Thyroid Homrones

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Thyroid Homrones

• Thyroid gland is derived from endoderm of the
  cephalic portion of the embryos alimentary
  canal.
• This organ becomes bilobed but remians connected
  to the pharynx by a thyroglossal duct.
• The two lateral lobes of the human thyroid become
  solid masses of tissue connected to each other
  by a narrow isthmus.
• The functional units of the thyroid are the
  individual thyroid follicles, which consist of a
  cuboidal epithelium arranged as a single layer
  surrounding a lumen that contains colloid
  material.

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Thyroid Hormones

• In the mammal, so called clear cells, (C), are
  present within the follicular wall and the
  extracellular space between the follicles.
• C cells are the source of calcitonin, important
  for Ca homeostasis.
• Follicular cells synthesize a protein, called
  thyroglobulin, which is released into the
  colloidal space by vesicular exocytosis.
• Thyroglobulin is the substrate for tyrosine
  iodination and subsequent synthesis of thyroid
  hormones.

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Thyroid Hormones

• In response to endocrine stimulation, follicular
  cells engulf the colloid by phagocytosis.
• The colloid within the endocytotic vesicles is
  enzymatically degraded to yield thyroid hormones
  that are released from follicular cells into the
  extracellular space where they enter the
  capillaries.

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Thyroid Hormones

• Thyroid is richly supplied with sympathetic
  postganglionic neurons that not only serve a
  vasomotor function, but in some species may
  innervate the individual follicular cells.
• In mice, unilateral sympathetic stimulation
  induces secretion of thyroid hormones from those
  areas supplied by the nerve.
• Sympathetic innervation of the thyroid may
  provide for prompt, short-term alterations in the
  rate of thyroid hormone secretion.
• Amine containing mast cells are present between
  the thyroid follicles they respond to TSH
  releasing histamine and serotonin, which may
  directly initiate thyroid hormone secretion or
  increase blood flow.

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Synthesis Chemistry

• Thyroid hormones are complexed through covalent
  bonds to iodine.
• Availability of iodine to terrestrial species is
  limited so cellular mechanisms have evolved to
  for utilization and conservation of I2.
• Thyroid follicular cells are able to trap I2 at
  the base of the cell and transport it against an
  electrical gradient across the cell.
  Accumulation of I2 by the thyroid requires
  energy.

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Synthesis Chemistry

• Na and I- co-transport is inserted into the
  basolateral membrane of the thyrocyte. Its
  activity is dependent upon the Na gradient
  across the membrane and therefore on the Na/K
  -ATPase. This is an example of a secondary
  active transport system.
• I2 is then converted by a peroxidase at the
  luminal surface of the cell to an oxidized
  species of iodine that is incorporated into
  tyrosyl groups of thyroglobulin (TG) as
  monoiodotyrosine, (MIT) and diiodotyrosine (DIT)
  residues.

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Synthesis Chemistry

• Within the TG, iodinated tyrosines undergo
  oxidative coupling that results mainly in the
  formation of T4 and smaller amounts of T3.
• This oxidative coupling may be catalyzed by the
  same peroxidase responsible for conversion of I2
  to iodine.
• Iodination of TG tyrosyl residues and subsequent
  oxidative coupling to form iodothyronines may be
  facilitated by intraluminal ciliary action and
  movement of TG to reactive sites at the apical
  surface of the follicular cells.

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Synthesis Chemistry

• Through the process of micropinocytosis and
  macropinocytosis, the colloid is engulfed by
  follicular cell pseudopods and transported to
  cells as colloid droplets.
• These colloid containing vesicles fuse with
  lysosomes and are referred to as secondary
  lysosomes. Much of the TG is degraded by the
  lysosomal proteolytic enzymes.
• The thyroid hormones are released into the
  cytoplasm and enter the extracellular space by
  diffusion through the basal or lateral follicular
  membranes.

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Synthesis Chemistry

• Exocytosis of vesicular products including T3 and
  T4, is not excluded as TG is also secreted into
  the circulation.
• The iodinated tyrosines that are released into
  the cytosol through lysosomal proteolysis are
  then deiodinated by a deiodinase and recycled for
  use within the cell.

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Thyrotropin Stimulation

• Continued stimulation of the thyroid by TSH
  results in a great increase in the quantity and
  activity of the synthetic machinery (RER Golgi)
  of the follicular cells.
• Cells become columnar in shape and the luminal
  content of the colloid is greatly decreased.
• In the absences of TSH, synthesis of thyroid
  hormones is nonexistent and there is loss of most
  protein-synthesizing machinery, follicular cells
  become flattened and the lumen remains large and
  full of colloid.

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Thyrotropin Stimulation

• In response to TSH there is an immediate
  activation of follicular cell thyroid
  hormone-synthesizing activity.
• TSH interacts with follicular cell membrane
  receptors resulting in activation of AC and cAMP
  production. All subsequent follicular activities
  may be mediated through cAMP PO4 of substrate
  proteins.
• TSH stimulates in vitro incorporation of 125I2
  into TG suggesting I2 uptake and peroxidase
  activities are stimulated by TSH.

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Thyrotropin Stimulation

• In response to TSH, O2 consumption is increased
  in incubated thyroid tissue and glucose is taken
  up and metabolized via the pentose monophosphate
  shunt to generate H2O2 which is used to oxidize
  I2 to an active form.
• This reaction is catalyzed by a thyroidal
  peroxidase. Conversion of I2 to active I2 and
  organification of I2 into tyrosine residues of TG
  may occur as TG is secreted into the follicular
  lumen.

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Thyrotropin Stimulation

• Immediately on stimulation of thyroid by TSH
  there is an enhanced pinocytotic activity at the
  apical follicular membrane.
• Colloid is actively engulfed and carried into the
  cell by endocytosis. Active removal of the
  colloid from the lumen is called resorption
  lacunae.

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Thyroglobulin

• TG is composed of two identical subunits each
  containing a 330 kDa polypeptide.
• Tyrosyl residues are necessary for I2
  incorporation but the amount of tyrosine in TG is
  low (2).
• Main intrathyroidal storage form thyroid hormones
  is TG and individual thyronines are liberated
  from TG as T3 T4 within the colloid droplets by
  the action of proteolytic enzymes.
• Iodination of TG requires conversion of inorganic
  I2 to an active iodide which then reacts with the
  tyrosine moieties.

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Thyroglobulin

• Incorporation of a single I2 into tyrosine yields
  3-monoiodotyrosine (MIT).
• A second I2 may be added at position 5 to yield
  3,5 diiodotyrosine (DIT).
• Coupling usually involves joining two DIT
  moieties to form 3,5,3,5 tetraiodothyronine,
  T4.
• Addition of MIT to a DIT yields
  3,5,3-triiodothyronine, T3.
• All iodinated tyrosines do not become coupled and
  much remains in the form of MIT and DIT.

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Antithyroid Drugs

• Antithyroid drugs are divided into those that
  inhibit iodide transport (trapping) and those
  that inhibit iodine incorporation into tyrosine.
• Univalent inhibitors of iodide transport include
  thiocyanate and other monvalent anions
  (perchlorate,chlorate, periodate).
• I2, itself, in large doses is transiently
  inhibitory to thyroid function.
• I2 uptake inhibitors antagonize I2 transport
  through competitive inhibition.

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Antithyroid Drugs

• Other antithyroid compunds include thionamides,
  sulfonamides and sulfonylureas.
• Over time these antithyroid drugs will cause
  thyroid hypertrophy and goiter and are referred
  to as goitrogens.
• Dietary goitrogens are responsible for endemic
  goiter, such as cyanogenic glucosides (in
  cassava, sorghum, sweet potatoes, cherries,
  almonds) which release thiocyanates.

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T3 T4

• Normally T4 is produced in greater quantities
  than T3. In the human T4 is about 50 X greater
  than T3.
• T4 is converted to T3 in athyreotic humans by
  extrathyroidal monodeiodination of T4 to T3.
• T3 is the major physiologically active thyroid
  hormone regulating cellular activity in species
  but T4 is though to exert a negative feedback on
  the hypothalamus.

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Control of Thyroid Hormone Secretion

• TH secretion is regulated by TSH from the AP that
  in turn is controlled by TRH from the
  hypothalamus.
• TH feed back to the AP and hypothalamus to
  inhibit TSH secretion. TSH is inhibited by
  stress in a number of species.
• TRH binds to the thyrotroph plasma membrane
  receptor and causes hydrolysis of PIP2 followed
  by intracellular Ca2, cAMP does not appear to be
  involved.

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Control of TH Secretion

• In many mammals, activation of the AP-thyroid
  axis occurs during exposure to the cold. Acute
  cold exposure of the rat leads to a rapid release
  of TSH. This occurs in infants as well but not
  in adult humans.
• An acute neuroendocrine reflex exists for TSH
  release in mammals and human infants and is
  mediated initially by peripheral sensory
  receptors then relayed to the hypothalamus where
  stimulation of TRH release occurs.
• Prior administration of T4 inhibits AP TSH
  release in response to cold, peripheral levels of
  TRH increase in hypox cold exposed rats, and TRH
  synthesis is increased in vitro in hypothalamic
  tissue taken from cold-exposed rats.

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Control of TH Secretion

• T4 in addition to providing negative feed back on
  TSH production, also control synthesis of TRH by
  regulating gene expression of the TRH prohomrone
  in the thyrotropic area of the hypothalamus.
• T4 feedback on TRH prohomrone is specific for TRH
  neurons located in the medial division of the
  PVN.
• Hypothyroidism enhances proTRH and release of TRH.

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Circulation Metabolism

• TH are hydrophobic molecules that require
  specific binding proteins in the plasma and cell
  cytosol to gain access to nuclear receptors.
• Two major thyroxine-binding proteins are
  transthyretin and thyroxine binding globulin
  (TBG).
• Transthyretin (55 kDa) is composed of four
  identical subunits of 127 a.a. arranged in a
  tetrahedral symmetry and has a pair of T4 binding
  sites.

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Circulation Metabolism

• TGB consist of a single polypeptide chain similar
  in weight to transthyretin.
• About 70 75 of T4 is bound to TGB about 20 to
  transthyretin and about 5 10 to albumin.
  These binding proteins are made in the liver.
• In normal individuals less than 0.5 of the toal
  serum T4 and about 0.3 of the serum T3 are
  present in the free state.
• Any factor that alters serum binding proteins,
  Particularly TGB, may affect the total T4
  concentration in the absence of thyroid
  dysfunction.

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Circulation Metabolism

• Pregnancy and estrogen-containing medications
  increase TBG, testosterone, corticosteroids,
  severe illness, cirrhosis and nephrotic disorders
  can lower TBG.
• During pregnancy in humans there is a doubling of
  TBG which is followed by increased T4 synthesis
  and secretion but the plasma concentrations of
  unbound iodothyronines remains unchanged.

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Physiological Roles of TH

• In 1858 an ablation replacement experiment was
  performed on dogs and after removal of the
  thyroid the animal died. If thyroid tissue were
  reimplanted into the body cavity the animals
  survived for a long time.
• Only later it was realized that death from
  thyroidectomy was due to removal of the
  parathyroid glands within the tissue.

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Physiological Roles of TH

• TH influence most bodily functions and directly
  affect a number of physiological processes and
  are often permissive for the actions of other
  hormones.
• TH are obligatory with GH for early growth and
  development.
• TH are unique in that they exert effects within
  almost every tissue of the body throughout life.

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Growth Development

• Absence of thyroid hormones results in severe
  growth retardation associated with arrest of bone
  elongation and retarded bone maturation.
• GH secretion is reduced without TH and is renewed
  when TH are given. Giving GH to hypothyroid
  patients is without effect unless TH are also
  given.
• TH are required both for production of GH and for
  its systemic actions.

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Growth Development

• Levels of hyaluronic acid are high in
  proliferating tissue and decrease as division
  decreases and cells become differentiated.
• Hyaluronidase splits hyaluronic acid into smaller
  oligosaccharides and is induced when tissues
  mature and may serve as a signal for
  differentiation.
• TH stimulates tadpole tissue differentiation and
  increases hyaluronidase, thus TH may stimulate
  differentiation through stimulation of
  hyaluronidase.

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Growth Development

• Decreased serum levels of TH results in retarded
  growth of the mammary ducts and little alveolar
  development. TH may also be required for normal
  levels of Prl by the AP.
• TH are required for normal development of the
  brain and without these there is decreased
  proteins synthesis, myelinogenesis and retarded
  axonal ramifications.
• These developmental processes are irreversible
  and lead to mental deficiency.
• NGF induces dendroitogenesis and regeneration of
  sympathetic neurons and TH increase NGF in the
  brain.

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Thermogenesis

• In the process of ATP hydrolysis by the Na pump,
  heat is liberated, which contributes to the
  maintenance of an elevated body temp.
• Activity of the Na pump requires a source of ATP
  produced mainly in the mitochondria.
• TH stimulate mitochondrial O2 consumption and
  production of ATP.
• T3 induced increase in Na/K-ATPase activity
  results from an increase in enzyme sites.

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Diet TH Function

• Increased caloric intake (mixed or CHO) results
  in increased diet-induced thermogenesis.
• Production of T3 is increased during short-term
  overfeeding, apparently due to increased
  conversion of T4 to T3.
• Plasma levels of T3 decrease during prolonged
  fasting which is correlated with a down
  regulation of hepatic nuclear T3 receptors.

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Diet TH Function

• A decrease in serum T3 per se does not decrease
  hepatic nuclear T3 receptor content as brain T3
  receptor number is not concomitantly changed.
• A particular cell type may be able to modify its
  nuclear T3 receptor content in response to its
  own metabolic status.
• This infers the possibility of individual target
  cell acceptance or rejection of the hormonal
  directive and may represent a homestatic
  protective mechanism to prolong survival of the
  organism when food is limited.

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Permissive Actions

• TH are required for the actions of other hormones
  on target tissues. Because TH and steroids
  mediate most of their actions at the genome to
  induce protein synthesis, it is likely that these
  proteins function as substrates in the action of
  other hormones.
• TH induce GH production in cultured rat pituitary
  tumor cells. Glucocorticoids also stimulate GH
  synthesis but only in the presence of TH. There
  is a synergistic activation of GH when both
  hormones are present.

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Mechanisms of Action

• The action of T3 is analogous to the model for
  steroid hormone action.
• There are two known TH receptor genes TH
  receptor b and TH receptor a.
• TH receptor b produces TH b1 and TH b2 proteins
  and TH a produces TH receptor a1 and a2.
• TH b1, b2 and TH a1 bind T3 and regulate thyroid
  hormone responsive gene transcription.

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Mechanisms of Action

• The a2 does not bind T3 and is believed to
  inhibit transcriptional effects of TH b1, b2 and
  a1.
• TH a1 is present in many tissues but TH b2
  appears to be restricted to the pituitary gland
  and the CNS.
• TH receptors are intranuclear proteins that have
  a distinct domains for binding T3 and DNA and for
  forming homodimers with nearby TH receptors or
  heterodimers with other nuclear recptors or
  thyroid hormone auxilary proteins.

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Mechanisms of Action

• Under normal circumstances T4 and T3 traverse the
  cell membrane by an enrgy dependent process, then
  T4 is converted into T3 which enters the nucleus
  where it binds to the TH receptor.
• T3-TH complexes bind as monomers, homodimers, or
  heterodimers to specific thyroid-response
  elements present in the thyroid-hormone regulated
  genes.
• This initiates the activity of RNA polymerase
  which controls transcription of the structural
  gene regions into mRNA.
• mRNA is then translated into protein products
  that mediate TH effects.

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Extranuclear Effects of TH

• TH stimulate human red cell Ca-ATPase activity.
• TH stimulate rapid uptake of a.a. into cells an
  action not blocked by actinomycin D or puromycin.
• 2 deoxyglucose uptake can be stimulated by T3 and
  this is not blocked by inhibitors of
  transcription or translation.
• TH also stimulate the Na/K-ATPase pump by
  increasing the number of Na pump units.

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Summary of TH Actions

• There appears to be no single intracellular
  effector mechanism for thyroid hormone action but
  several pathways contribute to an integrated
  cellular response.
• Nuclear actions of TH may be related to slower
  anabolic effects such as those involved in growth
  and differentiation.
• Actions of TH on the plasma membrane are rapidly
  initiated events that control increased heart
  rate, O2 consumption, and ATP production.

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Pathophysiology

• TSH controls thyroid function by binding to its
  receptor at the basolateral membrane of the
  follicular cells. Mutations in the gene encoding
  the TSH receptor can lead to hypo- or
  hyperthyroidism.
• Overstimulation of the thyroid may result from an
  autoimmune response involving AB to the TSH
  receptor. TSAb is the name given to the AB
  responsible for this.

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Pathophysiology

• This type of hyperthyroidism has been referred to
  as Graves disease (exopthalmic or toxic goiter).
• In rare instances hyperthyroidism may result from
  ectopic production of TSH or even from a
  trophoblastic tumor secreting either excessive
  amounts of hCG or a TSH like molecule.

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Pathophysiology

• Cretins are individuals who suffer from a
  deficiency or total absence of thyroid hormones.
• Major symptoms of cretinism are failure of
  skeletal growth and maturation, mental
  retardation.
• Hypothyroidism in the adult is called myxedema
  because of the characteristic mucinous protein
  deposit in the subcutaneous tissues.

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Pathophysiology

• Failure of the glands to produce T4 T3 may lead
  to goiter as well, since in the abvsence of
  negative feedback to the hypothalamus and AP,
  there is excessive TSH secretion.
• TSH continues to lead to hypertrophy of the
  thyroid follicular cells and thyroid glands
  become hyperplastic and have grossly columnar
  follicular cells with decreased amount of colloid
  due to enhanced engulfment and degradation.