Hemodynamic properties and arterial structure in male rat offspring with fetal hypothyroidism.

Thyroid hormones (THs) play a crucial role in the development of different systems during fetal life; fetal hypothyroidism (FH) is associated with reduced cardiac function and dimensions in neonates. The aim of this study is to determine whether TH deficiency during fetal life is associated with arterial structural and hemodynamic changes during adulthood. Hypothyroidism was induced by adding 0.025% 6-propyl-2-thiouracil in drinking water throughout pregnancy, while controls consumed only tap water. Hemodynamic parameters, cross-sectional area, intima-media thickness (IMT), and density of nuclei of smooth muscle cells and endothelial cells (ECs) in the aorta and mesenteric arteries were measured. Compared to controls, in the FH group, baseline systolic blood pressure (105.7 ± 3.1 vs. 87.9 ± 3.3 mm Hg, p < 0.01), diastolic blood pressure (64.4 ± 1.7 vs. 53.2 ± 2.1 mm Hg, p < 0.05), and mean arterial pressure (80.9 ± 2.1 vs. 67.1 ± 2.1 mm Hg, p < 0.01) were significantly lower. In addition, in the FH group, intensity and latency of response to phenylephrine were significantly lower and longer, respectively, as were the IMT and density of ECs in the aorta and superior mesenteric arteries. In conclusion, this study showed that TH deficiency during fetal life can have long-lasting functional and histological effects, which can compromise cardiovascular function during adulthood.

Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration.

Though aberrant neuronal migration in response to maternal thyroid hormone (TH) deficiency before the onset of fetal thyroid function (embryonic day [E] 17.5) in rat cerebral cortex has been described, molecular events mediating morphogenic actions have remained elusive. To investigate the effect of maternal TH deficiency on neocortical development, rat dams were maintained on methimazole from gestational day 6 until sacrifice. Decreased number and length of radial glia, loss of neuronal bipolarity, and impaired neuronal migration were correctible with early (E13-15) TH replacement. Reelin downregulation under hypothyroidism is neither due to enhanced apoptosis in Cajal-Retzius cells nor mediated through brain-derived neurotrophic factor-tyrosine receptor kinase B alterations. Results based on gel shift and chromatin immunoprecipitation assays show the transcriptional control of reelin by TH through the presence of intronic TH response element. Furthermore, hypothyroidism significantly increased TH receptor α1 with decreased reelin, apolipoprotein E receptor 2, very low-density lipoprotein receptor expression, and activation of cytosolic adapter protein disabled 1 that compromised the reelin signaling. Integrins (α(v) and ß1) are significantly decreased without alteration of α3 indicating intact neuroglial recognition but disrupted adhesion and glial end-feet attachment. Results provide mechanistic basis of essentiality of adequate maternal TH levels to ensue proper fetal neocortical cytoarchitecture and importance of early thyroxine replacement.

[Assessment of thyroid hormones and androgens in amniotic fluid: clinical interest]. / Dosage des hormones thyroïdiennes et surrénaliennes dans le liquide amniotique: aide au diagnostic.

Ultrasound scanning is able to detect foetal goiter due either to an hypothyroidy either to an hyperthyroidy, or clitoris hypertrophia resulting from adrenal hyperplasia in female, during the second half of pregnancy. The diagnosis of these rare diseases is of interest because the treatment can be started during pregnancy. An amniotic fluid punction can be discussed and its biochemical analysis may be of interest even though very few commercial assays have been tested on amniotic fluid. Our aim was two investigate the practicability and the value of free thyroxin (FT4), thyrotropin (TSH), 17alpha hydroxyprogesterone (17-OHP) and delta 4 androstenedione (Delta4A) measurement on amniotic fluid using commercially available assays for serum. FT4 and TSH are detectable at low levels in amniotic fluid. FT4 significantly increases from 2.1 pmol/L to 4.2 pmol/L while TSH significantly decreases from 0.27 mU/L to 0.12 mU/L during the second half of pregnancy. An increase in amniotic fluid TSH concentration contributes to the diagnosis of foetal hypothyroidy while the measurement of amniotic fluid FT4 is not informative in case of foetal goiter. 17-OHP and Delta4A are present in amniotic fluid at the same level as in serum. 17-OHP significantly decreases from 1.9 ng/mL to 1 ng/mL during the second half of pregnancy while Delta4A significantly increases from 0.5 ng/mL to 0.8 ng/mL. Absence of increase in their concentrations excludes any severe adrenal hyperplasia.

Graves' disease complicated by fetal goitrous hypothyroidism treated with intra-amniotic administration of levothyroxine.

Fetal goitrous hypothyroidism is a rare entity and is caused mainly by maternal treatment of Graves' disease (GD). We report a case of a 22-year-old woman referred at 12 weeks of gestation due to hyperthyroidism subsequent to recently diagnosed GD. She started treatment with propylthiouracil and, at 21 weeks of gestation, fetal goitre was detected. A cordocentesis confirmed the diagnosis of fetal goitrous hypothyroidism, and intra-amniotic administration of levothyroxine (LT4) was performed and repeated through the pregnancy due to maintenance of fetal goitre. The pregnancy proceeded without further complications and a healthy female infant was born at 37 weeks of gestation, with visible goitre and thyroid function within the normal range at birth. Although there is no consensus on the optimal dose, the number of injections and the interval between them, intra-amniotic LT4 administration is recommended once fetal goitrous hypothyroidism is suspected, in order to prevent long-term complications of fetal hypothyroidism.

Fetal thyroid disorders: Pathophysiology, diagnosis and therapeutic approaches.

Fetal thyroid disorders while uncommon in general, have significant morbidity and profound effects in the neonate. Pregnancy provides the opportunity not only for the diagnosis of these conditions but also for therapeutic interventions. In careful balance, these disorders range from hypothyroidism to hyperthyroidism, both may manifest with fetal thyroid goiters as well. The intrauterine therapeutic approach of these must also weight the balance in this range as well as the maternal well being which may also express thyroid dysfunction. In this review we explore the different fetal manifestations of thyroid disease, describe the pathophysiology and therapeutic approaches both in practice and in development.

Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study.

Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspring. Pregnant rats were exposed to PTU (0 or 3 ppm) through the drinking water from gestational day 6 until postnatal day (PN) 14. On PN2 a subset of pups was cross-fostered to a dam of the opposite treatment, to create 4 conditions: pups exposed to PTU prenatally, postnatally, during both periods, or not at all (control). Both PTU and TH concentrations were characterized in the mother and offspring over time, to capture the dynamics of a developmental xenobiotic exposure. Brains of offspring were examined for heterotopia presence and severity, and adult littermates were assessed for memory impairments. Heterotopia were observed under conditions of prenatal exposure, and its severity increased in animals in the most prolonged exposure group. This malformation was also permanent, but not sex biased. In contrast, behavioral impairments were limited to males, and only in animals exposed to PTU during both the gestational and postnatal periods. This suggests a distinct TH-dependent etiology for both phenotypes, and illustrates how timing of hypothyroxinemia can induce abnormal brain structure and function.

Polychlorinated biphenyls exert selective effects on cellular composition of white matter in a manner inconsistent with thyroid hormone insufficiency.

Developmental exposure to polychlorinated biphenyls (PCBs) is associated with a variety of cognitive deficits in humans, and recent evidence implicates white matter development as a potential target of PCBs. Because PCBs are suspected of interfering with thyroid hormone (TH) signaling in the developing brain, and because TH is important in oligodendrocyte development, we tested the hypothesis that PCB exposure affects the development of white matter tracts by disrupting TH signaling. Pregnant Sprague Dawley rats were exposed to the PCB mixture Aroclor 1254 (5 mg/kg), with or without cotreatment of goitrogens from gestational d 7 until postnatal d 15. Treatment effects on white matter development were determined by separately measuring the cellular density and proportion of myelin-associated glycoprotein (MAG)-positive, O4-positive, and glial fibrillary acidic protein (GFAP)-positive cells in the genu of the corpus callosum (CC) and in the anterior commissure (AC). Hypothyroidism decreased the total cell density of the CC and AC as measured by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) staining and produced a disproportionate decrease in MAG-positive oligodendrocyte density with a simultaneous increase in GFAP-positive astrocyte density. These data indicate that hypothyroidism reduces cellular density of CC and AC and fosters astrocyte development at the expense of oligodendrocyte density. In contrast, PCB exposure significantly reduced total cell density but did not disproportionately alter MAG-positive oligodendrocyte density or change the ratio of MAG-positive oligodendrocytes to GFAP-positive astrocytes. Thus, PCB exposure mimicked some, but not all, of the effects of hypothyroidism on white matter composition.

Gestational dexamethasone alters fetal neuroendocrine axis.

This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-ß, tumor necrosis factor-alpha; TNF-α, and interferon-γ; IFN-γ) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction.

Expression and localization of caveolins during postnatal development in rat heart: implication of thyroid hormone.

Caveolins modulate signaling pathways involved in cardiac development. Caveolin-1 exists in two isoforms: the beta-isoform derivates from an alternative translational start site that creates a protein truncated by 31 amino acids, mainly expressed in endothelial cells, whereas caveolin-3 is present in muscle cells. Our aim was to define caveolin distribution and expression during cardiac postnatal development using immunofluorescence and Western blotting. Caveolin-3 sarcolemmal labeling appeared as dotted lines from days 1 to 5 and as continuous lines after 14 days of age. Caveolin-3 expression, low at birth, increased (4-fold) to reach a maximum (P < 0.05) by day 5 and then decreased to stabilize in adults. Total caveolin-1 and its alpha-isoform were codistributed at birth in endothelial and smooth muscle cells; afterward, only the caveolin-1alpha labeling became limited to endothelium. Quantitative analysis indicated a similar temporal pattern of both total caveolin-1 and caveolin-1alpha expression, suggesting that caveolin-1alpha and -1beta are coregulated; the caveolin-1alpha levels increased fourfold by day 5 to reach a maximum by day 14 (P < 0.05). Tyrosine-14-caveolin-1 phosphorylation, low at birth, increased suddenly around day 14 (8-fold vs. day 1) and returning afterward to basal level. Because the T3/T4 level is maximal by day 14, caveolin-1 expression/phosphorylation profiles were analyzed in hypothyroid heart. The levels of caveolin-1alpha and consequently tyrosine-14-caveolin-1 phosphorylation, but not that of caveolin-3, decreased (50%) in hypothyroid 14-day-old rats. Our data demonstrate that, during postnatal cardiac growth, 1) caveolins are distinctly regulated, and 2) thyroid hormones are involved in caveolin-1alpha expression.

The roles of the iodothyronine deiodinases in mammalian development.

The thyroid hormones (TH) are essential for normal development in vertebrate species. This review considers the roles that the three deiodinases, types 1, 2 and 3 (D1, D2, and D3), play in regulating intracellular levels of TH during this critical period. The focus is on rodents and humans with emphasis on brain development. There is little evidence to suggest that the D1 plays a significant role in development and this is substantiated by the absence of any obvious developmental impairment in a D1-deficient mouse model. There is, however, compelling indirect evidence pertaining to the importance of the D2 in development, particularly with respect to that of the brain. However, surprisingly, a D2-deficient mouse model exhibits a very mild phenotype. This, together with the fact that D2 activity is increased in hypothyroidism, suggests that this deiodinase may be of greater importance in development when supplies of thyroxine are limited. The D3 is clearly essential for development in the euthyroid mammal. Information, both indirect and that obtained from a D3-deficient mouse model, strongly suggests that its presence in placenta, uterus and some fetal tissues are critical for limiting exposure of fetal tissues to inappropriate levels of TH.

Development of the olfactory nerve in the clawed frog, Xenopus laevis: II. Effects of hypothyroidism.

Quantitative and morphological data were obtained on developing olfactory axons in normal and hypothyroid larvae of the African clawed frog Xenopus laevis. Hypothyroid larvae were produced by rearing the animals, beginning at stage 48, in a 0.01% solution of propylthiouracil (PTU), a treatment that blocks synthesis of thyroid hormone. These PTU-treated larvae were compared to their age-matched siblings when these siblings reached stage 52 (premetamorphic larvae; prior to synthesis of thyroid hormone), stage 57 (late premetamorphic larvae; after the onset of thyroid hormone synthesis), or stage 58 (larvae at the onset of metamorphic climax; thyroid hormone levels continue to rise). The number of olfactory axons did not differ between stage 52 control animals and the age-matched, PTU-treated animals, but there were only about half the number of axons in the PTU-treated animals that were age-matched to the stage 57 or 58 controls. Thus, PTU had no effect on olfactory axon number prior to the normal rise in thyroid hormone levels. But PTU significantly reduced the normal increase in olfactory axon number compared to stage 58 control larvae, whose thyroid hormone levels are high. While PTU also produced some changes in several other body measurements, the effect on the olfactory axons was the most consistent and prominent. The results presented here support our previous findings that thyroid hormone plays a significant role in the development of the olfactory system in Xenopus.

Prevention of auditory dysfunction in hypothyroid Tshr mutant mice by thyroxin treatment during development.

Based on previous work, it is clear that genetically hypothyroid Tshr(hyt) mutant mice are congenitally deaf [O'Malley et al. (1995) Hear. Res. 88: 181-189, Sprinkle et al. 2001b, J. Assoc. Res. Otolaryngol. DOI: 10.1007/s101620010077]. However, the extent to which auditory development is dependent on the availability of thyroxin (T4) during specific developmental stages is unknown. The aim of this study was to determine the relative importance of prenatal and postnatal thyroxin on the ontogeny of hearing in the hyt mouse. Experimental hypothyroid subjects were offspring of hyt/hyt breeders implanted with T4 or placebo controlled-release pellets 14 days prior to mating. Pups received T4 or saline placebo injections from birth through postnatal day 14 (P14) or the time of testing on P28. In the absence of exogenous T4 replacement, very high stimulus levels (>80 dB SPL) were required to elicit responses. Remarkably, T4 treatment confined to the postnatal period failed to significantly improve auditory function relative to untreated animals, while response thresholds, latencies, and amplitudes of mice born to dams that received T4 during pregnancy were significantly improved relative to both of the untreated groups. Response thresholds were improved somewhat when maternal T4 replacement was followed by treatment during the first 14 days of life, and animals treated throughout prenatal and postnatal life were comparable to those of age-matched euthyroid individuals. Findings from this study show that treatment of hyt/hyt mice with exogenous T4 significantly attenuates hypothyroid-induced otopathology in a develop-mental-stage-dependent manner. In addition, we demonstrate that postnatal development is critically dependent on prenatal exposure to thyroxin and that the critical window of T4 dependence extends throughout development.

Morphometric analysis of the cerebellar Purkinje cell in the developing normal and hypothyroid chick.

A morphometric analysis of Purkinje cells in the developing cerebellar cortex of the chick was performed in normal animals and embryos made hypothyroid by one or two spaced injections of tetramethylthiourea. Profiles of 162 Purkinje cells, from Golgi-Cox treated sections were analysed. Soma area, perimeter and circularity index, cumulative length of the dendrites and number of dendritic bifurcations were studied. The results showed significant differences between control and hypothyroid animals. There were no important differences between birds rendered transiently hypothyroid with a single injection and those made chronically hypothyroid with dual injections. This confirms that the Purkinje cell is very dependent on thyroid hormone especially during the early phases of its morphogenesis. The development of the Purkinje cell was the most affected process of cerebellar cortex maturation in the thyroid-deficient chick. The dendritic arborization was particularly hypoplastic. Moreover, a dynamic balance appeared to exist between the development of the dendritic arborization and that of the perikaryon.

The development of the anterior commissure in normal and hypothyroid rats.

The development of axon number in the anterior commissure (AC) was analyzed in 39 normal and 37 hypothyroid rats using conventional electron microscopy. Hypothyroid rats underwent antithyroid treatment with methimazole from embryonic day (E) 14 onwards, followed in a fraction of the animals by thyroidectomy at postnatal day (P) 6. In normal rats, the midsagittal cross-sectional anterior commissure area (ACA) increased throughout their life; in hypothyroid rats, ACA was stationary from P4 onwards and at P174-180 it was reduced by 39% relative to normal rats. In normal rats, the number of AC axons increased rapidly from 168,500 at E18 to, on average, 1,049,000 from P4 onwards. Similarly, in hypothyroid rats, the number of axons increased from 135,000 at E18 to, on average, 1,052,000 from P4 onwards. At all ages, the number of axons was similar in normal and hypothyroid rats. During development of the AC, the evolution of axon number observed in normal and hypothyroid rats is different from what was reported for other telencephalic commissures, including the AC of the monkey, where an important fraction of the axons are eliminated postnatally. Antithyroid treatment dissociated ACA from total number of AC axons.

Radioiodine and pregnancy.

The fetal thyroid begins to accumulate radioiodine around the 12th week of pregnancy. Iodide easily crosses the placenta and fetal thyroid uptake can be effectively blocked by administration of radioiodine to the mother. Therapeutic administration of radioiodine to the mother will usually result in fetal hypothyroidism and may be associated with attention deficit disorders and impairment of figurative memory in the offspring. The hazard to a fetus from exposure to a family member, not the mother, who has been treated with radioiodine is very small and can be minimized by adherence to standard post treatment guidelines. Lactating mothers who have received standard diagnostic doses of 131I or who have been treated with 131I should not breast-feed their infant from that point forward. Breast-feeding in future pregnancies is not contraindicated. Pregnancy testing within 48 hours before 131I administration to potentially fertile women is a wise clinical practice. Demonstrated effects of radioiodine on spermatogenesis suggest that it is wise to recommend a 120-day waiting period between radioiodine and fertilization.

Biochemical investigation of foetal and neonatal thyroid function using the ACS-180SE analyser: clinical application.

Despite sonographic detection of foetal goitre, uncertainty persists in the initial diagnosis of thyrotoxicosis and hypothyroidism. The aim of this study was to establish foetal and neonatal iodothyronine and thyrotrophin reference values for the ACS-180SE analyser. From 22 to 36 weeks of gestation, median foetal serum free thyroxine (FT4) levels increased from 6.0 pmol/L to 143 pmol/L, while free tri-iodothyronine (FT3) levels increased from 0.7 pmol/L to 1.9 pmol/L and mean thyrotrophin (TSH) levels remained stable (10.2 +/- 3.8mU/L; n = 33). At birth, concentrations were independent of gender and gestational age. Among the 10 cases of sonographically detected foetal goitre, serum TSH and FT4 were measured in five, showing hypothyroidism (3/5) or hyperthyroidism (2/5). Cord blood TSH levels reflected the efficacy of prenatal therapy. Measurement of foetal FT4 and TSH can be used to confirm foetal thyroid dysfunction, whereas treatment efficacy can be assessed sonographically and confirmed by measurement of TSH assay at birth.

Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism.

Temporary hypothyroidism was induced in neonatal rats by 0.02% propylthiouracil (PTU) administration to lactating dams during days 0-19 after delivery, and its effects on the behavior and learning of their male offspring were examined. The serum T4 (thyroxine) level was returned to normal around 1 week after the last PTU administration, but the body weight gain was still depressed. The open field and Biel water maze tests at the age of 6 weeks showed an increased number of ambulations and an increase in errors with prolonged swimming time in the PTU rats. The radial arm maze test started at 13 weeks revealed that the PTU animals required more trials until they showed the first well-performed trial. The total number of choices was also larger, with less correct choices, and treatment effects on the response distribution and pattern were significant. Thus, the rats, which had suffered from temporary hypothyroidism in the neonatal period, showed hyperactivity and irreversible impairment in maze learning. These results suggest an involvement of temporary neonatal hypothyroidism in hippocampal dysfunction.

[Prenatal diagnosis and treatment of fetal hypothyroid goiter]. / Diagnostic et traitement anténataux d'un goitre foetal hypothyroïdien.

We report on a case of fetal goitrous hypothyroidism confirmed by the study of fetal thyroid function. Two injections of intra amniotic levo-thyroxine were performed at 35 and 36 WA. The serial ultra sonographic examination showed the disappearance of the fetal goiter. A healthy baby were delivered by cesarean section at 37 WA. At birth, the thyroid gland was slightly enlarged and the neonatal thyroid hormones were within the normal range. This case suggests that cordocentesis is a reliable method of assessing the status of the fetal thyroid, and that even as early as 35 WA a prenatal treatment of fetal goitrous hypothyroidism is possible by amniocentesis.