1

REVIEW

Thyroid hormones and fetal neurological development

J Patel1,2, K Landers2, H Li2, R H Mortimer1,2,3 and K Richard1,2
1
School of Medicine, The University of Queensland, Herston, 4006 Brisbane, Queensland, Australia
2
Conjoint Endocrine Laboratory, Queensland Institute of Medical Research, Bancroft Centre, Royal Brisbane and Women’s Hospital, 300 Herston Road, Herston,
4029 Brisbane, Queensland, Australia
3
Disciplines of Medicine, Obstetrics and Gynaecology, The University of Queensland, Herston, 4006 Brisbane, Queensland, Australia
(Correspondence should be addressed to J Patel at Conjoint Endocrine Laboratory, Queensland Institute of Medical Research, Bancroft Centre, Royal Brisbane
and Women’s Hospital; Email: [email protected])

Abstract
The development of fetal thyroid function is dependent on such as the cerebral cortex at specific developmental stages.
the embryogenesis, differentiation, and maturation of the There are many known cell membrane thyroid hormone
thyroid gland. This is coupled with evolution of the transporters in fetal brain that play an essential role in
hypothalamic–pituitary–thyroid axis and thyroid hormone regulating thyroid hormone concentrations in key structures.
metabolism, resulting in the regulation of thyroid hormone They also provide the route for intracellular thyroid
action, production, and secretion. Throughout gestation hormone interaction with associated thyroid hormone
there is a steady supply of maternal thyroxine (T4) which has receptors, which activate their action. There is a growing
been observed in embryonic circulation as early as 4 weeks body of experimental evidence from rats and humans to
post-implantation. This is essential for normal early fetal suggest that even mild maternal hypothyroxinemia may lead
neurogenesis. Triiodothyronine concentrations remain very to abnormalities in fetal neurological development. Our
low during gestation due to metabolism via placental and review will focus on the ontogeny of thyroid hormone in
fetal deiodinase type 3. T4 concentrations are highly fetal development, with a focus on cell membrane
regulated to maintain low concentrations, essential for transporters and TR action in the brain.
protecting the fetus and reaching key neurological sites Journal of Endocrinology (2011) 209, 1–8

Introduction (HPT) axis and thyroid hormone metabolism by liver and

brain deiodinase enzymes (deiodinase type 2 (D2) and
While the impaired mental and physical development of deiodinase type 3 (D3)) to ensure basal levels are sustained
inhabitants of the iodine-deficient Alps was recognized as (Zoeller et al. 2007)).
cretinism hundreds of years ago, the link between iodine The fetal thyroid gland reaches maturity by week 11–12,
deficiency, hypothyroidism, and impaired neurologic close to the end of the first trimester and begins to secrete
development was made very much later (Cranefield 1962, thyroid hormones by about week 16 (Obregon et al. 2007).
Morreale de Escobar et al. 2004). Thyroid hormones During this period, an adequate supply of maternal thyroid
(thyroxine (T4) and triiodothyronine (T3)) are essential for hormones must be sustained to ensure normal neurological
the development and maintenance of normal physiological development. Hypothyroid fetuses suffer various postnatal
processes, especially those of the central nervous system, disorders including mental retardation, deafness, and spasti-
where thyroid hormones assist in brain maturation through- city. Severe iodine deficiency, which causes both maternal and
out gestation (Joffe & Sokolov 1994, Neale et al. 2007). fetal hypothyroidism, is, worldwide, the most common cause
Thyroid hormones primarily regulate genes involved in of mental retardation (Glinoer 2001, Morreale de Escobar
myelination and neuronal\glial cell differentiation (Bernal et al. 2004, Pearce 2009). If thyroid hormone replacement
2005). Delivery of thyroid hormones to the fetal brain is a for congenital hypothyroid babies is not initiated soon after
complex process requiring, at different times, expression of birth, further impairment of cognitive development occurs.
brain thyroid hormone receptors (TRs), materno-fetal More recent evidence suggests that even mild reductions in
thyroid hormone and iodide transport, an intricate system maternal thyroid hormone levels in early pregnancy are
of endocrine feedback (the hypothalamic–pituitary–thyroid associated with reduced IQ in offspring (LaFranchi & Austin

Journal of Endocrinology (2011) 209, 1–8 DOI: 10.1530/JOE-10-0444

0022–0795/11/0209–001 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org
2 J PATEL and others . Thyroid hormone and neurological development

2007, Gyamfi et al. 2009). The molecular mechanisms by This emphasizes the need for maternal T4 levels to be
which thyroid hormones affect fetal neurological structures maintained to ensure normal fetal brain development. This
are still not well understood. This review will briefly discuss also explains why even minimally reduced maternal T4 levels
some current aspects of the role of thyroid hormones in fetal in early pregnancy can result in adverse outcomes to the
neurological development, focusing on TH transporters and offspring (Lavado-Autric et al. 2003, Auso et al. 2004).
receptor activation in the brain.

Deiodination of thyroid hormones

Ontogenesis of thyroid hormone action in fetal
development As mentioned above, locally generated T3 in the brain from
maternally transported T4 has been reported to be essential for
There is growing evidence that thyroid hormones act on normal early brain development (Zoeller 2010). Almost
embryological and fetal tissues early in development. Thyroid 80% of brain T3 is produced locally by D2 (Crantz et al. 1982).
hormone and associated receptors are already found in human D2 is found almost exclusively in astrocytes, whereas TRs
fetal tissues prior to the production and secretion of fetal are highly expressed in oligodendrocytes and neurons
thyroid hormones at 16–18 weeks of gestation, as evidenced (Guadano-Ferraz et al. 1997). In the fetal rat, D2 expression
by detection of T4 and T3 in the human cerebral cortex by is first seen at E16.5 and increases steadily until P15. In human
week 12 gestation (Calvo et al. 2002, Kester et al. 2004). This brain, D2 expression is first detectable in the cerebral cortex
is confirmation that active transport of maternal thyroid in the first trimester of pregnancy at the same time that T3 can
hormone across the placenta is occurring during this crucial be measured there (Chan et al. 2002). D2 is largely responsible
period of gestation and highlights the need for maternal for maintaining appropriate concentrations of T3 during fetal
thyroid hormones to be at optimal levels at that time (Fig. 1; brain development (Guadano-Ferraz et al. 1999). D2 knock-
Bernal 2007). Following onset of active T4 secretion by the out (KO) mice also demonstrate impaired cochlea and visual
fetus, levels of T4 in fetal tissues parallel those in fetal plasma. development, poor thermal regulation, reduced anxiety, and
T4 levels are, however, low, reflecting active type 3 crucially pituitary resistance to T4, further highlighting the
deiodination in the fetus (Ruiz de Ona et al. 1988, Obregon importance of D2 in developmental processes (Obregon et al.
et al. 2007). D3 converts T4 to the biologically inactive reverse 1991). In cases of hypothyroidism, D2 expression and activity
T3. In contrast to tissue T4 levels, T3 concentrations vary in are up-regulated, enhancing T3 supply, whereas in hyperthy-
different tissues, for example levels are low in fetal liver and roidism, the opposite is true (Burmeister et al. 1997).
plasma and high in brain and brown adipose tissue (Obregon Interestingly, however, a more recent study in D2KO mice
et al. 2007). These differences have been attributed to demonstrated that locomotor activity and learning and
variations in the activity of the D2, which converts T4 to memory skills were normal despite low local T3 generation
biologically active T3. This suggests an important role for T3 (Galton et al. 2007).
in brain developmental and maturation processes. D3 is also Raised brain levels of thyroid hormone in the fetus can also
active in placenta, ensuring the fetus is not exposed to cause neurological damage. D3 plays an important role in fetal
excessive amounts of maternal T4 (Galton 2005). neurological development by ensuring that safe levels of
Much of the information known about thyroid hormones thyroid hormones are maintained (Gereben et al. 2008). D3 is
and brain development has been derived from rodent highly expressed in neurons and in contrast to D2 is positively
experiments. As in humans, normal neurological develop- regulated by thyroid hormone. D3KO mice demonstrate
ment depends on thyroid hormone. TRs and deiodinase significant increases in perinatal mortality and an abnormal
enzymes are expressed in the early brain before the thyroid HPT axis (Hernandez et al. 2006, 2007). Furthermore, D3KO
gland develops (Obregon et al. 2007). The critical time period mice are born hypothyroid with impaired growth and fertility
for thyroid hormone action in rat brain is estimated to extend (Galton 2005). They exhibit excessive T3-responsive gene
from around embryonic day 18 (E18) to postnatal day 21–25 activation during development and reduced activation later in
(P21–25; Porterfield & Hendrich 1993). Abnormalities in life (Horn & Heuer 2010).
brain development in hypothyroid rats are mostly seen in the
postnatal period and are demonstrated by reduced maturation
of key structures such as the cerebellum, where delayed Thyroid hormone transporters in the brain
granular cell migration and Purkinje cell maturation are
prevented (Koibuchi et al. 2003). Although this may suggest Over the last decade, the notion of thyroid hormone uptake
that rat brain is more affected by thyroid hormone action after into cells by passive diffusion has been dismissed following the
birth, it should be recognized that TRs are seen very early in discovery of a number of thyroid hormone cell membrane
rat development (discussed below). Rat studies also indicate transporters. Thyroid hormones are amino acid derivatives,
that the developing brain is dependent on a supply of T4, and several classes of transmembrane transporter proteins can
which is locally deiodinated to T3, and that replacement with transport thyroid hormones, including organic anion
T3 does not adequately replenish brain T3 levels (Calvo et al. 1990). transporters 2 and 3 (Oatp2 and Oatp3), L-type amino acid

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 Thyroid hormone and neurological development . J PATEL and others 3

A Maternal thyroid hormone

Increasing D2 and T3 in cerebral cortex

T3 binding to brain nuclear receptors

Nuclear receptors in brain, liver, lung, kidney, etc.

Thyroid gland Thyroid hormone secretion

B
Neurological cretinism Myxedermatous cretinism

Maternal hypothyroxinemia Prematurity Congenital hypothyrodism

C
Striatum

Neocortex

Cerebellum, dentate gyrus granular cells

Cochlea

Myelination

Glial cell proliferation

Synapse formation

Axon and dendrite sprouting

Neuronal migration

Neuronal proliferation

0 5 10 15 20 25 30 35 40 1 2 3 4
Birth

Weeks Years
Figure 1 (A) The ontogeny of fetal thyroid function and expression of thyroid hormone receptors and deiodinase enzymes during gestation
and early years postnatal are demonstrated. (B) Critical time points during gestation that require thyroid hormone action for fetal
neurological development. Neurological abnormalities can be seen if maternal or fetal hypothyroidism is present during gestation. (C) Rodent
studies, where time-specific actions of thyroid hormones on precise neurological and auditory structures were observed. Adapted image from
Bernal (2007).

transporters (Lat1 and Lat2), and monocarboxylate transpor- Horn & Heuer 2010). The T4-binding protein, transthyretin,
ters 8 and 10 (MCT8 and MCT10) (Abe et al. 1998, Friesema produced in significant amounts by the choroid plexus, has
et al. 2001, 2003, 2008). For thyroid hormone to gain access been implicated in this transport, and transthyretin may be
to the brain during maturation, it must pass through many involved in delivery of CSF thyroid hormone to the brain
different cell types which express the various cell membrane (Patel et al. 2010). T4 transported to the brain via blood
transporters. For rodents, the preferred route of TH entry is circulation passes through endothelial cells and is taken up by
through the cerebral circulation and its blood–brain barrier, astrocytes, probably through the Oatp1c1 cell membrane
with some thyroid hormone entering the cerebrospinal transporter (Fig. 2; Hernandez et al. 2007). Within the
fluid (CSF) via the choroid plexus (Dratman et al. 1991, astrocyte, T4 is deionated via D2 to produce T3, which then

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4 J PATEL and others . Thyroid hormone and neurological development

T4

Oatp1c1

Nucleus

T4

D2 T2
T3
D3
Astrocyte T3
T 3 TR
A
MCT8 mRN

in
Neuron Prote

Figure 2 T4 is transported to the brain thyroid hormone-binding proteins such as transthyretin (TTR), where T4 then
passes out through endothelial cells lining the blood vessels. T4 is rapidly transported through the cell membrane
transporter, Oatp1c1, located on the surface of astrocytes. T4 is then metabolized intracellularly by D2 to T3, where it
can then be transported out from astrocytes by an as yet unidentified cell membrane transporter. Within the brain
parenchyma, T3 is then promptly uptaked by neurons and oligodendrocytes via the MCT8 cell membrane transporter.
Within the cell, T3 can either translocate and bind to thyroid hormone receptors (TRs), resulting in thyroid hormone
action, or be metabolized via D3 to biologically inactive T2.

exits the cell possibly via MCT8 (yet to be elucidated) and is MCT8 expression, cell surface translocation, and specific
taken up via MCT8 by oligodendrocytes and neurons (Fig. 2; substrate transport deficits, consequently producing a
Heuer et al. 2005). complete loss-of-function phenotype in patients (Kinne
In humans, the lack of MCT8 leads to greater neurological et al. 2009). MCT8 may transport other molecules essential
damage than in rodents, suggesting that other but as yet for brain maturation and which could explain the difference
undefined transporters are present in rodents. Lat2 has been between human and rodent brain maturation in the presence
proposed as a candidate, which although expressed in of MCT8 transporter mutations.
developing rat brain is not present in human developing
neurons (Wirth et al. 2009). In humans, the absence of the
MCT8 transporter (the Allan–Herndon–Dudley syndrome) TR genes and activity
results in X-linked moderate to severe mental retardation and
muscle hypotonia and hypoplasia (Dumitrescu et al. 2004, There are two TR genes (THRA and THRB), which encode
Friesema et al. 2004, Schwartz et al. 2005). Raised serum T3 for the four isotypes of TR (TRa1, TRb1, TRb2, and
concentrations and low T4 levels are present, but TSH levels TRb3) (Bernal 2007). The four isotypes all bind to T3 and
are normal suggesting a role for MCT8 in pituitary thyroid DNA and drive intracellular thyroid hormone action. Several
hormone uptake (Friesema et al. 2006). Patients also display isoforms of the TR from alternate RNA splicing are also seen.
altered and delayed maturation of myelination (Namba et al. Two of these are the TRa2 (c-erbAa2) and truncated TRb3
2008). More than two dozen MCT8 gene mutations have (DTRb3), which are known as nonreceptor proteins (Bassett
been reported linked to the X-chromosome (Friesema et al. et al. 2003). TRa2 has a conserved DNA-binding region but
2010). Almost all are missense mutations resulting in reduced is unable to bind T3. Conversely, DTRb3 is able to bind T3

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 Thyroid hormone and neurological development . J PATEL and others 5

but not to DNA. The physiological role of these nonreceptor rhombencephalon (Bradley et al. 1992). It is believed that the
proteins is still unknown (Forrest & Vennstrom 2000, O’Shea TRs found in these regions mediate the biological effects of T3
& Williams 2002, Bernal 2007). that has been locally generated from transported maternal T4,
TRs mediate their actions following homodimerization early in gestation. Conversely, TRb isoforms are expressed
or heterodimerization with retinoic acid receptors (RXR), more postnatally within specific neuronal populations such as
which then bind to specific sequences known as thyroid hippocampal pyramidal and granule cells, paraventricular
response elements (TREs) in the regulatory regions of target hypothalamic neurons, and cerebellar Purkinje cells (Bradley
genes (Wagner et al. 1995, Feng et al. 1998). A multitude of et al. 1989, Horn & Heuer 2010). Studies in TRb KO mice
transcription factors are involved. Without the presence of have shown that these isoforms are predominant in mediating
T3, the unliganded receptor (aporeceptor) recruits corepres- thyroid hormone effects on the development of the vision and
sors, such as nuclear receptor corepressors (NCoR) or auditory systems (Jones et al. 2003).
silencing mediator for retinoic and thyroid receptor There is a growing body of evidence suggesting that
(SMRT) and histone deacetylases, which retain the chromatin deficiencies in TR may not lead to abnormal brain
in a compact repressed position (Bernal 2007). However, in development as seen in hypothyroidism, which suggests that
the presence of T3, the binding of the hormone to TR the lack of the ligand (T3) is more detrimental than being TR
initiates transcription by the release of corepressors deficient (Bernal 2007). This has been demonstrated by Bernal
and recruiting coactivators (steroid receptor coactivators 1, et al. in TRa1 KO mice, which have normal cerebellar
SRC-1), histone acetylases (CREB-binding protein, CBP; development, even though the mice were hypothyroid
p300; and mammalian homolog of the yeast transcriptional (Morte et al. 2002). Another interesting study has demon-
activator GCN5, pCAF), and other mediators, all of which strated that TRa1 deletion did not affect cerebellar granule cell
assist in the access of transcription apparatus to the promoter migration during development, which is now known to take
regions (Fig. 3; Bernal 2007, Cheng et al. 2010). place in the absence of both receptor and T3 (Yacubova &
Both TR genes, THRA and THRB, are found within the Komuro 2002). It has been postulated by Bernal et al. that this
brain. In adult rat brain, more than 70–80% of all TRs result could well demonstrate that in vivo thyroid hormones are
present are in the TRa1 isoform. The receptor proteins are permissive when the TR are present, releasing any blocking
predominantly found in the cerebrum and cerebellum function that TR may be regulating (Bernal 2007). In contrast,
(Ercan-Fang et al. 1996). It has been postulated that the the absence of ligand could lead to aberrant receptor signaling,
TRa1 isoform also plays an important role during fetal brain which has been demonstrated with hypothyroid wild-type
development, both in humans and in rodents. This is animals with cell migration defects. This phenomenon has also
evidenced by detection in fetal rat brain of mRNA E11.5 been demonstrated using pheochromocytoma PC12 cells.
in the neural tube and E12.5 in the diencephalon and ventral When exposed to nerve growth factors, these cells differentiate
into neurons. Specifically, T3 has no effect on this process;
A Repression however, exogenous unliganded TRa1 will block this process
Corepressors T3 unless T3 is added to the culture medium (Munoz et al. 1993).
(CoR)
This has led to the hypothesis that the aporeceptor has
Transcriptional some transcriptional activity that may play an as yet unreco-
RXR TR machinery
gnized role in developmental processes. This also poses the
possibility of the aporeceptor possibly repressing specific
TRE
gene expression until T3 becomes available to the cells in a
B Activation time-specific manner.
Further analysis into the role of TR and brain development
Coactivators
(CoA) has been studied using mouse mutants expressing dominant
T3 Transcriptional
negative TR, where DNA binding is conserved with reduced
RXR TR machinery or absent T3-binding capacity. In two different models of
TRb mutant mice, impaired cerebellar Purkinje cell
TRE development and maturation and motor deficits were
observed, with cerebellar morphology similar to that seen
Figure 3 Schematic representation of thyroid hormone receptor in hypothyroidism (Forrest & Vennstrom 2000). This also
(TR) action. (A) Without the presence of the T3 ligand, corepressors
confirms the dominant role of TRb isoforms within the
(CoR) (nuclear receptor corepressors (NCoR) or silencing mediator
for retinoic and thyroid receptor (SMRT)) and histone deacetylases Purkinje cells of the brain. In TRa mutant models where
are recruited by TR to prevent transcription and translation of target T3-binding affinity was reduced by almost tenfold, mice
genes is demonstrated. (B) A bound TR with T3 results in the showed significant growth retardation and cardiac abnorm-
recruitment of coactivators (CoA) (steroid receptor coactivators 1, alities, with the heterozygous strain also demonstrating similar
SRC-1) and histone acetylases (CREB-binding protein, CBP; p300;
and mammalian homolog of the yeast transcriptional activator cerebellar abnormalities seen in hypothyroidism (Tinnikov
GCN5, pCAF) as well as the release of CoR, resulting in changes in et al. 2002). These mice also displayed striking anxiety-related
expression of target genes is demonstrated. behavior as evidenced by time spent motionless and reduced

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6 J PATEL and others . Thyroid hormone and neurological development

exploratory behavior compared to the wild-type controls Bassett JH, Harvey CB & Williams GR 2003 Mechanisms of thyroid
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mice strains are of particular interest, with additional work now
Bradley DJ, Young WS III & Weinberger C 1989 Differential expression of
being conducted in generating cell-specific TR mutant alpha and beta thyroid hormone receptor genes in rat brain and pituitary.
models (Quignodon et al. 2007, Flamant & Quignodon 2010). PNAS 86 7250–7254. (doi:10.1073/pnas.86.18.7250)
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Calvo R, Obregon MJ, Ruiz de Ona C, Escobar del Rey F & Morreale de
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relevant free thyroxine concentrations during early phases of development.
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ensuring normal fetal development is increasing. Knowledge jc.87.4.1768)
Chan S, Kachilele S, McCabe CJ, Tannahill LA, Boelaert K, Gittoes NJ,
of the key relationships between thyroid hormone and brain Visser TJ, Franklyn JA & Kilby MD 2002 Early expression of thyroid
development has progressed significantly over the past decade. hormone deiodinases and receptors in human fetal cerebral cortex. Brain
However, many issues regarding TR and thyroid hormone Research. Developmental Brain Research 138 109–116. (doi:10.1016/
cell membrane transporters have yet to be clarified. S0165-3806(02)00459-5)
Cheng SY, Leonard JL & Davis PJ 2010 Molecular aspects of thyroid hormone
Differences between rodent and human development are
actions. Endocrine Reviews 31 139–170. (doi:10.1210/er.2009-0007)
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Declaration of interest endo-110-2-367)
Dratman MB, Crutchfield FL & Schoenhoff MB 1991 Transport of
iodothyronines from bloodstream to brain: contributions by blood:brain
The authors declare that there is no conflict of interest that could be perceived
and choroid plexus:cerebrospinal fluid barriers. Brain Research 554 229–236.
as prejudicing the impartiality of the research reported.
(doi:10.1016/0006-8993(91)90194-Z)
Dumitrescu AM, Liao XH, Best TB, Brockmann K & Refetoff S 2004 A
novel syndrome combining thyroid and neurological abnormalities is
Funding associated with mutations in a monocarboxylate transporter gene. American
Journal of Human Genetics 74 168–175. (doi:10.1086/380999)
This research did not receive any specific grant from any funding agency in the Ercan-Fang S, Schwartz HL & Oppenheimer JH 1996 Isoform-specific
public, commercial or not-for-profit sector. 3,5,3 0 -triiodothyronine receptor binding capacity and messenger ribonu-
cleic acid content in rat adenohypophysis: effect of thyroidal state and
comparison with extrapituitary tissues. Endocrinology 137 3228–3233.
(doi:10.1210/en.137.8.3228)
Feng W, Ribeiro RC, Wagner RL, Nguyen H, Apriletti JW, Fletterick RJ,
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