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.

Hipotiroidismo subclínico en mujeres en edad reproductiva y embarazadas / Subclinical hypothyroidism in women of reproductive age and in pregnancy

El hipotiroidismo subclínico suele ser identificado como un cuadro que disminuye la capacidad reproductiva de las mujeresy está asociado a un riesgo aumentado de complicaciones perinatales. A partir de un caso clínico real, revisamos laevidencia disponible y encontramos que existen pruebas que contradicen este conocimiento tradicional sobre el pronósticoy la necesidad de tratamiento de este cuadro. (AU)

Subclinical hypothyroidism is usually identified as a condition that decreases the reproductive capacity of women and isassociated with a higher risk of perinatal complications. From a real clinical case, we review the available evidence andfound that there is evidence that contradicts this traditional knowledge about the prognosis and the need for treatment ofthis condition. (AU)

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.

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.

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.

Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R study.

CONTEXT: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function. DESIGN, SETTING, AND PARTICIPANTS: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates. RESULTS: sFlt1 levels were positively associated with TSH (ß 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (ß -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (ß 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01). CONCLUSION: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.

Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues.

Methimazole (MMI) is an anti-thyroid drug used in the treatment of chronic hyperthyroidism. There is, however, some debate about its use during pregnancy as MMI is known to cross the mammalian placenta and reach the developing foetus. A similar problem occurs in birds, where MMI is deposited in the egg and taken up by the developing embryo. To investigate whether maternally derived MMI can have detrimental effects on embryonic development, we treated laying hens with MMI (0.03% in drinking water) and measured total and reduced MMI contents in the tissues of hens and embryos at different stages of development. In hens, MMI was selectively increased in the thyroid gland, while its levels in the liver and especially brain remained relatively low. Long-term MMI treatment induced a pronounced goitre with a decrease in thyroxine (T4) content but an increase in thyroidal 3,5,3'-triiodothyronine (T3) content. This resulted in normal T3 levels in tissues except in the brain. In chicken embryos, MMI levels were similar in the liver and brain. They gradually decreased during development but always remained above those in the corresponding maternal tissues. Contrary to the situation in hens, T4 availability was only moderately affected in embryos. Peripheral T3 levels were reduced in 14-day-old embryos but normal in 18-day-old embryos, while brain T3 content was decreased at all embryonic stages tested. We conclude that all embryonic tissues are exposed to relatively high doses of MMI and its oxidised metabolites. The effect of maternal MMI treatment on embryonic thyroid hormone availability is most pronounced for brain T3 content, which is reduced throughout the embryonic development period.

Irreversible damage to auditory system functions caused by perinatal hypothyroidism in rats.

We examined the effect of perinatal hypothyroidism on auditory function in rats using a prepulse inhibition paradigm. Pregnant rats were treated with the antithyroid drug methimazole (1-methyl-2-mercaptoimidazole) from gestational day 15 to postnatal day 21 via drinking water at concentrations (w/v) of 0 (control), 0.002 (low dose), or 0.02% (high dose). Rats from methimazole-treated mothers were tested at ages 1, 6, and 12months using techniques to examine prepulse inhibition and startle response. The startle stimulus consisted of 40ms of white noise at 115dB, whereas the prepulse, which preceded the startle stimulus by 30ms, consisted of 20ms of white noise at 75, 85, or 95dB. When the prepulse intensity was 75 or 85dB, the high-dose group showed decreased prepulse inhibition percentages compared with the control and low-dose groups. The reduced percentages of prepulse inhibition did not return to control levels over the 12-month study period. In contrast, no differences in prepulse inhibition were observed among the three dose groups when prepulse intensity was 95dB. Moreover, the high-dose group displayed excessive reaction to auditory startle stimuli compared with the other groups. Reductions in plasma free thyroxine and body weight gain were observed in the high-dose group. We conclude that perinatal hypothyroidism results in irreversible damage to auditory function in rats.

[Thyroid hormone resistance syndromes]. / Síndromes de resistencia a las hormonas tiroideas.

Thyroid hormone resistance syndromes are a group of genetic conditions characterized by decreased tissue sensitivity to thyroid hormones. Three syndromes, in which resistance to hormone action is respectively due to mutations in the gene encoding for thyroid hormone receptor TRß, impaired T4 and T3 transport, and impaired conversion of T4 to T3 mediated by deiodinases. An updated review of each of these forms of resistance is provided, and their pathogenetic mechanisms and clinical approaches are discussed.

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.

Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway.

Thyroid hormones influence brain development through regulation of gene expression mediated by nuclear receptors. Nuclear receptor concentration increases rapidly in the human fetus during the second trimester, a period of high sensitivity of the brain to thyroid hormones. In the rat, the equivalent period is the last quarter of pregnancy. However, little is known about thyroid hormone action in the fetal brain, and in rodents, most thyroid hormone-regulated genes have been identified during the postnatal period. To identify potential targets of thyroid hormone in the fetal brain, we induced maternal and fetal hypothyroidism by maternal thyroidectomy followed by antithyroid drug (2-mercapto-1-methylimidazole) treatment. Microarray analysis identified differentially expressed genes in the cerebral cortex of hypothyroid fetuses on d 21 after conception. Gene function analysis revealed genes involved in the biogenesis of the cytoskeleton, neuronal migration and growth, and branching of neurites. Twenty percent of the differentially expressed genes were related to each other centered on the Ca(2+) and calmodulin-activated kinase (Camk4) pathway. Camk4 was regulated directly by T(3) in primary cultured neurons from fetal cortex, and the Camk4 protein was also induced by thyroid hormone. No differentially expressed genes were recovered when euthyroid fetuses from hypothyroid mothers were compared with fetuses from normal mothers. Although the results do not rule out a specific contribution from the mother, especially at earlier stages of pregnancy, they indicate that the main regulators of thyroid hormone-dependent, fetal brain gene expression near term are the fetal thyroid hormones.

[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.

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.

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.

Intrauterine therapy of goitrous hypothyroidism in a boy with a new compound heterozygous mutation (Y453D and C800R) in the thyroid peroxidase gene. A long-term follow-up.

We report the results of intrauterine L-thyroxine therapy, and the long-term follow-up in a fetus who presented at 32 weeks' gestation with goitrous hypothyroidism, hyperextension of the neck, and polyhydramnios. Spontaneous delivery was possible and hypothyroidism improved. Molecular analysis revealed a new compound heterozygous mutation (Y453D/C800R) in the TPO gene.

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.