampal CA1 region. Although the magnitude of the change was decreased at the adult stage, Tacr3 in the CA1 region showed a sustained increase in expressing cells until the adult stage after developmental hypothyroidism. On the other hand, EphA5-expressing cells did not show sustained increase at the adult stage. The results suggest that developmental hypothyroidism caused sustained neuronal expression of Tacr3 in the hippocampal CA1 region, probably reflecting a neuroprotective mechanism for mismigration.

Topics: Animals; CA1 Region, Hippocampal; Congenital Hypothyroidism; Female; Gene Expression Profiling; Immunohistochemistry; Male; Maternal Exposure; Methimazole; Oligonucleotide Array Sequence Analysis; Pregnancy; Propylthiouracil; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, EphA5; Receptors, Tachykinin; Statistics, Nonparametric

Color vision is mediated by cone photoreceptors that express opsin photopigments with sensitivities to different light wavelengths. Most mammals, including mice, differentially express M and S opsins for response to medium-long and short wavelengths, respectively. Previous studies demonstrated that a thyroid hormone receptor (TRbeta2) is critical for opsin patterning: in TRbeta2-deficient mice, M opsin is lost and all cones instead express S opsin. Here, to investigate the requirement for thyroid hormone in cone development, we studied Tshr(-/-)mice as a model of congenital hypothyroidism. The onset of M opsin expression in Tshr(-/-)mice was severely delayed until after postnatal d 17 (P17), and M opsin expression failed to attain normal levels at older adult ages. S opsin showed a subtler change with an extended distribution pattern over the superior-inferior axis of the retina. Similar opsin abnormalities were detected in wild-type C57BL/6J mice made hypothyroid by methimazole treatment. In Tshr(-/-) mice, T(3) treatment from P8 recovered significant M opsin expression at P17. Tshr(-/-) mice produced normal numbers of cones, indicating that the major requirement for thyroid hormone is in opsin patterning rather than in cone generation. The phenotype is similar to, although milder than, that caused by loss of TRbeta2 and indicates the necessity for thyroid hormone for cone maturation.

Topics: Animals; Body Patterning; Cone Opsins; Congenital Hypothyroidism; Female; Gene Expression Regulation, Developmental; Methimazole; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Pregnancy; Receptors, Thyrotropin; Retina; Retinal Cone Photoreceptor Cells; Time Factors; Triiodothyronine

Thyroid hormone plays a critical role in mitochondrial biogenesis in two areas of the developing brain, the cerebral cortex and the striatum. Here we analyzed, in the cerebral cortex of neonatal rats, the effect of hypothyroidism on the biogenesis in free and synaptosomal mitochondria by analyzing, in isolated mitochondria, the activity of respiratory complex I, oxidative phosphorylation, oxygen consumption, and the expression of mitochondrial genome. In addition, we studied the effect of thyroid hormone in oxygen consumption in vivo by determining metabolic flow through (13)C nuclear magnetic resonance spectroscopy. Our results clearly show that in vivo, hypothyroidism markedly reduces oxygen consumption in the neural population of the cerebral cortex. This effect correlates with decreased free mitochondria biogenesis. In contrast, no effect was observed in the biogenesis in synaptosomal mitochondria. The parameters analyzed were markedly improved after T(3) administration. These results suggest that a reduced biogenesis and the subsequent reduction of respiratory capacity in free mitochondria could be the underlying cause of decreased oxygen consumption in the neurons of the cerebral cortex of hypothyroid neonates.

Topics: Animals; Cerebral Cortex; Congenital Hypothyroidism; Female; Hypothyroidism; Magnetic Resonance Spectroscopy; Male; Methimazole; Mitochondria; Mitochondrial Proteins; Oxidative Phosphorylation; Oxygen Consumption; Rats; Rats, Wistar

In the present study, the effects of methimazole (a major anti-thyroid drug) administration to rat dams on the development of cerebellum of their pups were investigated with morphological, morphometrical and functional procedures. A motor performance in the pups was evaluated by a rota-rod test. Brains removed on 6, 9, 12, 15, 25, and 30 postnatal days were analyzed using the sagittal sections of the cerebellum. Results showed that orally administered methimazole to dams produced a congenital hypothyroid model accompanied with an impaired motor coordination assured by the reduced thyroid hormones. The prominent anomaly was found in the internal granular layer in that there were excess bulges or branching and formation of excess sublobules although the normal lobulation pattern was kept. Three dimensional reconstruction imaging revealed the complex morphological pattern of internal granular layer of the cerebellar hemispheres as well as of the vermis, in which bulges and branches were viewed stereoscopically as the smooth ridges rather than irregular or nodal. In addition, the external granular layer in hypothyroidism survived another several days than that in controls. It is suggested that the complex internal granular layer resulted from the overproduced internal granular cells, which originate in the prolonged external granular layer.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cerebellar Cortex; Cerebellum; Congenital Hypothyroidism; Female; Imaging, Three-Dimensional; Male; Methimazole; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Performance; Rats; Rotarod Performance Test; Thyroid Hormones

This study examined the effects of thyroxine (T(4)) treatment on spatial learning and memory in congenitally hypothyroid (CH) rats. Forty CH male offspring of methimazole-treated dams were randomly divided into three groups: no T(4) (vehicle) treatment (n=12), T(4) treatment commencing on postnatal day (P-) 7 (n=14), and T(4) treatment commencing on P-21 (n=14). Normal male rats were used as a control group (n=14). T(4) was administered daily (sc, 0.02 microg/g) to the treatment groups for 30 days. A water-maze was used to assess behaviour at 42, 70 and 98 days of age. T(4) treatment beginning at P-7 improved learning and memory associated with CH at 70 and 98 days of age but T(4) treatment beginning at P-21 did not improve CH-impaired learning and memory.

Topics: Age Factors; Analysis of Variance; Animals; Congenital Hypothyroidism; Critical Period, Psychological; Discrimination Learning; Disease Models, Animal; Drug Administration Schedule; Female; Hormone Replacement Therapy; Male; Maze Learning; Methimazole; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Space Perception; Thyroid Hormones; Thyroxine

Thyroid destruction leading to endemic myxoedematous cretinism is highly prevalent in central Africa, where iodine (I) and selenium (SE) deficiencies as well as thiocyanate (SCN) overload are combined. All three factors have been studied experimentally in the etiology of the disease, but they have never been studied in combination. In a model using rats, we have previously shown that combining I and SE deficiencies increases the sensitivity of the thyroid to necrosis after iodide overload, an event unlikely to occur in the African situation. To develop a model that would more closely fit with the epidemiological findings, we have determined whether an SCN overload would also result in thyroid necrosis as does the I overload. The combination of the three factors increased by 3.5 times the amount of necrotic cells, from 5.5 +/- 0.3% in the I-SE+ thyroids to 18.9 +/- 1.6% in the I-SE-SCN-overloaded ones. Methimazole administration prevented the SCN-induced necrosis. SE- thyroids evolved to fibrosis, whereas SE+ thyroids did not. TGFbeta was prominent in macrophages present in SE- glands. Thyroid destruction in central Africa might therefore originate from the interaction of three factors: I and SE deficiencies by increasing H(2)O(2) accumulation, SE deficiency by decreasing cell defense and promoting fibrosis, and SCN overload by triggering follicular cell necrosis.

Topics: Africa, Central; Animals; Antithyroid Agents; Congenital Hypothyroidism; Disease Models, Animal; Endemic Diseases; Female; Fibrosis; Hydrogen Peroxide; Inflammation; Iodine; Macrophages; Methimazole; Myxedema; Necrosis; Perchlorates; Rats; Rats, Wistar; Selenium; Sodium Compounds; Thiocyanates; Thyroid Gland; Transforming Growth Factor beta

Two sibs from an inbred Arab family are described with an autosomal syndrome of choanal atresia, hypothelia/athelia and thyroid gland anomalies overlapping Bamforth syndrome, ANOTHER syndrome and methimazole embryopathy. In one case the syndrome described was lethal. Cases with similar features are reviewed and genetic mutations discussed.

Topics: Abnormalities, Multiple; Child, Preschool; Choanal Atresia; Congenital Hypothyroidism; Facies; Female; Genes, Recessive; Humans; Infant; Infant, Newborn; Male; Methimazole; Nipples; Syndrome; Thyroid Gland

Thyroid hormones are critical for maturation of the central nervous system. In a previous study, we showed a change in the pattern of mature myelinated nerve fibers by 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in developing hypothyroid animals, which suggests a possible role for thyroid hormones in myelin compaction. The classical myelin markers myelin basic protein (MBP) and proteolipidic protein (PLP) are expressed later in oligodendroglial development, when myelin sheath formation is in progress. A myelin constituent designated myelin-associated/oligodendrocytic basic protein (MOBP) has been identified and related to myelin compaction. We assessed the developmental sequence of appearance of CNPase, MBP, MOPB, and PLP proteins in cerebellum (Cb) and corpus callosum (cc) in an experimental hypothyroidism model. The appearance of both MOBP isoforms occurred at postnatal day (P)25 and P30 in cc and Cb, respectively, followed by an increase with age in the control group. However, all the MOBP isoforms were weakly detectable in both regions at P30 from the hypothyroid (H) group, and the higher molecular weight isoform remains decreased in cc, even at P90. The developmental pattern of expression of CNPase, MBP, and PLP proteins was also delayed in the H group. CNPase and MBP expression was recovered in cc and Cb, whereas PLP remained below control levels at P90 in cc. Our data show that the experimental hypothyroidism affects the developmental pattern of the oligodendrocytic/myelin markers. Furthermore, thyroid hormone may modulate specific genes, as demonstrated by permanent down-regulation of MOBP and PLP expression in adulthood.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Cerebellum; Congenital Hypothyroidism; Corpus Callosum; Female; Fetal Diseases; Fetal Proteins; Gene Expression Regulation, Developmental; Hypothyroidism; Methimazole; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Pregnancy; Pregnancy Complications; Protein Isoforms; Rats; Rats, Wistar

The behavior of five groups of rats (seven rats per group) made hypothyroid for varying lengths of time and one group of seven normal control rats was assessed under forced alternation fixed-ratio (FR1, FR3, FR5 and FR10), alternating lever cyclic-ratio (ALCR) and progressive-ratio (PR3) schedules of reinforcement. Hypothyroidism was produced by adding methimazole (MMI) to the drinking water of pregnant dams from embryonic day E16 to postnatal day P25. Four groups were given replacement thyroxine (T4) injections beginning at specific time points (P1, P7, P13, and P19). There were no differences in behavioral performance between control and experimental groups under the FR schedule, which indicates that the animals' sensorimotor abilities were intact. Under the forced ALCR schedule, all groups reached criteria similarly. However, under the choice lever ALCR schedule, control animals and those which received T4 replacement from early on (P1, P7, P13 groups) performed well and all had reached criteria by 11 sessions. In contrast, animals which did not receive any T4 replacement or received it late (P19 group) took longer to reach criteria and 5/14 animals had not reached criteria at all by 20 sessions. This deterioration in performance was paralleled by an increase in perseverative behavior as evidenced by an increased frequency of pressing the wrong lever when alternation of lever was required. This suggests that congenital hypothyroidism results in increased perseveration leading to a decrease in learning when a discrimination between correct and incorrect operanda is made available.

Topics: Animals; Antithyroid Agents; Behavior, Animal; Congenital Hypothyroidism; Discrimination Learning; Dose-Response Relationship, Drug; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Rats; Rats, Wistar; Task Performance and Analysis; Thyroxine; Time Factors

The effects of hypothyroidism on oligodendroglial differentiation and myelination are for the first time studied by immunohistochemical localization of an early oligodendroglial marker, the 2'3'cyclic nucleotide 3'phosphodiesterase (E.C. 3.1.4.37-CNPase), in developing rats. Two groups received methimazol; one during gestation (H) and another postnatally (PN). One H sub-group received thyroxine after birth (T). We observed a delay in CNPase expression followed by a decrease in the number of CNPase immunoreactive fibers in both H and PN groups. The T sub-group was not different from controls. Furthermore, the immunoreactive fibers, in mature hypothyroid animals, showed a continuous pattern of staining in contrast with a discontinuous one in controls. Myelinogenesis is a highly regulated timed event. CNPase links myelin related proteins to the cytoskeleton also interacting with membrane lipids during extension and wrapping of the oligodendroglial process around the axon (ensheathment phase). In mature myelinated fiber the CNPase is absent from compact myelin sheath, being located only in the inner and outer loops and in paranodal loops. Thus, our data suggest a disorder in myelin compaction and point once more to the post-natal period as critical for the mechanisms that are thyroid hormone regulated in myelinogenesis.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antithyroid Agents; Brain; Congenital Hypothyroidism; Female; Hypothyroidism; Immunohistochemistry; Methimazole; Myelin Sheath; Oligodendroglia; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Thyroxine

The behavior of six congenitally hypothyroid and six normal control rats was assessed under forced alternation fixed-ratio, alternating lever cyclic-ratio (ALCR) and progressive-ratio schedules of reinforcement. Hypothyroidism was produced by adding methimazole (MMI) to the drinking water of pregnant dams from embryonic day 16 to postnatal day 25. There were no differences in behavioral performance between MMI-treated and control animals under the fixed-ratio and progressive ratio schedules. There were also no differences in circulating triiodothyronine levels between groups at the end of the study. Under the ALCR schedule, when alternation of responding was forced during the first three cycles but both levers (choice) were presented during the last three cycles (correct lever active), the entire control group reached a competency criteria in nine sessions. In contrast, only two MMI-treated animals reached criteria after 17 sessions, and the remaining four MMI-treated animals did not reach criteria by 30 sessions of training. These results suggest that congenital hypothyroidism impairs learning when a discrimination between correct and incorrect operanda is made available.

Topics: Animals; Antithyroid Agents; Conditioning, Operant; Congenital Hypothyroidism; Discrimination Learning; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Rats; Rats, Wistar; Triiodothyronine

Mental retardation associated with hypothyroidism may be caused by impairment of brain ketone body-metabolizing enzymes during the suckling period. However, much evidence suggests that, immediately after delivery, lactate, instead of ketone bodies or glucose, may be the best substrate for the brain. In this work, we have studied the effect of experimentally induced congenital hypothyroidism on the rate of lactate, glucose, and 3-hydroxybutyrate utilization in early neonatal brain slices. Methimazole (MMI) administration to the mothers caused a 5.4- and 1.7-fold decrease in neonatal plasma concentrations of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3), respectively. Propylthiouracil (PTU) administration to the mothers caused a 7.3- and > 2-fold decrease in plasma T4 and T3 concentrations, respectively. MMI-induced hypothyroidism did not significantly modify the rate of lactate, glucose, or 3-hydroxybutyrate oxidation to CO2 and their incorporation into lipids by the neonatal brain. However, PTU-induced hypothyroidism decreased the rate of lactate and glucose oxidation to CO2 and their incorporation into lipids by 17% (p < 0.05). 3-Hydroxybutyrate utilization was not modified by this treatment. Separation by HPLC of the lipids revealed that PTU-mediated inhibition of lipid synthesis from lactate and glucose may be accounted for by specific inhibition of the rate of sterol synthesis (15%, p < 0.05), whereas the rate of phospholipid synthesis was unaffected. These results suggest that the early newborn may develop mechanisms aimed at avoiding the possible brain damage caused by the inhibition of lipid synthesis brought about by mild neonatal hypothyroidism.

Topics: 3-Hydroxybutyric Acid; Animals; Animals, Newborn; Antithyroid Agents; Brain; Congenital Hypothyroidism; Energy Metabolism; Female; Glucose; Hydroxybutyrates; Hypothyroidism; In Vitro Techniques; Lactic Acid; Methimazole; Phospholipids; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

The presence of human blood-group antigens in developing and adult hypothyroid rat cochleas was analyzed using antibodies directed against antigens H and B. During postnatal development, hypothyroid rat cochleas exhibited a highly selective expression of both B and H antigens, mainly at the hair cell level. Labeling for antigen B was found throughout the hair cells, whereas the antibody directed against antigen H selectively labeled the apical part of these cells. These immunostaining patterns were similar to those found in normal (euthyroid) rat cochleas, but antigenic expression periods were clearly prolonged. Thus, whereas in normal rat cochleas, the B and H antigenic expression disappears from postnatal day (PD) 9 on, in cochleas of hypothyroid rats the reactivity was intense until PD15; it decreased from this developmental stage, and was negative or only faintly positive at PD30. Therefore, in congenital hypothyroidism, hair cell immunoreactivity is present at developmental stages that are negative in normal rat cochleas. These results suggest that human blood-group antigen expression on the developing cochlear hair cells of rats is modulated by thyroxine and that thyroxine is necessary for the temporal expression pattern and secretion of normal glycoproteins.

Topics: ABO Blood-Group System; Age Factors; Animals; Antibodies, Monoclonal; Cell Differentiation; Cochlea; Cochlear Diseases; Congenital Hypothyroidism; Female; Fluorescent Antibody Technique; Gene Expression Regulation; Hair Cells, Auditory; Hypothyroidism; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Thyroxine

In the rat a developmental switch in the serum insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) profile takes place during the first 3 postnatal weeks. The fetal expression pattern of high IGF-II and IGFBP-2 is replaced by the adult pattern of low levels of IGF-II and IGFBP-2 and high levels of IGF-I and IGFBP-3. The regulatory mechanisms mediating these changes are unknown, but may include perinatal changes in endocrine function. To study the effects of thyroid function and the perinatal thyroid secretory burst on IGF and IGFBP expression, we established a rat model of congenital hypothyroidism, leading to marked postnatal growth retardation during the perinatal period. The hypothyroid animals lacked the steep rise in serum IGF-I levels normally occurring during the third week of life, showing only a modest rise to approximately 50% of control levels. The pattern of serum IGF-II decline in hypothyroid animals was slightly different from that in controls, with lower IGF-II levels during the second week of life and a slower decline down to the very low final levels. The hypothyroid pups continued to express high levels of IGFBP-2 up to the age of 19 days, while the control animals, after a slow initial decline, showed an abrupt fall of IGFBP-2 serum levels during the third week of life. Liver IGFBP-2 mRNA levels reflected the serum changes, with elevated IGFBP-2 mRNA in hypothyroid animals. The expression of other IGFBPs did not differ from that in the control group. At the age of 18 days, serum GH levels in the hypothyroid animals were approximately one third of control GH levels, which suggests a role for GH as a possible mediator of thyroid hormone actions on the IGF system. The changes in growth parameters and in the IGF and IGFBP profile of hypothyroid pups could be abolished by thyroid hormone replacement from birth. We conclude that thyroid hormone is, directly or indirectly, essential for some of the neonatal changes in IGF and IGFBP profiles.

Topics: Animals; Animals, Newborn; Carrier Proteins; Congenital Hypothyroidism; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Proteins; Methimazole; Rats; Rats, Inbred Strains; Somatomedins; Thyroid Hormones; Thyroxine; Time Factors

We have examined the oligosaccharide structure of secreted thyrotropin (TSH) in perinatal and mature rats with congenital primary hypothyroidism. Rat pituitaries from euthyroid control animals and those rendered hypothyroid by methimazole treatment were incubated with [3H]glucosamine in vitro. Secreted TSH was purified, and oligosaccharides were enzymatically released and characterized by anion-exchange HPLC. In perinatal hypothyroid animals compared with control animals, oligosaccharides from TSH alpha and beta subunits contained more species with three or more negative charges. Moreover, perinatal hypothyroid animals demonstrated a dramatic increase in the ratio of sialylated to sulfated species within oligosaccharides of the same negative charge (2.9- to 7.4-fold increase for TSH-alpha; 15.1- to 25.5-fold increase for TSH-beta). In mature hypothyroid 9-week-old animals compared with control animals, changes were less pronounced, suggesting that endocrine regulation of oligosaccharide structure is dependent upon the maturational state of the animal. These changes were specific for TSH because glycosylation of free alpha subunit (synthesized by the thyrotroph and gonadotroph) and of total glycoproteins was minimally altered by hypothyroidism. Together, these data provide direct evidence and characterization of specific changes in the structure of a secreted pituitary glycoprotein hormone occurring as a result of in vivo endocrine alterations during early development. Moreover, they provide a potential structural basis to explain the delayed clearance of both TSH and the gonadotropins with end-organ deficiency, which may have important implications for the in vivo biological activities of these hormones. Specifically, such posttranslational changes may be an important adaptive response to prevent the consequences of endocrine deficiency during early development.

Topics: Animals; Chromatography, High Pressure Liquid; Congenital Hypothyroidism; Female; Fetus; Glucosamine; Glycoprotein Hormones, alpha Subunit; Hypothyroidism; Methimazole; Oligosaccharides; Pituitary Gland; Pregnancy; Rats; Rats, Inbred Strains; Reference Values; Sialic Acids; Thyrotropin

In view of the defective neurotubule assembly observed in congenital hypothyroidism and the striking morphological abnormalities of the cerebellum in this condition, we have investigated the expression of microtubule-associated protein-2 (MAP2) in the cerebellum of rats with congenital hypothyroidism. Analysis included the measurement of immunoreactive MAP2 and its mRNA. In addition, the intracellular distribution of MAP2 was studied by immunostaining of the appropriate histological preparations. The results showed that the developmental increase in MAP2 is delayed in congenital hypothyroidism, but eventually the concentration of this protein reached normal levels in animals with this condition, even if untreated. These abnormalities in the immunoreactive protein are not paralleled by abnormalities in the abundance of MAP2 mRNA, which was not affected by the thyroid status of the animals. In spite of the normalization of the content of the protein, the distribution of MAP2 in the Purkinje cells of hypothyroid rats remained abnormal. Whereas in euthyroid rats the protein rapidly migrated into the dendrites, in the Purkinje cells of hypothyroid pups, MAP2 remained largely confined to the body and the most proximal part of the dendrites. These results suggest that thyroid hormone affects the expression of MAP2 at translation or posttranslational levels. The abnormality in distribution may result from some posttranslational abnormality of the protein itself or some underlying defect in the function of the neurons. These observations are probably relevant to the abnormalities in cerebellar function seen in animals and humans with untreated congenital hypothyroidism.

Topics: Animals; Animals, Newborn; Cerebellum; Congenital Hypothyroidism; Cytosol; Dendrites; Gene Expression; Hypothyroidism; Immunoassay; Methimazole; Microtubule-Associated Proteins; Nucleic Acid Hybridization; Purkinje Cells; Rats; Rats, Inbred Strains; RNA, Messenger; Tissue Distribution

To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in congenital hypothyroidism, we gave pregnant rats methimazole (MMI), an antithyroid drug that crosses the placenta, and infused them with three different doses of T4 or T3. The concentrations of both T4 and T3 were determined in maternal and fetal plasma and tissues (obtained near term) by specific RIAs. Several thyroid hormone-dependent biological end-points were also measured. MMI treatment resulted in marked fetal T4 and T3 deficiency. Infusion of T4 into the mothers increased both these pools in a dose-dependent fashion. There was a preferential increase of T3 in the fetal brain. Thus, with a T4 dose maintaining maternal euthyroidism, fetal brain T3 reached normal values, although fetal plasma T4 was 40% of normal and plasma TSH was high. The infusion of T3 pool into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation of T3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3. The results show that (a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency; (b) maternal T4, but not T3, plays a crucial role in this protection, and (c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain of a hypothyroid fetus. Recent confirmation of transplacental passage of T4 in women at term suggests that present results are relevant for human fetuses with impairment of thyroid function. Finding signs of hypothyroidism at birth does not necessarily mean that the brain was unprotected in utero, provided maternal T4 is normal. It is crucial to realize that maintainance of maternal "euthyroidism" is not sufficient, as despite hypothyroxinemia, the mothers may be clinically euthyroid if their T3 levels are normal.

Topics: Animals; Brain; Congenital Hypothyroidism; Female; Fetal Blood; Maternal-Fetal Exchange; Methimazole; Pregnancy; Rats; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Aging; Animals; Cerebral Cortex; Congenital Hypothyroidism; Female; Hypothyroidism; Iodide Peroxidase; Methimazole; Nutrition Disorders; Pregnancy; Rats; Thyroxine; Triiodothyronine

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Iodine Radioisotopes; Long-Acting Thyroid Stimulator; Male; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyroxine; Twins

Topics: Abnormalities, Multiple; Antithyroid Agents; Congenital Hypothyroidism; Humans; Iodine; Iodine Radioisotopes; Methimazole; Radioisotopes; Syndrome; Thyroid Gland