Talk:Endocrine - Thyroid Development

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Cite this page: Hill, M.A. (2021, October 21) Embryology Endocrine - Thyroid Development. Retrieved from

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A Practical Approach for the Verification and Determination of Site and Trimester Specific Reference Intervals for Thyroid Function Tests in Pregnancy

Thyroid. 2018 Dec 29. doi: 10.1089/thy.2018.0439. [Epub ahead of print]

Donovan LE Dr1, Metcalfe A2, Chin AC3, Yamamoto JM4, Virtanen H5, Johnson JA6, Krause R7. Author information Abstract BACKGROUND: Population, assay and trimester specific reference intervals for thyroid function tests are necessary to accurately assess thyroid status and manage thyroid disease throughout pregnancy. This study's objective was to verify if the manufacturer's recommended trimester specific reference intervals for thyroid tests and American Thyroid Association's recommended Total T4 (TT4) pregnancy reference intervals were verifiable and appropriate for use in our population.

METHODS: Blood samples were obtained from the following sources: stored frozen surplus blood from women undergoing routine aneuploidy screening (first and second trimester samples, n = 274), and women participating in an observational cohort study, (second and third trimester samples, n = 135) and blood collected from women presenting for assessment to the labour and delivery ward (third trimester samples n =35). Exclusions included thyroid medications or disease and positive thyroid peroxidase antibodies (anti-TPO). Samples were analyzed for thyrotropin (TSH), free thyroxine (FT4), triiodothyronine (FT3), TT4 and anti-TPO using the Roche Cobas 8000 Modular e602 electrochemiluminescence immunoassay.

RESULTS: Nine percent of the aneuploidy screening samples were excluded prior to thyroid testing due to maternal use of thyroid medications. Six percent of analyzed samples were excluded: 5.9% with positive anti-TPO and one with a TSH above 10 mIU/L. The manufacturer's recommended trimester specific reference intervals for TSH were not verified by described standardized methods. Therefore, 95th percentile reference intervals were determined using a minimum number of samples. Reference intervals for TSH and FT4 were as follows; 9-12 weeks: 0.18 - 2.99 mIU/L and 11 -19.2 pmol/L; second trimester: 0.11 - 3.98 mIU/L and 10.5 - 18.2 pmol/L; and third trimester 0.48 - 4.71 mIU/L and 9.0 - 16.1 pmol/L respectively. The TT4 reference interval after 19 weeks gestation was 77 - 186 nmol/L.

CONCLUSIONS: Our study provides a simple approach to verify or establish trimester specific thyroid function reference intervals in local populations. Our TT4 reference interval was lower than the interval proposed by the American Thyroid Association, suggesting the need for further study of TT4 in pregnancy and reliance on locally established FT4 reference intervals after 19 weeks especially when there are no equivalent reference intervals for TT4.

PMID: 30595114 DOI: 10.1089/thy.2018.0439

A branching morphogenesis program governs embryonic growth of the thyroid gland

Development. 2018 Jan 25;145(2). pii: dev146829. doi: 10.1242/dev.146829.

Liang S1, Johansson E1, Barila G2, Altschuler DL2, Fagman H1,3, Nilsson M4.


The developmental program that regulates thyroid progenitor cell proliferation is largely unknown. Here, we show that branching-like morphogenesis is a driving force to attain final size of the embryonic thyroid gland in mice. Sox9, a key factor in branching organ development, distinguishes Nkx2-1+ cells in the thyroid bud from the progenitors that originally form the thyroid placode in anterior endoderm. As lobes develop the thyroid primordial tissue branches several generations. Sox9 and Fgfr2b are co-expressed distally in the branching epithelium prior to folliculogenesis. The thyroid in Fgf10 null mutants has a normal shape but is severely hypoplastic. Absence of Fgf10 leads to defective branching and disorganized angiofollicular units although Sox9/Fgfr2b expression and the ability of cells to differentiate and form nascent follicles are not impaired. These findings demonstrate a novel mechanism of thyroid development reminiscent of the Fgf10-Sox9 program that characterizes organogenesis in classical branching organs, and provide clues to aid understanding of how the endocrine thyroid gland once evolved from an exocrine ancestor present in the invertebrate endostyle. KEYWORDS: Differentiation; Fgf10; Growth; Mouse; Progenitor; Sox9; Thyroid

PMID: 29361553 DOI: 10.1242/dev.146829


Development of the thyroid gland

Development. 2017 Jun 15;144(12):2123-2140. doi: 10.1242/dev.145615.

Nilsson M1, Fagman H2,3.


Thyroid hormones are crucial for organismal development and homeostasis. In humans, untreated congenital hypothyroidism due to thyroid agenesis inevitably leads to cretinism, which comprises irreversible brain dysfunction and dwarfism. Elucidating how the thyroid gland - the only source of thyroid hormones in the body - develops is thus key for understanding and treating thyroid dysgenesis, and for generating thyroid cells in vitro that might be used for cell-based therapies. Here, we review the principal mechanisms involved in thyroid organogenesis and functional differentiation, highlighting how the thyroid forerunner evolved from the endostyle in protochordates to the endocrine gland found in vertebrates. New findings on the specification and fate decisions of thyroid progenitors, and the morphogenesis of precursor cells into hormone-producing follicular units, are also discussed. © 2017. Published by The Company of Biologists Ltd.

KEYWORDS: Endoderm; Evolution; Morphogenesis; Neural crest; Pharyngeal; Thyroid PMID 28634271 DOI: 10.1242/dev.145615


Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study

Lancet Diabetes Endocrinol. 2016 Jan;4(1):35-43. doi: 10.1016/S2213-8587(15)00327-7. Epub 2015 Oct 20.

Korevaar TI1, Muetzel R2, Medici M1, Chaker L3, Jaddoe VW4, de Rijke YB5, Steegers EA6, Visser TJ3, White T7, Tiemeier H8, Peeters RP3.


BACKGROUND: Thyroid hormone is involved in the regulation of early brain development. Since the fetal thyroid gland is not fully functional until week 18-20 of pregnancy, neuronal migration and other crucial early stages of intrauterine brain development largely depend on the supply of maternal thyroid hormone. Current clinical practice mostly focuses on preventing the negative consequences of low thyroid hormone concentrations, but data from animal studies have shown that both low and high concentrations of thyroid hormone have negative effects on offspring brain development. We aimed to investigate the association of maternal thyroid function with child intelligence quotient (IQ) and brain morphology. METHODS: In this population-based prospective cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), we investigated the association of maternal thyroid function with child IQ (assessed by non-verbal intelligence tests) and brain morphology (assessed on brain MRI scans). Eligible women were those living in the study area at their delivery date, which had to be between April 1, 2002, and Jan 1, 2006. For this study, women with available serum samples who presented in early pregnancy (<18 weeks) were included. Data for maternal thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies (at weeks 9-18 of pregnancy), and child IQ (assessed at a median of 6·0 years of age [95% range 5·6-7·9 years]) or brain MRI scans (done at a median of 8·0 years of age [6·2-10·0]) were obtained. Analyses were adjusted for potential confounders including concentrations of human chorionic gonadotropin and child thyroid-stimulating hormone and free thyroxine. FINDINGS: Data for child IQ were available for 3839 mother-child pairs, and MRI scans were available from 646 children. Maternal free thyroxine concentrations showed an inverted U-shaped association with child IQ (p=0·0044), child grey matter volume (p=0·0062), and cortex volume (p=0·0011). For both low and high maternal free thyroxine concentrations, this association corresponded to a 1·4-3·8 points reduction in mean child IQ. Maternal thyroid-stimulating hormone was not associated with child IQ or brain morphology. All associations remained similar after the exclusion of women with overt hypothyroidism and overt hyperthyroidism, and after adjustment for concentrations of human chorionic gonadotropin, child thyroid-stimulating hormone and free thyroxine or thyroid peroxidase antibodies (continuous or positivity). INTERPRETATION: Both low and high maternal free thyroxine concentrations during pregnancy were associated with lower child IQ and lower grey matter and cortex volume. The association between high maternal free thyroxine and low child IQ suggests that levothyroxine therapy during pregnancy, which is often initiated in women with subclinical hypothyroidism during pregnancy, might carry the potential risk of adverse child neurodevelopment outcomes when the aim of treatment is to achieve high-normal thyroid function test results. FUNDING: The Netherlands Organisation for Health Research and Development (ZonMw) and the European Community's Seventh Framework Programme. Copyright © 2016 Elsevier Ltd. All rights reserved. Comment in Maternal thyroid function and child IQ. [Lancet Diabetes Endocrinol. 2016] Pregnancy: Maternal thyroid function in pregnancy - a tale of two tails. [Nat Rev Endocrinol. 2016] Defining and achieving normal thyroid function during pregnancy. [Lancet Diabetes Endocrinol. 2016] Maternal thyroid function and child IQ - Authors' reply. [Lancet Diabetes Endocrinol. 2016] PMID 26497402

Maternal thyroid function in pregnancy - a tale of two tails

Nat Rev Endocrinol. 2016 Jan;12(1):10-1. doi: 10.1038/nrendo.2015.212. Epub 2015 Dec 4.

Stagnaro-Green A, Rovet J.

  • Maternal levels of free T4 during pregnancy correlate with their offspring's IQ, cortex volume and grey matter volume

• Both the upper and lower limits of normal maternal levels of free T4 during pregnancy are associated with reduced child IQ, as well as decreased child cortex and grey matter volume • Maternal levels of TSH during pregnancy are not associated with child IQ or child brain morphology

Erratum PMID 26678810

PMID 26635112

Thyroid follicle development requires Smad1/Smad5- and endothelial-dependent basement membrane assembly

Development. 2016 Apr 11. pii: dev.134171. [Epub ahead of print]

Villacorte M1, Delmarcelle AS1, Lernoux M1, Bouquet M1, Lemoine P1, Bolsée J1, Umans L2, de Sousa Lopes SC3, Van Der Smissen P1, Sasaki T4, Bommer G1, Henriet P1, Refetoff S5, Lemaigre FP1, Zwijsen A6, Courtoy PJ1, Pierreux CE7.


Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. Developmental mechanisms whereby follicles are formed by reorganization of a non-structured mass of non-polarized epithelial cells (folliculogenesis) largely unknown. Here we show that assembly of the epithelial basement membrane is critical for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes. Thyroid-specific double Smad1 and Smad5 knockout mice (Smad1/5dKO) displayed growth retardation, hypothyroidism and defective follicular architecture. In Smad1/5dKO embryonic thyroids, epithelial cells remained associated in large clusters and formed small follicles. Although similar follicular defects are found in VegfaKO thyroids, Smad1/5dKO thyroids had normal endothelial cell density yet impaired endothelial differentiation. Interestingly, both VegfaKO and Smad1/5dKO thyroids displayed impaired basement membrane assembly. Furthemore, conditioned medium (CM) from embryonic endothelial progenitor cells (eEPC) rescued the folliculogenic defects of both Smad1/5dKOand VegfaKOthyroids. Laminin α1β1γ1, abundantly released by eEPC into CM, was critically required for folliculogenesis. Thus, epithelial Smad signaling and endothelial cell invasion promote folliculogenesis via assembly of the basement membrane. © 2016. Published by The Company of Biologists Ltd. PMID 27068110


Pyramidal lobe of the thyroid gland and the thyroglossal duct remnant: a study using human fetal sections

Ann Anat. 2015 Jan;197:29-37. doi: 10.1016/j.aanat.2014.09.001. Epub 2014 Oct 22.

Takanashi Y1, Honkura Y2, Rodriguez-Vazquez JF3, Murakami G4, Kawase T5, Katori Y2.


To investigate developmental changes in the thyroglossal duct, we observed serial sagittal sections of eight embryos (crown-rump length (CRL) 6-12 mm; approximately 5-6 weeks of gestation) as well as serial horizontal or cross-sections of 70 embryos and fetuses (CRL 15-110 mm; 6-15 weeks). In the sagittal sections, the thyroglossal duct was identified as a small sheet or mass of relatively large cells with vacuolization anterior, superior or inferior to the fourth pharyngeal arch artery. However, we found no continuous duct-like structure that reached the thyroid gland. Thus, previous classical schemes might have overestimated the continuity of the duct. Among cross-sections of 70 specimens, we found the thyroglossal duct remnant in only two specimens (CRL 15 mm and 100 mm), in contrast to the pyramidal lobe, which was seen in one-third of the specimens. The duct remnant ran downward along the lateral edge of the hyoid body to reach the anterior aspect of the thyroid cartilage. However, the connection between the pyramidal lobe and the duct remnant was interrupted by the anterior cervical muscles. Therefore, it was unlikely that the thyroglossal duct remnant would more frequently be evident in fetuses than in adults. The highly tortuous course of the duct along the lingual aspect of the hyoid body, which has been reported previously, appeared to become established near term. Descent of the thyroid gland was not evident after the CRL 20 mm stage (6 weeks): the gland appeared to retain its position at the level of the third-sixth cervical vertebrae. Copyright © 2014 Elsevier GmbH. All rights reserved. KEYWORDS: Development; Human embryo; Pyramidal lobe; Thyroglossal duct; Thyroid gland PMID 25458181


Gestational doxorubicin alters fetal thyroid-brain axis

Int J Dev Neurosci. 2013 Apr;31(2):96-104. doi: 10.1016/j.ijdevneu.2012.11.005. Epub 2012 Nov 23.

Ahmed RG, Incerpi S. Source Division of Anatomy and Embryology, Zoology Department, Faculty of Science, Beni-Suef University, Egypt. Electronic address:


Administration of chemotherapy during pregnancy may represent a big risk factor for the developing brain, therefore we studied whether the transplacental transport of doxorubicin (DOX) may affect the development of neuroendocrine system. DOX (25mg/kg; 3 times interaperitoneally/week) was given to pregnant rats during whole gestation period. The disturbances in neuroendocrine functions were investigated at gestation day (GD) 15 and 20 by following the maternal and fetal thyroid hormone levels, fetal nucleotides (ATP, ADP, AMP) levels and adenosine triphosphatase (Na(+), K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) activities in two brain regions, cerebrum and cerebellum. In control group, the levels of maternal and fetal serum thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and fetal serum growth hormone (GH) increased from days 15 to 20, whereas in the DOX group, a decrease in maternal and fetal T4, T3 and increase in TSH levels (hypothyroid status) were observed. Also, the levels of fetal GH decreased continuously from GD 15 to 20 with respect to control group. In cerebrum and cerebellum, the levels of fetal nucleotides and the activities of fetal ATPases in control group followed a synchronized course of development. The fetal hypothyroidism due to maternal administration of DOX decreased the levels of nucleotides, ATPases activities, and total adenylate, instead, the adenylate energy charge showed a trend to an increase in both brain regions at all ages tested. These alterations were dose- and age-dependent and this, in turn, may impair the nerve transmission. Finally, DOX may act as neuroendocrine disruptor causing hypothyroidism and fetal brain energetic dysfunction. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

PMID: 23183240


Periconceptional changes in thyroid function: a longitudinal study

Reprod Biol Endocrinol. 2012 Mar 21;10:20.

Balthazar U, Steiner AZ. Source Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.


ABSTRACT: BACKGROUND: Limitations in our current knowledge of normative physiologic changes in thyroid function during the periconception window narrow our ability to establish an optimal approach to screening and diagnosis of thyroid disease in pregnant women. The objective of this study was to characterize changes in thyroid function during the transition from the pre-pregnant to pregnant state in normal fertile women. METHODS: Women (N = 60) ages 30-42 years without a history of thyroid disease, who were planning pregnancy, were observed prospectively before and during early pregnancy. Thyroid function (thyroid stimulating hormone, TSH and free thyroxine, FT4) was measured before conception and between 6 and 9 weeks gestation. Pre-pregnancy samples were analyzed for thyroid antibodies. Bivariate analyses and longitudinal curves (general estimating equation models) were used to analyze changes in thyroid function during the periconception window by antibody status. RESULTS: Pre-pregnancy TSH values were significantly higher than early pregnancy TSH (p < 0.001), but FT4 values did not differ (p = 0.53). TSH declined as gestational age increased (P < 0.01). Thyroid antibody positive women had a higher pre-pregnancy TSH compared to antibody negative women (p < 0.01). Periconceptional change in thyroid function was more variable among women with antibodies (p < 0.001). 50% of women with elevated pre-pregnancy TSH values (TSH > 3.0 mIU/L) had normal TSH values (TSH < 2.5 mIU/L) in pregnancy. CONCLUSIONS: TSH values decline during the transition from pre-pregnancy to early pregnancy. The change in TSH appears to be less predictable in women with thyroid antibodies. Periconceptional changes in thyroid function should be considered in formulating prenatal thyroid screening guidelines.

PMID 22436200


Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy?

J Thyroid Res. 2011;2011:342189. Epub 2011 Sep 11.

Hartoft-Nielsen ML, Boas M, Bliddal S, Rasmussen AK, Main K, Feldt-Rasmussen U. Source Department of Medical Endocrinology PE-2131, Rigshospitalet, University Hospital of Copenhagen, 2100 Copenhagen, Denmark.


Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals-endocrine disrupting chemicals (EDCs)-has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce.

PMID 21918727 PMC3170895

Thyroidology over the ages

Indian J Endocrinol Metab. 2011 Jul;15(Suppl 2):S121-6.

Niazi AK, Kalra S, Irfan A, Islam A. Source Shifa College of Medicine, Islamabad, Pakistan.


Thyroidolody, the study of the thyroid gland, is considered to be a relatively new field of endocrinology. However, references to the thyroid gland and its diseases can be seen in the literature of ancient Greek, Indian and Egyptian medicine. Goiter has always been a disease of immense interest of the general population due to its widespread prevalence. It is one of the most common medical problems portrayed in ancient paintings. Owing to the lack of awareness and poor nutritious habits of the people in that era, diseases such as iodine deficiency goiter were common. Physicians, healers and philosophers had been attempting time and again until the 19(th) century to come up with explanations of the thyroid gland and provide a reasonable basis of its diseases. Although the discovery of thyroid gland, its structure, function and diseases has been accredited to modern scientists who presented their work mostly in the 19(th) and 20(th) century, it is of significance to note that much of what we discovered in the 19(th) and 20(th) century had already been known centuries ago. This review attempts to explain the knowledge of thyroid gland, its function and diseases as held by the people in the previous centuries; and how this knowledge evolved over the years to become what it is today.

PMID 21966648

Levothyroxine treatment in pregnancy: indications, efficacy, and therapeutic regimen

J Thyroid Res. 2011;2011:843591. Epub 2011 Aug 25.

Klubo-Gwiezdzinska J, Burman KD, Van Nostrand D, Wartofsky L. Source Section of Endocrinology, Department of Medicine, Washington Hospital Center, Washington, DC 20010, USA.


The prevalence of overt and subclinical hypothyroidism during pregnancy is estimated to be 0.3-0.5% and 2-3%, respectively. Thyroid autoantibodies are found in 5-18% of women in the childbearing age. The aim of this review is to underscore the clinical significance of these findings on the health of both the mother and her offspring. Methods of evaluation of thyroid function tests (TFTs) during pregnancy are described as are the threshold values for the diagnosis of overt and subclinical hypothyroidism or hypothyroxinemia. Anticipated differences in TFTs in iodine-sufficient and iodine-deficient areas are discussed and data are provided on potential complications of hypothyroidism/hypothyroxinemia and autoimmune thyroid disease during pregnancy and adverse effects for the offspring. The beneficial effects of levothyroxine therapy on pregnancy outcomes and offspring development are discussed with a proposed treatment regimen and follow up strategy.

PMID 21876837

Identification of Novel Pax8 Targets in FRTL-5 Thyroid Cells by Gene Silencing and Expression Microarray Analysis

PLoS One. 2011;6(9):e25162. Epub 2011 Sep 23.

Di Palma T, Conti A, de Cristofaro T, Scala S, Nitsch L, Zannini M. Source Institute of Experimental Endocrinology and Oncology 'G. Salvatore' (IEOS), National Research Council, Naples, Italy.


BACKGROUND: The differentiation program of thyroid follicular cells (TFCs), by far the most abundant cell population of the thyroid gland, relies on the interplay between sequence-specific transcription factors and transcriptional coregulators with the basal transcriptional machinery of the cell. However, the molecular mechanisms leading to the fully differentiated thyrocyte are still the object of intense study. The transcription factor Pax8, a member of the Paired-box gene family, has been demonstrated to be a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well-characterized with respect to its role in regulating genes involved in thyroid differentiation, genomics approaches aiming at the identification of additional Pax8 targets are lacking and the biological pathways controlled by this transcription factor are largely unknown.

METHODOLOGY/PRINCIPAL FINDINGS: To identify unique downstream targets of Pax8, we investigated the genome-wide effect of Pax8 silencing comparing the transcriptome of silenced versus normal differentiated FRTL-5 thyroid cells. In total, 2815 genes were found modulated 72 h after Pax8 RNAi, induced or repressed. Genes previously reported to be regulated by Pax8 in FRTL-5 cells were confirmed. In addition, novel targets genes involved in functional processes such as DNA replication, anion transport, kinase activity, apoptosis and cellular processes were newly identified. Transcriptome analysis highlighted that Pax8 is a key molecule for thyroid morphogenesis and differentiation.

CONCLUSIONS/SIGNIFICANCE: This is the first large-scale study aimed at the identification of new genes regulated by Pax8, a master regulator of thyroid development and differentiation. The biological pathways and target genes controlled by Pax8 will have considerable importance to understand thyroid disease progression as well as to set up novel therapeutic strategies.

PMID 21966443

Hes1 Is Required for Appropriate Morphogenesis and Differentiation during Mouse Thyroid Gland Development

PLoS One. 2011 Feb 25;6(2):e16752.

Carre A, Rachdi L, Tron E, Richard B, Castanet M, Schlumberger M, Bidart JM, Szinnai G, Polak M.

INSERM U845, Université Paris-Descartes, Paris, France.


Notch signalling plays an important role in endocrine development, through its target gene Hes1. Hes1, a bHLH transcriptional repressor, influences progenitor cell proliferation and differentiation. Recently, Hes1 was shown to be expressed in the thyroid and regulate expression of the sodium iodide symporter (Nis). To investigate the role of Hes1 for thyroid development, we studied thyroid morphology and function in mice lacking Hes1. During normal mouse thyroid development, Hes1 was detected from E9.5 onwards in the median anlage, and at E11.5 in the ultimobranchial bodies. Hes1(-/-) mouse embryos had a significantly lower number of Nkx2-1-positive progenitor cells (p<0.05) at E9.5 and at E11.5. Moreover, Hes1(-/-) mouse embryos showed a significantly smaller total thyroid surface area (-40 to -60%) compared to wild type mice at all study time points (E9.5-E16.5). In both Hes1(-/-) and wild type mouse embryos, most Nkx2-1-positive thyroid cells expressed the cell cycle inhibitor p57 at E9.5 in correlation with low proliferation index. In Hes1(-/-) mouse embryos, fusion of the median anlage with the ultimobranchial bodies was delayed by 3 days (E16.5 vs. E13.5 in wild type mice). After fusion of thyroid anlages, hypoplastic Hes1(-/-) thyroids revealed a significantly decreased labelling area for T4 (-78%) and calcitonin (-65%) normalized to Nkx2-1 positive cells. Decreased T4-synthesis might be due to reduced Nis labelling area (-69%). These findings suggest a dual role of Hes1 during thyroid development: first, control of the number of both thyrocyte and C-cell progenitors, via a p57-independent mechanism; second, adequate differentiation and endocrine function of thyrocytes and C-cells.

PMID 21364918

Why is the thyroid so prone to autoimmune disease?

Horm Res Paediatr. 2011;75(3):157-65. Epub 2011 Feb 22.

Saranac L, Zivanovic S, Bjelakovic B, Stamenkovic H, Novak M, Kamenov B. Source Pediatric Clinic, University Clinical Center, Nis, Serbia.


The thyroid gland plays a major role in the human body; it produces the hormones necessary for appropriate energy levels and an active life. These hormones have a critical impact on early brain development and somatic growth. At the same time, the thyroid is highly vulnerable to autoimmune thyroid diseases (AITDs). They arise due to the complex interplay of genetic, environmental, and endogenous factors, and the specific combination is required to initiate thyroid autoimmunity. When the thyroid cell becomes the target of autoimmunity, it interacts with the immune system and appears to affect disease progression. It can produce different growth factors, adhesion molecules, and a large array of cytokines. Preventable environmental factors, including high iodine intake, selenium deficiency, and pollutants such as tobacco smoke, as well as infectious diseases and certain drugs, have been implicated in the development of AITDs in genetically predisposed individuals. The susceptibility of the thyroid to AITDs may come from the complexity of hormonal synthesis, peculiar oligoelement requirements, and specific capabilities of the thyroid cell's defense system. An improved understanding of this interplay could yield novel treatment pathways, some of which might be as simple as identifying the need to avoid smoking or to control the intake of some nutrients. Copyright © 2011 S. Karger AG, Basel.

PMID 21346360


Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity

Cereb Cortex. 2010 Jun;20(6):1462-75. Epub 2009 Oct 7.

Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM.

Instituto de Neurociencias, Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas, Sant Joan d'Alacant, Alicante, Spain. Abstract Hypothyroxinemia affects 35-50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers' organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

PMID 19812240

Surgical anatomy of the thyroid and parathyroid glands

Otolaryngol Clin North Am. 2010 Apr;43(2):221-7, vii.

Fancy T, Gallagher D 3rd, Hornig JD.

Department of Otolaryngology-Head & Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA. Abstract This article describes the anatomy and embryology of the thyroid and parathyroid glands and the recurrent laryngeal nerve, discussing how the anatomy affects function and dysfunction of the glands.

PMID 20510710


Thyroid dysfunction and kidney disease

Eur J Endocrinol. 2009 Apr;160(4):503-15. Epub 2008 Dec 18.

Iglesias P, Díez JJ.

Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar, Madrid, Spain. Abstract Thyroid hormones (TH) are essential for an adequate growth and development of the kidney. Conversely, the kidney is not only an organ for metabolism and elimination of TH, but also a target organ of some of the iodothyronines' actions. Thyroid dysfunction causes remarkable changes in glomerular and tubular functions and electrolyte and water homeostasis. Hypothyroidism is accompanied by a decrease in glomerular filtration, hyponatremia, and an alteration of the ability for water excretion. Excessive levels of TH generate an increase in glomerular filtration rate and renal plasma flow. Renal disease, in turn, leads to significant changes in thyroid function. The association of different types of glomerulopathies with both hyper- and hypofunction of the thyroid has been reported. Less frequently, tubulointerstitial disease has been associated with functional thyroid disorders. Nephrotic syndrome is accompanied by changes in the concentrations of TH due primarily to loss of protein in the urine. Acute kidney injury and chronic kidney disease are accompanied by notable effects on the hypothalamus-pituitary-thyroid axis. The secretion of pituitary thyrotropin (TSH) is impaired in uremia. Contrary to other non-thyroidal chronic disease, in uraemic patients it is not unusual to observe the sick euthyroid syndrome with low serum triodothyronine (T(3)) without elevation of reverse T(3) (rT(3)). Some authors have reported associations between thyroid cancer and kidney tumors and each of these organs can develop metastases into the other. Finally, data from recent research suggest that TH, especially T(3), can be considered as a marker for survival in patients with kidney disease.

PMID 19095779

Early thyroid development requires a Tbx1-Fgf8 pathway.

Dev Biol. 2009 Apr 1;328(1):109-17. Epub 2009 Jan 20.

Lania G, Zhang Z, Huynh T, Caprio C, Moon AM, Vitelli F, Baldini A.

Telethon Institute of Genetics and Medicine, and University Federico II, Naples, Italy. Abstract The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. The many derivatives of the pharyngeal apparatus develop at similar times and sometimes from common cell types, explaining why many syndromic disorders express multiple birth defects affecting different structures that share a common pharyngeal origin. Thus, different derivatives may share common genetic networks during their development. Tbx1, the major gene associated with DiGeorge syndrome, is a key player in the global development of the pharyngeal apparatus, being required for virtually all its derivatives, including the thyroid. Here we show that Tbx1 regulates the size of the early thyroid primordium through its expression in the adjacent mesoderm. Because Tbx1 regulates the expression of Fgf8 in the mesoderm, we postulated that Fgf8 mediates critical Tbx1-dependent interactions between mesodermal cells and endodermal thyrocyte progenitors. Indeed, conditional ablation of Fgf8 in Tbx1-expressing cells caused an early thyroid phenotype similar to that of Tbx1 mutant mice. In addition, expression of an Fgf8 cDNA in the Tbx1 domain rescued the early size defect of the thyroid primordium in Tbx1 mutants. Thus, we have established that a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid.

PMID 19389367

Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review.

Zimmermann MB. Am J Clin Nutr. 2009 Feb;89(2):668S-72S. Epub 2008 Dec 16. Review. PMID 19088150


Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton

Bone. 2008 Nov;43(5):921-30. doi: 10.1016/j.bone.2008.06.020. Epub 2008 Jul 17.

Capelo LP1, Beber EH, Huang SA, Zorn TM, Bianco AC, Gouveia CH.


Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To study this, pregnant mice were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved up to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocytes, in addition to a slight delay in endochondral and intramembranous ossification. This suggests that up to E16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly ( approximately 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast, D2 mRNA expression increased significantly by E18.5 and markedly ( approximately 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development.

  • during development serum thyroid hormone levels are low and tissue concentration of thyroid hormone can be modified by the iodothyronine deiodinases
  • While the type II deiodinase (D2) activates T4 to T3, the type III deiodinase (D3) inactivates T4 to rT3 and T3 to T2 in a tissue- and time-specific fashion.

PMID 18682303

Classification and etiology of congenital hypothyroidism

Classification Etiology
Primary Thyroid dysgenesis (developmental anomaly)

Thyroid dyshormonogenesis (impaired hormone production)

Resistance to TSH binding or signaling

Central Isolated TSH deficiency

Thyrotropin-releasing hormone deficiency

Thyrotropin-releasing hormone resistance

Deficiency in pituitary development transcription factors

Peripheral Resistance to thyroid hormone

Abnormalities of thyroid hormone transport

Syndromic Pendred syndrome

Bamforth-Lazarus syndrome

Ectodermal dysplasia


Kocher - Deber - Semilange syndrome

Benign chorea - hypothyroidism


Obesity - colitis

Transient Maternal intake of antithyroid drugs

Transplacental passage of maternal TSH receptor blocking antibodies

Maternal and neonatal iodine deficiency or excess

Heterozygous mutations of THOX2 or DUOXA2

Congenital hepatic hemangioma/hemangioendothelioma

Based on Table 3 from review on congenital hypothyroidism.[1]

Transthyretin - (TTR, prealbumin) the serum protein which acts as a major carrier of thyroid hormones in the blood.

The protein can also bind plasma retinol-binding protein and may therefore regulate retinoid availability.

Links: OMIM - Transthyretin

Maternal Abnormalities

File:10.1371 journal.pmed.0020370.g002-M.jpg (A) Normal

(B) Graves disease: diffuse increased uptake in both thyroid lobes.

(C) Toxic multinodular goiter (TMNG): “hot” and “cold” areas of uneven uptake.

(D) Toxic adenoma: increased uptake in a single nodule with suppression of the surrounding thyroid.

(E) Thyroiditis: decreased or absent uptake.

Image: Perros P. Thyrotoxicosis and pregnancy. PLoS Med. 2005 Dec;2(12):e370.

Thyroid Uptake Scans (Technetium 99)  

Maternal Graves Disease - "The dose of anti-thyroid drug usually needs to be decreased during pregnancy, and often Graves disease remits completely and the medication can be withdrawn. This is probably due to the overall immunosuppressive effect of pregnancy." (Perros P. Thyrotoxicosis and pregnancy. PLoS Med. 2005 Dec;2(12):e370.)

Graves' disease in mothers can cause thyrotoxic fetus - may have increased fetal motility and develop a range of abnormalities including: goitre, tachycardia, heart failure associated hydrops, growth retardation, craniosynostosis and accelerated bone maturation.

Maternal Hashimoto's Thyroiditis (common autoimmune thyroid disease) usually no consequences on fetal thyroid, even if antibodies (anti-TPO and anti-Tg) found in the newborn due to transplacental passage.

maternal hypothyroxinemia

Links: NIH Genes & Disease - Chapter 41 - Endocrine | EPA (USA) - Radiation Technetium

External Links

  1. <pubmed>20537182</pubmed>| Orphanet J Rare Dis.