Thyroid Hormone Supply Research Articles

6622 Severe Primary Hypothyroidism in a Child Presented as a Pituitary Tumour; a case Report

Abstract Disclosure: S.S. Awadalla: None. A 9-year-old patient showed up to the emergency department due to a headache that had been going on for a month without other symptoms and no neurological alterations. Complete blood count and glycemia were normal. A Cerebral MRI was requested and showed a pituitary adenoma. The patient was initially evaluated by neurosurgeons and referred to a pediatric endocrinologist. TSH, free T4, IGFI, and cortisol were evaluated, TSH was found to be high at 936 (normal, 0.4-4.2), free T4 < 0.4; suggestive of severe primary hypothyroidism. The case was analysed with the neurosurgery department, and a joint decision to start therapy with LT4 was taken, whilst monitoring the evolution of the pituitary adenoma. TSH and Free T4 were normal, and the MRI of Sella Turcica three months later showed complete pituitary normality. The presentation of this case is of relevance as the primary modality of treatment is thyroid hormone supply and not surgery. Interprofessional team integration is recommended for the treatment of patients with this condition. Presentation: 6/1/2024

6415 Resistance to Thyroid Hormone -A Challenge to Manage

Abstract Disclosure: A. Altaf: None. F. Iqbal: None. E. Hamoudeh: None. C. Coyne: None. K. Anne: None. L. Buckley: None. Background: Resistance to thyroid hormone (RTH) or Refetoff syndrome was first introduced in 1967. It is an autosomal dominant or recessive genetic disease with a mutation in the thyroid hormone receptorβ (THR-β) gene or the thyroid hormone receptorα (THR-α) gene. The distinguishing biochemical feature of RTHβ is an elevated level of circulating free thyroid hormones with normal or high TSH concentration and decreased peripheral tissue response to thyroid hormone. Common signs and symptoms in patients with RTHβ are short stature, attention deficit disorder, and resting tachycardia and many patients might be asymptomatic. Case: We report a case of a 36-year-old patient with past medical history of congenital bilateral hearing loss, atrial fibrillation, CHF, and slow learning/comprehending who presented to the ER with shortness of breath and atrial fibrillation with tachycardia. Admission labs revealed elevated TSH 3.9, elevated fT4 3.28, and elevated TT3 205. He reported that for the past year, he has been on levothyroxine 50mcg for abnormal TSH. Levothyroxine was stopped and the patient was discharged on methimazole 10mg daily. Further workup revealed negative thyroglobulin and thyroid peroxidase antibodies. Thyroid ultrasound with Doppler demonstrated a mildly hypervascular thyroid gland without evidence of nodules. Brain MRI was negative for any pituitary abnormalities. HAMA testing continued to show elevated TSH. Patient was followed by cardiology and due to continued atrial fibrillation, had multiple cardioversions and was managed on a beta blocker. Due to his atrial fibrillation, endocrinology service continued his methimazole till his genetic testing came positive for an autosomal dominant heterozygous pathogenic mutation in THRB c.1373 T>C (p. Val458Ala). His thyroid hormones and TSH continue to be elevated. Currently, he is not on thyroid medication and getting monitored. The need for multiple cardioversions for atrial fibrillation in this patient makes resistance to thyroid hormone management challenging. Discussion: Hyperthyroidism is commonly mistaken for RTH. However, the lack of TSH suppression should be further investigated. Most patients with RTHβ are adequately compensated by the increased endogenous supply of thyroid hormone showing increased serum fT3 and fT4 levels and normal or near normal TSH levels. Beta Blockers like atenolol cannot inhibit the conversion of T4 to T3 and can be used for RTHβ with tachycardia. Triiodothyroaceticacid (TRIAC) or dextrothyroxine (DT4) have also been used to treat thyrotoxicosis. In summary, treatment for RTHβ remains a challenge for clinicians, especially in patients with atrial fibrillation and many patients are misdiagnosed and managed as hyperthyroidism. Presentation: 6/3/2024

Effects of gestational hypothyroidism on mouse brain development: Gabaergic systems and oxidative stress

Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.

P-756 Neurodevelopmental outcomes at school-age after conception with hysterosalpingography using iodinated contrast media - follow-up of the nationwide multicentre H2Oil trial

Abstract Study question How does conception <6 months after hysterosalpingography (HSG) with iodinated contrast media affect the neurodevelopment of the offspring compared to naturally-conceived peers at a school-age? Summary answer Children conceived <6 months after HSG with iodinated contrast media perform lower on intelligence tests and information processing and attention control compared to naturally-conceived peers. What is known already Tubal patency in subfertile women is commonly assessed using hysterosalpingography (HSG), but the potential risks of exposure to high iodine content in contrast media used remains unknown. Exposure to iodine excess can cause transient reduction in thyroid hormone synthesis due to the Wolff-Chaikoff effect. Thyroid hormone sufficiency in early pregnancy is vital for children’s neurodevelopment. When conception occurs shortly after HSG with iodinated contrast, a temporary reduction of maternal and/or foetal thyroid hormone supply could jeopardize children’s neurodevelopment. Study design, size, duration We evaluated neurodevelopmental outcomes of 6–9-year-old children conceived <6 months after HSG with oil-based (iodine content: 480mg/ml) or water-based contrast (iodine content: 240-300mg/ml) in a nationwide randomised controlled trial (H2Oil trial; Netherlands; 2012-2014; NCT05168228). Naturally-conceived children (n = 44) with similar age, sex and parental education were used as a comparison group (NTR9574). We also compared children conceived <4w, 4-12w, >12w after HSG with those conceived naturally. The study took place January 2022 until November 2023. Participants/materials, setting, methods We contacted 140 mothers from the H2Oil trial, 69 children conceived <6m after HSG participated, and parallelly we recruited 44 naturally-conceived children. Primary outcomes were intelligence (Wechsler’s Intelligence Scale for Children V), behavioural functioning (SDQ and SWAN, administered to parents and teachers), and academic performance. Secondary outcomes were neurocognitive function assessed by a battery of computerized tests. We used linear regression adjusted for age, sex, and parental education and applied FDR correction. Main results and the role of chance Compared to naturally conceived children, children conceived <6m after HSG had lower performance on intelligence tests (-6.81; 95%CI-10.97 to -2.65; p = 0.02) and the neurocognitive domain Processing & Control (-0.52; 95%CI-0.84 to -0.19; p = 0.02), with functions relating to information processing speed and consistency affected. No differences were found for other neurocognitive domains, behaviour or academic performance. Considering time between HSG and conception, intelligence scores were lower for children conceived <4w after HSG compared to naturally-conceived peers (-11.47; 95%CI-17.98 to -4.95; p = 0.03), while no significant differences were found for the groups of children conceived 4-12 weeks after HSG (-7.17; 95%CI -12.28 to -2.06; p = 0.10) or > 12 weeks after HSG (-4.20; 95%CI -9.33 to 0.94; p = 0.52). The findings of this study warrant replication in larger independent samples in order to evaluate the long-term neurodevelopment of children conceived after HSG with iodinated contrast media. Limitations, reasons for caution We aimed to recruit 64 children for each group, but our study was not sufficiently powered for small- and medium-sized differences. We did not collect information on the thyroid or iodine status of the mothers following HSG, and there is limited knowledge about pharmacokinetics of iodinated contrast media in humans. Wider implications of the findings Replication studies with are needed to further evaluate the safety of iodinated contrast media use periconception, including their effects on thyroid function and children’s neurodevelopment. Closer monitoring and treatment of thyroid dysfunction in the months following HSG may be warranted. Trial registration number NCT05168228

Regulation of Thyroid Hormone Gatekeepers by Thyrotropin in Tanycytes.

Background: Tanycytes are specialized glial cells within the mediobasal hypothalamus that have multiple functions, including hormone sensing and regulation of hypophysiotropic hormone secretion. There are ongoing discussions about the role of tanycytes in regulating the supply of hypothalamic thyroid hormones (THs) through the expression of TH transporters (Slc16a2, Slco1c1) and deiodinases (Dio2, Dio3). In this study, we investigated the potential feedback effect of thyrotropin (TSH) on the transcription of these gatekeeper genes on tanycytes. Methods: We analyzed the changes in the expression of TH-gatekeeper genes, in TSH-stimulated primary tanycytes, using quantitative polymerase chain reaction (qPCR). We also used RNAScope® in brain slices to further reveal the local distribution of the transcripts. In addition, we blocked intracellular pathways and used small-interfering RNA (siRNA) to elucidate differences in the regulation of the gatekeeper genes. Results: TSH elevated messenger RNA (mRNA) levels of Slco1c1, Dio2, and Dio3 in tanycytes, while Slc16a2 was mostly unaffected. Blockade and knockdown of the TSH receptor (TSHR) and antagonization of cAMP response element-binding protein (CREB) clearly abolished the increased expression induced by TSH, indicating PKA-dependent regulation through the TSHR. The TSH-dependent expression of Dio3 and Slco1c1 was also regulated by protein kinase C (PKC), and in case of Dio3, also by extracellular signal-regulated kinase (ERK) activity. Importantly, these gene regulations were specifically found in different subpopulations of tanycytes. Conclusions: This study demonstrates that TSH induces transcriptional regulation of TH-gatekeeper genes in tanycytes through the Tshr/Gαq/PKC pathway, in parallel to the Tshr/Gαs/PKA/CREB pathway. These differential actions of TSH on tanycytic subpopulations appear to be important for coordinating the supply of TH to the hypothalamus and aid its functions.

Prevalence of Hypothyroidism in Pregnancy in a Tertiary Care Hospital

Introduction: Thyroid disorders are the most common endocrine disorders affecting women of reproductive age. The most frequent thyroid disorder in pregnancy is maternal hypothyroidism. During early pregnancy, the fetus is totally dependent on maternal thyroid hormone supply. Thyroid hormone is critical for fetal brain and intellectual development. Thyroid hormone is also important for some preventable pregnancy complications like anaemia, low birth weight, abruptio placenta, preeclampsia, etc., which pose special risks for the mother and developing fetus. Aim of the study: To assess the prevalence of hypothyroidism in pregnant women and thus ensure appropriate treatment for the wellbeing of the mother and baby. Methods: This prospective obsessional study was conducted on 113 pregnant women at US Bangla Medical College Hospital, Dhaka, Bangladesh, who attended obstetrics outdoors. Women were randomly chosen irrespective of age, parity, residence, and socioeconomic status. Women with multiple pregnancies or having any pre-existing medical disorder were excluded. All women were investigated for TSH along with routine pregnancy tests. All were divided into two groups: normal/euthyroid and abnormal/thyroid disorders, considering their thyroid status. Result: We found the prevalence of thyroid dysfunction in pregnancy was 17.7%, with hypothyroidism being 15.93%, of which 10.62% were subclinical hypothyroidism, 5.31% were cases of overt hypothyroidism, and 1.77% were cases of hyperthyroidism. Conclusion: This study showed an increased prevalence of hypothyroidism in pregnancy, recommending a need for universal screening for all pregnant women in the early weeks of pregnancy. This study aims at validating the efficacy of the above-mentioned screening for a better pregnancy outcome.

Distribution of Monocarboxylate Transporters in Brain and Choroid Plexus Epithelium.

The choroid plexus (CP) plays central roles in regulating the microenvironment of the central nervous system by secreting the majority of cerebrospinal fluid (CSF) and controlling its composition. A monolayer of epithelial cells of CP plays a significant role in forming the blood-CSF barrier to restrict the movement of substances between the blood and ventricles. CP epithelial cells are equipped with transporters for glucose and lactate that are used as energy sources. There are many review papers on glucose transporters in CP epithelial cells. On the other hand, distribution of monocarboxylate transporters (MCTs) in CP epithelial cells has received less attention compared with glucose transporters. Some MCTs are known to transport lactate, pyruvate, and ketone bodies, whereas others transport thyroid hormones. Since CP epithelial cells have significant carrier functions as well as the barrier function, a decline in the expression and function of these transporters leads to a poor supply of thyroid hormones as well as lactate and can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases. In this review paper, recent findings regarding the distribution and significance of MCTs in the brain, especially in CP epithelial cells, are summarized.

Abstract #1405611: A Case Regarding Severe Hypothyroidism Which Complicated to De Novo Nephrotic Syndrome (Minimal Change Disease)

Hypothyroidism is a condition of an under-reactive thyroid. More prevalent in women, 10% exhibit some degree of thyroid insufficiency. It has numerous metabolic effects and may have an impact on renal physiology and worsening kidney function. Hypothyroidism was cited in certain case studies as a contributing factor to minimal change disease, which we will be highlighting here. We report a case of an 82-year-old female with PMH of graves’ disease status post left thyroidectomy in 2009 and was started on Levothyroxine, reported non-compliance, presented to the emergency department with a complaint of generalized edema mostly lower extremities that is progressively worsening over 2 weeks along with foamy urine. Unremarkable physical exam except for 2+ lower extremity pitting edema. On lab, high thyroid stimulating hormone (TSH) was 65.2 ulU/ml, normal Free Thyroxin (FT4) and low Free Triiodothyronine (FT3) 0.4 pg/ml, Serum Creatinine is 4.35 mg/dl, Urinalysis shows >500 protein, urine protein/Cr was 3, hypoalbuminemia and hyperlipidemia were present. A Glomerulopathy workup was initiated. She was admitted for further testing. Autoimmune kidney diseases were ruled out and a renal biopsy was performed, the specimen revealed Minimal change disease. She was started on Prednisone 60 mg daily and Levothyroxine 125 mcg. Three weeks later, patient showed a good response to therapy with an improvement of symptoms and repeated creatinine was 3.8. Hypothyroidism can be caused by partial or total thyroidectomy. As a highly lipophilic substance, Thyroxine binds to receptors that are expressed in cells all over the body to exhibit its physiological action. In patients with thyroidectomy, exogenous levothyroxine is the thyroid hormone supply to the body. Not having enough supply, can alter kidney function by affecting vascular resistance, re-absorptive process, and renal blood flow. It can also affect the RAAS system, beta-adrenergic receptors, and dopaminergic activation of the renal tubular cells. Gradual worsening of kidney function leads to an increase in the loss of free and bound thyroid hormones and eventually increases thyroxine requirement. GFR is reversibly reduced (by about 40%) in more than 55% of adults with hypothyroidism. Thyroxine treatment is effective by reducing edema, capillary permeability of albumin, and plasma colloid osmotic pressure. Proteinuria can sometimes be reversible by prompt initiation of thyroxine treatment. Also, the severity of symptoms plays a role in recovery. More research is needed to determine the relationship between hypothyroidism and nephrotic syndrome as only a few isolated occurrences were reported in the literature.

Thyroid hormone regulators in human cerebral cortex development.

Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood-brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan-Herndon-Dudley syndrome, with altered thyroid hormone concentrations in the blood and profound neurological impairment and intellectual deficit. Mouse disease models have revealed interplay between transport, deiodination, and availability of T3 to receptors in specific cells. However, the mouse models are not satisfactory, given the fundamental differences between the mouse and human brains. The goal of the present work is to review human neocortex development in the context of thyroid pathophysiology. Recent developments in single-cell transcriptomic approaches aimed at the human brain make it possible to profile the expression of thyroid hormone regulators in single-cell RNA-Seq datasets of the developing human neocortex. The data provide novel insights into the specific cellular expression of thyroid hormone transporters, deiodinases, and receptors.

Thyroid Hormone Transporters in Pregnancy and Fetal Development

Thyroid hormone is essential for fetal (brain) development. Plasma membrane transporters control the intracellular bioavailability of thyroid hormone. In the past few decades, 15 human thyroid hormone transporters have been identified, and among them, mutations in monocarboxylate transporter (MCT)8 and organic anion transporting peptide (OATP)1C1 are associated with clinical phenotypes. Different animal and human models have been employed to unravel the (patho)-physiological role of thyroid hormone transporters. However, most studies on thyroid hormone transporters focus on postnatal development. This review summarizes the research on the thyroid hormone transporters in pregnancy and fetal development, including their substrate preference, expression and tissue distribution, and physiological and pathophysiological role in thyroid homeostasis and clinical disorders. As the fetus depends on the maternal thyroid hormone supply, especially during the first half of pregnancy, the review also elaborates on thyroid hormone transport across the human placental barrier. Future studies may reveal how the different transporters contribute to thyroid hormone homeostasis in fetal tissues to properly facilitate development. Employing state-of-the-art human models will enable a better understanding of their roles in thyroid hormone homeostasis.

AAV9-MCT8 Delivery at Juvenile Stage Ameliorates Neurological and Behavioral Deficits in a Mouse Model of MCT8-Deficiency.

Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.

Nicotine binds to the transthyretin-thyroxine complex and reduces its uptake by placental trophoblasts

BackgroundA supply of maternal thyroid hormone (thyroxine, T4) is essential for normal human fetal development. Human placental trophoblasts synthesize, secrete and take up the T4 binding protein transthyretin, providing a route for maternal T4 to enter the placenta. Transthyretin is also involved in T4 transport in other tissues such as the brain choroid plexus. Nicotine alters transthyretin synthesis and function in rat choroid plexus. If nicotine influences trophoblast turnover of transthyretin, then it may directly affect placental transfer of T4 to the developing fetus and contribute to the negative impacts of smoking on fetal growth, development and placental function. MethodsThe effect of nicotine on trophoblast uptake of Alexa-labelled transthyretin was measured using live cell imaging. The effect of nicotine on protein expression was measured by western blotting. Interactions between transthyretin, T4 and nicotine were investigated using chemical cross-linking techniques and molecular dynamic simulations. ResultsNicotine blocks uptake of transthyretin-T4 by human placental trophoblast cells. Nicotine reduces the expression of the trophoblast scavenger receptor class B type 1 (SR-B1) that plays a role in transthyretin-T4 uptake. Molecular dynamic modelling suggests that when T4 is bound to transthyretin, nicotine binding increases tetramer stability, reducing the ability of the transthyretin-T4 complex to enter trophoblast cells. ConclusionOur data suggest that nicotine exposure during pregnancy reduces transplacental transport of transthyretin and T4 to the placenta and developing fetus. This may contribute to the negative effects of smoking on fetal growth, development and pregnancy viability.

Enhanced re-myelination in transthyretin null mice following cuprizone mediated demyelination

Thyroid hormones (THs) impact nearly every tissue in the body, including the adult and developing central nervous system. The distribution of THs around the body is facilitated by specific TH distributor proteins including transthyretin (TTR). In addition to being produced in the liver, TTR is synthesized in the choroid plexus of the brain. The synthesis of TTR by choroid plexus epithelial cells allows transport of THs from the blood into the brain. Adequate supply of THs to the brain is required for developmental myelination of axons and the maintenance of mature myelin throughout adult life, essential for the proper conduction of nerve impulses. Insufficient THs in developing mice results in hypo-myelination (thinner myelin around axons). However, confounding evidence demonstrated that in developing brain of TTR null mice, hyper-myelination of axons was observed in the corpus callosum. This raised the question whether increased myelination occurs during re-myelination in the adult brain following targeted demyelination. To investigate the effect of TTR during re-myelination, cuprizone induced depletion of myelin in the corpus callosum of adult mice was initiated, followed by a period of myelin repair. Myelin thickness was measured to assess re-myelination rates for 6 weeks. TTR null mice displayed expedited rates of early re-myelination, preferentially re-myelinating smaller axons compared to those of wild type mice. Furthermore, TTR null mice produced thicker myelin than wild type mice during re-myelination. These results may have broader implications in understanding mechanisms governing re-myelination, particularly in potential therapeutic contexts for acquired demyelinating diseases such as multiple sclerosis.

Human type 1 Iodothyronine deiodinase (DIO1) mutations cause abnormal thyroid hormone metabolism

Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristic in vivo parameters are also present in Dio1 heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions: We report the identification and characterization of two missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.

Thyroid hormones during the perinatal period are necessary to respiratory network development of newborn rats

Thyroid hormones (THs) are essential for foetal brain development. Because the gestating mother is the main source of THs to the foetus, maternal hypothyroidism and/or premature birth compromise neurological outcomes in the offspring. Respiratory instability and recurrent apneas due to immaturity of the respiratory control network are major causes of morbidity in infants. Inadequate TH supply may be sufficient to delay perinatal maturation of the respiratory control system; however, this hypothesis remains untested. To address this issue, maternal hypothyroidism was induced by adding methimazole (MMI; 0.02% w/v) to the drinking water of pregnant dams from conception to postpartum day 4 (P4). The effect of TH supplementation on respiratory function was tested by injecting levothyroxine (L-T4) in newborns at P1. Respiratory function was assessed by plethysmography (in vivo) and recording of phrenic output from medullary preparations (in vitro). By comparison with controls, TH deficiency increased the frequency of apneas and decreased basal ventilation in vivo and prevented the age-dependent increase in phrenic burst frequency normally observed in vitro. The effects of TH deficiency on GABAergic modulation of respiratory activity were measured by bath application of muscimol (GABAA agonist) or bicuculline (GABAA antagonist). The phrenic burst frequency responses to GABAergic agents were consistently greater in preparations from TH deficient pups. L-T4 supplementation reversed part of the respiratory anomalies related to MMI treatment in vitro. We conclude that TH deficiency during the perinatal period is sufficient to delay maturation of the respiratory control network development. Excessive GABAergic inhibition may contribute to this effect.

Association between thyroid cysts and hypertension by atherosclerosis status: a cross-sectional study

Our recent studies indicate that thyroid cysts have clinical implications. Thyroid cysts could have a positive effect on the supply of thyroid hormones. Both hyperthyroidism and hypothyroidism cause hypertension. Hypothyroidism, but not hyperthyroidism, is a risk factor for atherosclerosis. Therefore, thyroid cysts could be associated with hypertension, and atherosclerosis might influence the association between thyroid cysts and hypertension. To evaluate the clinical significance of thyroid cysts, a cross-sectional study was conducted with 1801 Japanese aged 40–74 years. Thyroid cysts were significantly positively associated with hypertension in participants without atherosclerosis. However, there was a significant inverse association in those with atherosclerosis. The potential confounding factor adjusted odd ratios and 95% confidence intervals (95% CIs) were 1.49 (95% CI 1.17–1.90) for participants without atherosclerosis and 0.49 (95% CI 0.24–0.98) for those with atherosclerosis. The present study demonstrates that thyroid cysts have clinical implications because thyroid cysts support thyroid hormone activity. Our findings provide sufficient evidence to develop a risk assessment for hypertension for the general population, even though further research is required.

Involvement of Thyroid Hormones in Brain Development and Cancer.

Simple SummaryDevelopment and function of the mammalian brain clearly require precise regulation of gene expression at both the transcriptional and post-transcriptional level. Thyroid hormones have been recognized to play a fundamental role in these processes, by acting at multiple levels and in different brain cell types, through direct effects on transcription, mediated by nuclear receptors, and also by triggering transduction pathways at the plasma membrane. At the same time, due to their effects on proliferation, differentiation, and cell metabolism, thyroid hormones may have a critical role in different kinds of cancer, including brain cancer.The development and maturation of the mammalian brain are regulated by thyroid hormones (THs). Both hypothyroidism and hyperthyroidism cause serious anomalies in the organization and function of the nervous system. Most importantly, brain development is sensitive to TH supply well before the onset of the fetal thyroid function, and thus depends on the trans-placental transfer of maternal THs during pregnancy. Although the mechanism of action of THs mainly involves direct regulation of gene expression (genomic effects), mediated by nuclear receptors (THRs), it is now clear that THs can elicit cell responses also by binding to plasma membrane sites (non-genomic effects). Genomic and non-genomic effects of THs cooperate in modeling chromatin organization and function, thus controlling proliferation, maturation, and metabolism of the nervous system. However, the complex interplay of THs with their targets has also been suggested to impact cancer proliferation as well as metastatic processes. Herein, after discussing the general mechanisms of action of THs and their physiological effects on the nervous system, we will summarize a collection of data showing that thyroid hormone levels might influence cancer proliferation and invasion.

Maternal iodine status in a multi-ethnic UK birth cohort: associations with autism spectrum disorder

BackgroundMaternal iodine requirements increase during pregnancy to supply thyroid hormones essential for fetal brain development. Maternal iodine deficiency can lead to hypothyroxinemia, a reduced fetal supply of thyroid hormones which, in the first trimester, has been linked to an increased risk of autism spectrum disorder (ASD) in the child. No study to date has explored the direct link between maternal iodine deficiency and diagnosis of ASD in offspring.MethodsUrinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6955 mothers at 26–28 weeks gestation participating in the Born in Bradford (BiB) cohort. Maternal iodine status was examined in relation to the probability of a Read (CTV3) code for autism being present in a child’s primary care records through a series of logistic regression models with restricted cubic splines.ResultsMedian (inter-quartile range) UIC was 76 μg/L (46, 120) and I:Cr was 83 μg/g (59, 121) indicating a deficient population according to WHO guidelines. Ninety two children (1·3%) in our cohort had received a diagnosis of ASD by the census date. Overall, there was no evidence to support an association between I:Cr or UIC and ASD risk in children aged 8–12 years (p = 0·3).ConclusionsThere was no evidence of an increased clinical ASD risk in children born to mothers with mild-to-moderate iodine deficiency at 26 weeks gestation. Alternative functional biomarkers of exposure and a wider range of conditions may provide further insight.

Maternal Thyroid Anomalies and Risk of Attention Deficit Hyperactivity Disorder in Progeny

Background. The fetus is dependent on adequate maternal supply of thyroid hormones, which have important neurodevelopmental roles. Impaired thyroid function was linked with exposure to several environmental toxicants, and these thyroid-related effects may be a mechanism through which environmental toxicants affect neurodevelopment. Extreme maternal thyroid dyshomeostasis causes adverse neurodevelopmental effects, but impacts of subtler thyroid disruption remain unclear. We evaluated the risk of Attention Deficit Hyperactivity Disorder (ADHD) in children of mothers with thyroid anomalies, and the relation between gestational maternal thyroid hormone levels and child ADHD risk. Methods. The study included 445,477 singletons born in 1999-2012 in a large Israeli health fund, with data on ADHD diagnoses retrieved through 2019. Maternal thyroid conditions were ascertained through ICD-9 codes with subsequent validation through review of drug dispensing and laboratory data. ADHD cases were identified through ICD-9 codes, with additional information on dispensing of stimulants and nonstimulants medications. Analyses were performed using Cox proportional hazard and additive Poisson regression models employing a robust variance estimator. Results. Children of mothers who experienced hypothyroidism had a higher ADHD risk compared to children of mothers without thyroid conditions (HR=1.11, 95% C.I:1.07-1.15), with more robust results in the subgroup of ADHD children who also received pharmaceutical ADHD treatments. Hyperthyroidism results were less consistent. Results were materially unchanged when restricting to mothers gestationally treated with levothyroxine. Analysis of maternal gestational thyrotropin and free-thyroxine levels did not show consistent associations with ADHD risk. Conclusions. Maternal hypothyroidism was associated with increased child ADHD risk, but seemingly not due to direct effects of thyroid hormones. Instead, factors that influence maternal thyroid function may have etiologic roles in ADHD through pathways independent of maternal gestational thyroid hormones, and thus be unaffected by medication treatment. Environmental factors known to disrupt thyroid function should be examined for possible involvement in ADHD etiology.

Human Type 1 Iodothyronine Deiodinase (DIO1) Mutations Cause Abnormal Thyroid Hormone Metabolism.

Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristic in vivo parameters are also present in Dio1 heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions: We report the identification and characterization of two missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.