Thyroid hormones

TR
and
BXR
Thyroid glands
• The thyroid gland is a strongly vascularized organ
• It is located in the neck, in close approximation to the first part of the trachea.
• In humans, the thyroid gland has a
"butterfly" shape, with two lateral lobes that
are connected by a narrow section called the
isthmus.
• Most animals, however, have two separate
glands on either side of the trachea.
• Thyroid glands are brownish-red in color.
Thyroid glands
• Thyroid epithelial cells - the cells responsible for synthesis of thyroid hormones - are
arranged in spheres called thyroid follicles.
• The follicle lumen is filled with a thick colloid which predominantly contains
thyroglobulin.
• Thyroglobulin is a highly glycosylated protein of two subunits, each of 330 kDa. The
subunit contains 115 tyrosine residues. This way, the thyroid gland maintains a large
reservoir of potential hormone.
Thyroid hormones
• Thyroid hormones are derivatives of the the amino acid tyrosine bound covalently to
iodine. The two principal thyroid hormones are:
• thyroxine (known also as T4 or L-3,5,3',5'-tetraiodothyronine)
• triiodotyronine (T3 or L-3,5,3'-triiodothyronine).
• Although both T3 and T4 are important for normal growth and development and
energy metabolism, T3 is three-five times more active than T4.
Thyroid hormones are basically two tyrosines linked together with the critical
addition of iodine at three or four positions on the aromatic rings.
Thyroid hormones
• Although T3 is the considerably more active hormone, a large majority of the thyroid
hormone secreted from the thyroid gland is T4.
• Some T3 is also secreted, but the bulk of the T3 is derived by deiodination of T4 in
peripheral tissues, especially liver and kidney.
• Deiodination of T4 also yields reverse T3, a molecule with no known metabolic activity.
Physiologic effects of
thyroid hormones
• It is likely that all cells in the body are targets for
thyroid hormones.
Mitochondrial ATP production in control
(open bars) and hyperthyroid (filled bars)
in rats.
• Thyroid hormones have profound effects on
many "big time" physiologic processes, such as
development, growth and metabolism.
Metabolism:
• Thyroid hormones stimulate diverse metabolic
activities in most tissues, leading to an increase in
basal metabolic rate.
• One consequence of this activity is to increase
body heat production, which seems to result, at
least in part, from increased oxygen consumption
and rates of ATP hydrolysis.
heart
liver
soleus plantaris
Physiologic effects of thyroid hormones
Lipid metabolism:
• Increased thyroid hormone levels stimulate fat mobilization, leading to increased
concentrations of fatty acids in plasma.
• They also enhance oxidation of fatty acids in many tissues.
• Finally, plasma concentrations of cholesterol
with thyroid hormone levels - one diagnostic
blood cholesterol concentration.
and triglycerides are inversely correlated
induction of hypothyroidism is increased
Carbohydrate metabolism:
Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including:
• enhancement of insulin-dependent entry of glucose into cells,
• increased gluconeogenesis and glycogenolysis to generate free glucose
• enhancement of intestinal glucose transport.
Physiologic effects of thyroid hormones
Growth:
• Thyroid hormones are clearly necessary for normal growth in children and young
animals, as evidenced by the growth-retardation observed in thyroid deficiency.
Development:
• A classical experiment in endocrinology was the demonstration that tadpoles deprived of
thyroid hormone failed to undergo metamorphosis into frogs.
Physiologic effects of thyroid hormones
Cardiovascular system:
• Thyroid hormones increase heart rate, cardiac contractility and cardiac output. They also
promote vasodilation, which leads to enhanced blood flow to many organs.
• The thyroid hormones appear to alter the expression of myosin isozymes so that calcium
and actin-activated ATPase activity of cardiac myosin in enhanced. This increases the
velocity of muscle fiber shortening.
Physiologic effects of thyroid hormones
Central nervous system:
• Both decreased and increased concentrations of thyroid hormones lead to alterations in
mental state. Too little thyroid hormone, and the individual tends to feel mentally sluggish,
while too much induces anxiety and nervousness.
• Of critical importance in mammals is the fact that normal levels of thyroid hormone are
essential to the development of the fetal and neonatal brain.
• Congenital thyroid deficiency results in cretinism, which includes dwarfism and mental
retardation.
Reproductive system:
• Normal reproductive behavior and physiology is dependent on having essentially normal
levels of thyroid hormone.
• Hypothyroidism in particular is commonly associated with infertility.
Synthesis of thyroid hormones
Substrates:
• Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin, which is
synthesized by thyroid epithelial cells and secreted into the lumen of the follicle - colloid
is essentially a pool of thyroglobulin.
• Iodine, ingested in diet reaches the circulation in form of iodide (I-) and is avidly taken
up from blood by thyroid epithelial cells, which have on their outer plasma membrane a
sodium-iodide symporter or "iodine trap”.
• This process is stimulated by thyroid-stimulating
hormone TSH (iodide is concentrated 20-200
fold over plasma in the gland). Once inside the cell,
iodide is transported into the lumen of the follicle
along with thyroglobulin.
Synthesis of thyroid hormones
• Synthesis of thyroid hormones is conducted by the enzyme thyroid peroxidase, an
integral membrane protein present in the apical (colloid-facing) plasma membrane of
thyroid epithelial cells.
Thyroid peroxidase catalyzes two sequential reactions:
• Iodination of tyrosines on thyroglobulin (also known as "organification of iodide").
• Synthesis of thyroxine or triiodothyronine from two iodotyrosines.
• thyroid hormones accumulate in colloid, on the surface of thyroid epithelial cells.
Thyroid hormones are excised from their thyroglobulin scaffold by digestion in
lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis
proceeds in the following steps:
• Thyroid epithelial cells ingest colloid by
endocytosis from their apical borders - that
colloid contains thyroglobulin decorated with
thyroid hormone.
• Colloid-laden
which contain
thyroglobulin,
hormones.
endosomes fuse with lysosomes,
hydrolytic enzymes that digest
thereby liberating free thyroid
• Finally, free thyroid hormones apparently
diffuse out of lysosomes, through the basal plasma
membrane of the cell, and into blood where they
quickly bind to carrier proteins for transport to
target cells.
• In peripheral tissues T4 can be converted to T3.
Thyroid hormones
• Thyroid hormones are poorly soluble in
water, and more than 99% of the T3 and
T4 circulating in blood is bound to
carrier proteins.
• The principle carrier of thyroid
hormones (carrying some 75% of
circulating thyroxine) is thyroxinebinding globulin, a glycoprotein synthesized in the liver.
• Two other carriers of import are
transthyrein and albumin.
• Carrier proteins allow maintenance of a
stable pool of thyroid hormones from
which the active, free hormones are
released for uptake by target cells.
• Synthesis of thyroid hormones is
upregulated by thyroid stimulating
hormone (TSH) from the anterior
pituitary gland.
• Binding of TSH to its receptors on
thyroid epithelial cells stimulates
synthesis of the iodine transporter,
thyroid peroxidase and thyroglobulin.
• The magnitude of the TSH signal also
sets the rate of endocytosis of colloid high concentrations of TSH lead to
faster rates of endocytosis, and hence,
thyroid hormone release into the
circulation.
• Conversely, when TSH levels are low,
rates of thyroid hormone synthesis and
release diminish.
Metabolism of thyroid hormones
• The major site of thyroxine conversion outside of the thyroid is in the liver. Thus, when
thyroxine is administered to patients in doses that produce normal thyroxine plasma, the
T3 also reaches the normal levels.
• T4 is converted to T3 by specific 5’-deiodinases. This represents activation of the
hormone:
* Type-I enzyme is expressed in liver, kidney,
and other tissues. These are inhibited by
propylthiouracil but not methimazole.
* Type-II enzyme, in the pituitary, has very high
affinity for T4, and is important for feedback
inhibition of TSH secretion that is mediated by T3.
Metabolism of thyroid hormones
* Hepatic metabolism: mainly conjugation of phenolic-OH with glucuronic or sulfuric
acid, followed by biliary secretion. A large portion of these conjugates are cleaved in the
intestine with reabsorption of active hormones, but some 40% of T4 ends up in feces.
* Plasma half-life of T4 is 6-7 days in adults; for T3 it is less than 2 days. In contrast, the
half-life of T4 is prolonged to 9-10 days in hypothyroid cases, and shortened o 3-4 days in
hyperthyroidism.
Receptor Structure:
• Mammalian thyroid hormone receptors are encoded by two genes, designated alpha and
beta.
• The primary transcript for each gene can be alternatively spliced, generating different
alpha and beta receptor isoforms.
• Currently, four different thyroid hormone receptors are recognized: alpha-1, alpha-2,
beta-1 and beta-2.
• Most notably, the alpha-2 isoform has a unique carboxy-terminus and does not bind
triiodothyronine (T3).
TR isoforms
• The different forms of thyroid receptors have patterns of expression that vary by tissue
and by developmental stage.
• Almost all tissues express the alpha-1, alpha-2 and beta-1 isoforms, but beta-2 is
synthesized almost exclusively in hypothalamus, anterior pituitary and developing ear.
• Receptor alpha-1 is the first isoform expressed in the conceptus, and there is a
profound increase in expression of beta receptors in brain shortly after birth.
• Interestingly, the beta receptor preferentially activates expression from several genes
known to be important in brain development (e.g. myelin basic protein), and
upregulation of this particular receptor may thus be critical to the well known the effects
of thyroid hormones on development of the fetal and neonatal brain.
• Thyroid hormone receptors can bind to a TRE as monomers, as homodimers or as
heterodimers with the retinoid X receptor (RXR).
• The heterodimer affords the highest affinity binding, and is thought to represent the
major functional form of the receptor.
• The most stable binding occurs on the classical DR4 thyroid response element (TRE).
• Thyroid hormone receptors bind to TRE DNA regardless of whether they are occupied
by T3. However, the biological effects of TRE binding by the unoccupied versus the
occupied receptor are dramatically different.
• In general, binding of thyroid hormone receptor alone to DNA leads to repression of
transcription, whereas binding of the thyroid hormone-receptor complex leads to
activation of transcription.
Mode of TR action
• Possibly, TR remains bound to DNA but exists in two mutually exclusive conformations:
* In the absence of hormone, binding of the co-repressor complex leads to
chromatin inactivation and gene repression,
* while binding of the ligand thyroid hormone causes dissociation of corepressors, co-activator binding and transcriptional activation accompanied by
local opening of chromatin structure.
• In addition, the TR in its non-liganded state may activate certain genes via AF-1 or AF2.
• Finally, the TR transrepresses genes in its liganded state via inhibiting other
transcription factors such as AP-1.
• Some effects are exerted by binding of TSH-thyroid hormone complex to TSH receptor.
Thyroid hormone receptor
Ligand-free state:
• The transactivation domain of the T3-free receptor, as a heterodimer with RXR,
assumes a conformation that promotes interaction with a group of transcriptional
corepressor molecules.
• A part of this corepressor complex has histone deacetylase activity (HDAC), which is
associated with formation of a compact, "turned-off" conformation of chromatin.
• The net effect of recruiting these types of
transcription factors is to repress transcription
from affected genes.
Thyroid hormone receptor
Ligand-bound state:
• Binding of T3 to its receptor induces a conformational change in the receptor that
makes it incompetent to bind the corepressor complex, but competent to bind a group of
coactivator proteins.
• The coactivator complex contains histone transacetylase (HAT) activity, which imposes
an open configuration on adjacent chromatin.
• The coactivator complex associated with the
T3-bound receptor functions to activate
transcription from linked genes.
Negative regulation of gene expression by TH: not so simple
• TH also downregulates numerous genes.
• Indeed, the most important physiological effect of TH is negative regulation of
thyrotropin (TSH) gene expression in the pituitary.
• Several fundamentally different models have been postulated:
I. TR binds directly, via its DNA-binding domain, to a “negative” TRE (nTRE) in a
negatively regulated gene. Indeed, an nTRE has been identified in the TSHa subunit gene.
The precise cofactors and downstream effectors of this form of DNA binding–dependent
repression by TH remain to be determined.
II. TR can negatively regulated gene through the recruitment of different DNAbinding protein, such as a component of AP-1 complexes that have been demonstrated to
interact with TR.
III. TR acts in the nucleus to steal coactivators and corepressors (in the presence or
absence of TH, respectively) from other NRs as well as additional transcription factors
(such as AP-1) that utilize the same coactivators or corepressors.
IV. TR may also have non-nuclear effects, leading to activation of kinase cascades that
ultimately impact on nuclear transcription factor function.
Potential mechanisms of negative regulation of gene expression by TH
TH binding to TR triggers a switch from
coactivator to corepressor binding on an
nTRE on DNA. This mechanism absolutely
requires direct DNA binding by TR.
TH binding to TR triggers a switch from
coactivator to corepressor binding in the
context of a protein-protein interaction,
shown here with the AP-1 complex (jun/fos).
TH binding to TR recruits coactivator away from
a DNA-bound factor such as AP-1.
Thyroid hormone receptors
• TR is also referred to as c-erbA. An oncogenic variant, v-erbA has also been identified,
which contribute to avian erythroblastosis virus (AEV)-induced leukemic transformation
by constitutively repressing transcription of target genes.
• Initially, v-ErbA was thought to act as a
dominant negative version of c-ErbA/TRα. It
would constitutively bind to TREs normally
occupied by endogenous receptors and thus
block their function.
• Later findings were inconsistent with this
idea that v-ErbA transforms via mechanisms
different from those employed by cErbA/TRa.
• In vivo, v-ErbA cooperates with tyrosine
kinase oncoproteins or endogenous c-Kit to
induce erythroleukemia.
v-ErbA and c-ErbA
• Like v-ErbA, unliganded, overexpressed c-ErbA/TRα cooperates with SCF-activated
endogenous c-Kit for proliferation induction and differentiation arrest in primary
progenitors.
• Ligand-free c-ErbA/TRα also substitutes for steroid hormone receptor function in
normal erythroid progenitor self-renewal, a trait only ascribed to the oncogene so far.
• To act like v-ErbA, c-ErbA proteins had to be expressed at levels comparable with vErbA. In addition, they had to be deprived of ligands able to activate the TRα/RXR
heterodimer, e.g. T3 and retinoids such as 9-cis RA.
TR and erythropoiesis
• Function of the thyroid hormone receptor α (c-ErbA/TRα) is important for
determination of cell fate in hematopoietic progenitors.
• In the complete absence of its ligands, c-ErbA/TRα causes sustained proliferation
accompanied by a tight differentiation arrest. After ligand (T3) addition, the same
receptor readily promotes terminal red-cell differentiation.
• Thus, c-ErbA/TRα acts as a T3-driven
molecular switch in regulating the balance
between proliferation and differentiation of
primary erythroblasts.
• Maybe proliferation induction and/or
differentiation arrest caused by nonliganded c-ErbA are at least in part due to
repression of target genes via activation of
histone deacetylases.
• Remember that similarly mechanism act
in the case of the RARα–PML fusion
protein.
Does the TR have a role in erythropoiesis?
• Evidence for a role of the TR in erythropoiesis is indirect and fragmentary:
• Importantly, hypothyroidism is frequently associated with certain forms of anemia or
hyperproliferation of immature erythroid progenitors. In these anemias, the viability of
erythrocytes is not affected.
• Perhaps, there is a direct involvement of unliganded TR in inducing anemia by delaying
maturation of erythroid progenitors in vivo.
• This is in agreement with the observation that thyroid replacement therapy corrects the
pathological events typical for these anemias.
• On its own, the TR would not arrest differentiation in vivo since it would not be exposed
to ligand-free conditions in the animal. Rather, TR functions downstream of the GR,
perhaps being stabilized in a nonliganded conformation by unknown proteins induced by
the GR. Since the liganded GR transactivates certain reporter genes via the promoter of
human TRα even the level of TR expression might be directly influenced by the GR.
Thyroid hormone resistance
Mice with targeted deletions in thyroid receptor genes have provided additional
understanding of the possible roles of different forms of thyroid hormone receptors:
• Knockout mice that are unable to produce the alpha-1 receptor showed subnormal body
temperature and mild abnormalities in cardiac function.
• Other mice which lacked expression of both alpha isoforms were severely hypothyroid
and died within the first few weeks of life.
• Mice with disruptions of the entire beta gene exhibited elevated TSH levels and deafness,
while mice with mutations that disrupted only beta-2 expression had elevated TSH, but
normal hearing. Such experiments are beginning to allow determination of which functions
of the different receptor isoforms are redundant and which are not.
• Inactivating mutations in thyroid hormone receptors do not produce a syndrome
analogous to the lack of thyroid hormones. This is the case even in mice with targeted
deletions in both alpha and beta receptor genes. The most likely explanation for the
relative mild effects of receptor deficiency is that responsive genes are left in a "neutral"
state, rather than being chronically suppressed as happens with hormone deficiency.
Resistance to thyroid hormones
There are two major forms of tissue resistance to thyroid hormones:
I. generalised resistance
II. pituitary resistance.
• Generalised resistance to thyroid hormone action (GRTH): All the tissues
including the pituitary have a decreased sensitivity to thyroid hormones. There is
a compensatory increase in thyroid hormone production due to which the
thyroid gland hypertrophies leading to a goitre.
• Pituitary resistance to thyroid hormone (PRTH): This is less common than the
above condition and in this the resistance is limited to the pituitary, while
peripheral tissues are normally responsive. It is characterised clinically, by the
presence of goitre, signs of hyperthyroidism such as weight loss, tremors,
tachycardia, or heat intolerance.
• Treatment: GRTH and PRTHcan be treated with high doses of thyroid hormones
and their analogs with a careful monitoring for signs of toxicity.
Mutations in TR
• Mutations in the ligand-binding domain of TR can lead to generalized resistance to
thyroid hormones.
• Children with this disorder have a high incidence of attention-deficit-hyperactivity
disorder (ADHD).
• A number of humans with a syndrome of thyroid
hormone resistance have been identified, and found to
have mutations in the receptor beta gene which abolish
ligand binding.
• Clinicially, such individuals show a type of
hypothyroidism characterized by goiter, elevated
serum concentrations of T3 and thyroxine and normal
or elevated serum concentrations of TSH.
Hypothyroidism and hyperthyroidism
• Up to 15% of women over the age of 60 have subclinical hypothyroidism,
defined as abnormally elevated plasma thyroid-stimulating hormone levels with
normal T4 levels. Some studies suggest that this condition leads to elevations of
LDL.
• In routine cases management of hypothyroidism is relatively straightforward,
and relies on replacement therapy.
• Subclinical hyperthyroidism, defined as a suppressed plasma level of
stimulating hormone and normal plasma T4 levels may be associated
increased incidence of atrial fibrillation.
thyroidwith an
• Management of hyperthyroidism is more complex. With overt disease, there is
the choice between medical therapy vs. radioactive iodine or surgery.
Hypothyroidism
Causes:
• Iodine deficiency: Iodide is absolutely necessary for production of thyroid hormones;
without adequate iodine intake, thyroid hormones cannot be synthesized. Historically, this
problem was seen particularly in areas with iodine-deficient soils; iodine deficiency has
been virtually eliminated by iodine supplementation of salt.
• Primary thyroid disease: Inflammatory diseases of the thyroid that destroy parts of the
gland are clearly an important cause of hypothyroidism (Hashimoto disease).
Symptoms:
• Lethargy, fatigue, cold-intolerance, weakness, hair loss and reproductive failure.
• In the case of iodide deficiency, the thyroid becomes inordinantly large and is called a
goiter.
• The most severe and devestating form of hypothyroidism is seen in young children with
congenital thyroid deficiency. If that condition is not corrected by supplemental therapy
soon after birth, the child will suffer from cretinism, a form of irreversible growth and
mental retardation.
Hyperthyroidism
Causes:
• Hyperthyroidism results from too high secretion of thyroid hormones.
• In most species, this condition is less common than hypothyroidism.
• In humans the most common form of hyperthyroidism is Graves disease, an immune
disease in which autoantibodies bind to and activate the thyroid-stimulating hormone
receptor, leading to continual stimulation of thyroid hormone synthesis.
• It can also results from thyroid cancer (adenoma or carcinoma) or thyroiditis.
• Another, but rare cause of hyperthyroidism is so-called hamburger thyroxicosis.
Symptoms:
• Common signs of hyperthyroidism are basically
the opposite of those seen in hypothyroidism, and
include nervousness, insomnia, high heart rate,
eye disease and anxiety.
Graves disease
• Graves' Disease is a type of autoimmune disease in which the immune system over
stimulates the thyroid gland, causing hyperthyroidism.
• This is rare disease that tends to affect women over the age of 20. The incidence is about
5 in 10 000 people.
• The most common symptoms of Grave’s Disease, include insomnia, irritability, weight
loss without dieting, heat sensitivity, increased perspiration, fine or brittle hair, muscular
weakness, eye changes, lighter menstrual flow, rapid heart beat, and hand tremors.
• Grave’s Disease is the only kind of hyperthyroidism that is associated with
inflammation of the eyes, swelling of the tissue around the eyes, and protrusion, or
bulging, of the eyes.
• Some patients will develop reddish thickening
of the skin called pretibial myxedema.
This skin condition is usually painless. The symptoms of
this disease can occur gradually or very suddenly.
Women can have Grave’s Disease and have no obvious
symptoms at all.
Strategy for treatment of Graves disease
No direct immunomodulation therapy is presently available. Therefore, the
strategy is:
• to control symptoms of adrenergic stimulation with β-blockers;
• to decrease production of thyroid hormone by temporary treatment with
thioureylenes (e.g. propylthiouracil and methimazole), which inhibit synthesis of
thyroid hormones and act as immunosuppresants
• treatment the patients with radioiodine
• surgery.
Hamburger thyroxicosis
• Thyroid hormones are orally active, which means that
consumption of thyroid gland tissue can cause thyrotoxicosis, a
type of hyperthyroidism.
• Several outbreaks of thyrotoxicosis have been attributed to a
practice (banned), where meat in the neck region of slaughtered
animals is ground into hamburger. Because thyroid glands are
reddish in color and located in the neck, it's not unusual to get
thyroid glands into hamburger or sausage.
• People, and presumably pets, that eat such hamburger can get dose of thyroid hormone
sufficient to induce disease.
• It has been described (1987) an outbreak of thyrotoxicosis in Minnesota and South
Dakota that was traced to thyroid-contaminated hamburger.
• A total of 121 cases were identified in USA.
• The patients complained of sleeplessness, nervousness, headache, fatique, excessive
sweating and weight loss.
Hamburger thyroxicosis
• Serum concentrations of thyroxine and thyroid-stimulating hormone in a volunteer
that consumed a well-cooked, 227 g hamburger (admittedly, a large meal) prepared
from the contaminated meat. Note how TSH levels were suppressed during the time
when thyroxine (T4) concentrations were elevated.
Thyroid hormone in fetal development
• Thyroid hormones are critical for development of the fetal and neonatal brain, as well as
for many other aspects of fetal growth.
• Hypothyroidism in either the mother or fetus frequently results in fetal disease; in
humans, this includes a high incidence of mental retardation.
• Normal pregnancy entails substantial changes in thyroid function in all animals. Major
alterations in the thyroid system during pregnancy include:
* Increased blood concentrations of T4-binding globulin: TBG is one of several
proteins that transport thyroid hormones in blood, and has the highest affinity for T4
(thyroxine) of the group. Estrogens stimulate expression of TBG in liver, and the normal
rise in estrogen during pregnancy induces roughly a doubling in serum TBG
concentratrations.
* Increased levels of TBG lead to lowered free T4 concentrations, which results in
elevated TSH secretion by the pituitary and, consequently, enhanced production and
secretion of thyroid hormones. The net effect of elevated TBG synthesis is to force a new
equilibrium between free and bound thyroid hormones and thus a significant increase in
total T4 and T3 levels.
Thyroid hormone in fetal development
• The increased demand for thyroid hormones is reached by about 20 weeks of gestation
and persists until term.
• Increased demand for iodine from a significant pregnancy-associated increase in iodide
clearance by the kidney, and siphoning of maternal iodide by the fetus.
• Toward the end of the first trimester of pregnancy,
when hCG levels are highest, a significant fraction
of the thyroid-stimulating activity is from hCG.
• In females with subclinical hypothyroidism, the
extra demands of pregnancy can precipitate
clinicial disease.
free T4 [ng/dL]
• The placentae of humans and other primates secrete huge amounts of chorionic
gonadotropin (hCG) which is very closely related to luteinizing hormone. TSH and hCG
are similar enough that hCG can bind and transduce signalling from the TSH receptor on
thyroid epithelial cells.
hCG [IU/Lx1000]
Thyroid hormone and fetal brain development
• In 1888 the Clinical Society of London issued a report
underlining the importance of normal thyroid function on
development of the brain.
• Thyroid hormones appear to have their most profound effects
on the terminal stages of brain differentiation, including
synaptogenesis, growth of dendrites and axons, myelination and
neuronal migration.
• Thyroid hormone receptors are widely distributed in the fetal
brain, and present prior to the time the fetus is able to synthesize
thyroid hormones.
• The promoter of the myelin basic protein gene is directly
responsive to thyroid hormones and contains the expected
hormone response element. This fits with the observation that
induced hypothyroidism in rats leads to diminished synthesis of
mRNAs for several myelin-associated proteins.
A fetal rat brain produced by in situ hybridization
with a probe for the rat thyroid hormone receptor.
Thyroid hormone and fetal development
• The fetus has two potential sources of thyroid hormones - it's own thyroid and the
thyroid of it's mother.
• Human fetuses acquire the ability to synthesize thyroid hormones at 10 to 12 weeks of
gestation.
• There is substantial transfer of maternal thyroid hormones across the placenta.
Additionally, the placenta contains deiodinases that can convert T4 to T3.
Thyroid hormone and fetal development
Thyroid deficiency states known to affect fetal development:
* Isolated maternal hypothyroidism: Overt maternal hypothyroidism typically is not a
significant cause of fetal disease because it usually is associated with infertility. When
pregnancy does occur, there is increased risk of intrauterine fetal death and gestational
hypertension.
* Subclincial hypothyroidism: mild maternal hypothyroidism, diagnosed only
retrospectively from banked serum, may adversely affect the fetus, leading in children to
such effects as slightly lower performance on IQ tests and difficulties with schoolwork.
The most common cause of subclinical hypothyroidism is autoimmune disease, and it is
known that anti-thyroid antibodies cross the human placenta. Thus, the cause of this
disorder may be a passive immune attack on the fetal thyroid gland.
* Isolated fetal hypothyroidism: failure of the fetal thyroid gland to produce adequate
amounts of thyroid hormone. Most children are normal at birth, because maternal
thyroid hormones are transported across the placenta during gestation. What is
absolutely critical is to identify and treat this condition very shortly after birth. If not, the
child will become permanently mentally and growth retarded - a disorder called
cretinism.
Cretinism
• Mental deficiency is characterised by a marked impairment of the capacity for
abstract thought but vision is unaffected. Autonomic, vegetative, personal, social
functions and memory appear to be relatively well preserved except in the most severe
cases.
• Deafness is the striking feature. This may be complete in as many as 50% cretins.
Deafness is sometimes absent in subjects with other signs of cretinism. All totally deaf
cretins were mute and many with some hearing had no intelligible speech.
• The motor disorder shows a characteristic proximal rigidity of both lower and upper
extremities and the trunk. There is a corresponding proximal spasticity with markedly
exaggerated deep tendon reflexes at the knees, adductors and biceps.
• Function of the hands and feet is characteristically preserved so that most cretins can
walk.
few months
thyroid hormone replacement
Iodine deficiency
Iodine deficiency - combined maternal and fetal hypothyroidism:
• Iodine deficiency is the most common preventable cause of mental retardation in the
world. Without adequate maternal iodine intake, both the fetus and mother are
hypothyroid, and if supplemental iodine is not provided, the child may well develop
cretinism, with mental retardation, deaf-mutism and spasticity.
• The World Health Organization estimated in 1990 that 20 million people had some
degree of brain damage due to iodine deficiency experienced in fetal life.
• Endemic iodine deficiency remains a substantial public health problem in many parts of
the world, including many areas in Europe, Asia, Africa and South America. In areas of
severe deficiency, a large fraction of the adult population may show goiters. In such
settings, cretinism may occur in 5 to 10 percent of offspring, and perhaps five times that
many children will have mild mental retardation.
• The fetus of an iodine-deficient mother can be successfully treated if iodine
supplementation is given during the first or second trimester. Treatment during the third
trimester or after birth will not prevent the mental defects.
BXR – adopted orphan receptor
• BXR heterodimerizes with RXR and binds high-affinity DNA sites composed of a
variant thyroid hormone response element.
• Recently, alkyl esters of amino and hydroxy benzoic acids were identified as potent,
stereoselective activators. These molecules as bona fide ligands.
• Benzoates comprise a new molecular class of nuclear receptor ligand and their activity
suggests that BXR may control a previously unsuspected vertebrate signaling pathway.
• BXR:RXR heterodimers bind preferentially to direct repeats of the sequence AGTTCA
separated by four nucleotides (DR4).
RXR
benzoic acid
salicylic acid
Benzoates
• The endogenous benzoates are related to the nutrient p-amino benzoic acid (PABA), an
integral component of the essential B-vitamin folic acid.
• Because PABA is generated from folate breakdown, it is impossible to achieve PABA
deficiency in mammals without folic acid deficiency. This implies that some symptoms of
folate deficiency might result from the absence of folate-derived PABA rather than folate
itself.
• Folate is required for the synthesis of methylcobalamin, which in turn is essential for
normal synthesis of purines, and pyrimidines, and therefore DNA. This methyl transfer is
also essential for the generation of tetrahydrofolate, which contributes to intermediary
metabolism by functioning as a substrate for numerous metabolic reactions.
• In addition, the folate-cobalamin interaction catalyzes the conversion of methylmalonyl
coenzyme A (CoA) to succinyl CoA, which is critical to lipid metabolism and triglyceride
synthesis.
BXR and benzoates
• It is possible that BXR may have a previously unexpected role in these metabolic
pathways, perhaps by controlling the activity of genes regulating pivotal enzymatic steps.
• Interestingly, folate lowers blood levels of homocysteine, which in high levels has been
linked to heart disease and hypertension.
• This further suggests a connection between folate metabolism and BXR activation.
folic acid
Thank you and see you next week...
What would be profitable to remember in June:
- Causes and symptoms of thyroid hormone deficiency or overloading
- Splicing forms and mode of action of TR.
- What is it BXR.
Slides can be found in the library and at the
Heme Oxygenase Fan Club page:
https://biotka.mol.uj.edu.pl/~hemeoxygenase