Endocrinology

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Endocrinology
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MODES OF HORMONE DELIVERY I

• ENDOCRINE
• Most common (classical) mode, hormones delivered
  to target cells by blood.
• PARACRINE
• Hormone released diffuses to its target cells
  through immediate extracellular space.
• Blood is not directly involved in the delivery.

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MODES OF HORMONE DELIVERY II

• NEUROENDOCRINE
• Hormone is produced and released by a neuron,
  delivered to target cells by blood.
• AUTOCRINE
• Hormone released feeds-back on the cell of
  origin, again without entering blood circulation.

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Major endocrine glands in the body
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HORMONE-TARGET CELL SPECIFICITY

• Only target cells, or cells that have specific
  receptors, will respond to the hormones
  presence.
• The strength of this response will depend on
• Blood levels of the hormone
• The relative numbers of receptors for that
  hormone on or in the target cells
• The affinity (or strength of interactions) of the
  hormone and the receptor.

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HALF-LIFE, ONSET, and DURATION of HORMONE
ACTIVITY

• The affinity of hormones to their specific
  receptors is typically very high
• The actual concentration of a circulating hormone
  in blood at any time reflects
• Its rate of release.
• The speed of its inactivation and removal from
  the body.

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• The half-life is the time required for the
  hormone to loose half of its original
  effectiveness (or drop to half of its original
  concentration.
• The time required for hormone effects to take
  place varies greatly, from almost immediate
  responses to hours or even days.
• In addition, some hormones are produced in an
  inactive form and must be activated in the target
  cells before exerting cellular responses.
• In terms of the duration of hormone action, it
  ranges from about 20 minutes to several hours,
  depending on the hormone.

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CONTROL OF HORMONE RELEASE

• The synthesis and secretion of most hormones are
  usually regulated by negative feedback systems.
• As hormone levels rise, they stimulate target
  organ responses. These in turn, inhibit further
  hormone release.
• The stimuli that induce endocrine glands to
  synthesize and release hormones belong to one of
  the following major types
• Humoral
• Neural
• Hormonal

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CHEMISTRY OF HORMONES

• Peptide hormones largest, most complex, and most
  common hormones. Examples include insulin and
  prolactin
• Steroid hormones lipid soluble molecules
  synthesized from cholesterol. Examples include
  gonadal steroids (e.g testosterone and estrogen)
  and adrenocortical steroids (e.g. cortisol and
  aldosterone).
• Amines small molecules derived from individual
  amino acids. Include catecholamines (e.g.
  epinephrine produced by the adrenal medulla), and
  thyroid hormones.
• Eicosanoids small molecules synthesized from
  fatty acid substrates (e.g. arachidonic acid)
  located within cell membranes

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Pituitary Gland
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Pituitary development
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The Master Gland

• The pituitary has been called the Master gland
  in the body.
• This is because most of the pituitary hormones
  control other endocrine glands

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Hormones of the anterior pituitary

• There are 6 main hormones which are secreted by
  the adenohypophysis
• 1) Growth hormone (also known as somatotropin).
• 2) Thyroid-stimulating hormone (also known as
  thyrotropin).
• 3) Adrenocorticotropic hormone (also known as
  corticotropin).
• 4) Prolactin.
• 5) Follicle-stimulating hormone.
• 6) Luteinizing hormone.

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Control of pituitary gland secretion

• Secretion of each hormone by the adenohypophysis
  is controlled by neurohormones secreted by
  nerves in the hypothalamus.
• In most cases there are two neurohormones
  controlling the secretion of a pituitary hormone.
  One which stimulates pituitary secretion and one
  which inhibits pituitary secretion.

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Neurohormones

• Are hormones secreted by nerve cells. These are
  true hormones, since they are secreted into the
  bloodstream.
• All are secreted by neurosecretory neurons in the
  hypothalamus.
• They are secreted into the hypophyseal portal
  system, which then carries the blood to the
  anterior pituitary.

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Pituitary portal system

• Arterioles break into capillaries in the
  hypothalamus.
• The axons of the neurosecretory cells form
  plexuses with these capillaries.
• Downstream, the capillaries combine into a vein
  which carries the blood to the pars distalis.
• The vein breaks into a capillary network which
  supplies all the cells of the anterior lobe.
• Thus, the neurohormones are carried directly
  (well, sort of) from the hypothalamus to the
  adenohypophysis.

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Portal system
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Growth hormone (GH)

• Growth hormone is secreted by somatotrophs.
• GH is a protein hormone consisting of a single
  peptide chain of 191 amino acids.
• GH secretion is stimulated by the secretion of
  Growth Hormone Releasing Hormone (GHRH) by the
  hypothalamus.
• GH secretion is inhibited by the secretion of
  somatostatin by the hypothalamus.
• GH activates a tyrosine kinase receptor.

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Functions of GH

• GH has effects of every cell of the body, either
  directly or indirectly. Primarily, it decreases
  the uptake and metabolism of glucose. (Elevates
  plasma glucose)
• Increases the breakdown of fat. (Increases the
  blood levels of fatty acids)
• Increases the uptake of amino acids from the
  blood and increases protein synthesis in cell.
  (Decreases plasma amino acids)

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Actions of GH on specific cell types

• Muscle cells
• Increases amino acid uptake
• Increases protein synthesis
• Decreases glucose uptake
• Net result Increased Lean body mass

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• Chondrocytes
• increases uptake of sulfur
• increases chondroitin sulfate production
• increases DNA, RNA synthesis
• increases Protein synthesis
• increases Amino acid uptake
• increases Collagen synthesis
• increases Cell size and number
• Net result Increased Linear growth

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• Hepatocytes
• Stimulates the production of somatomedins by the
  liver.
• These somatomedins directly regulate metabolic
  function in target cells. They are also called
  insulin-like growth factors, or IGFs.

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• Adipocytes
• Decreases glucose uptake
• Increases lypolysis
• Net result Decreased Adiposity

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• Other cell types in general
• Increased protein synthesis
• Increased DNA, RNA synthesis
• Increased cell size and number
• Net result Increased organ size
• Increased organ function

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Other considerations

• GH has a short half-life of about 20 minutes.
  However, the IGFs are much longer lived (T1/2 of
  about 20 hours).

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GH and Insulin actions are correlated

• When there is ample dietary intake of proteins
  and carbohydrates, then amino acids can be used
  for protein synthesis and growth.
• Under these conditions, both insulin and GH
  secretion are stimulated.
• Net result Amino acids are shunted to protein
  synthesis and glucose is shunted to metabolism.
• However, under conditions where only
  carbohydrates are ingested, insulin secretion is
  increased, but GH secretion is decreased.
• Net result Both glucose AND amino acids are
  shunted to metabolism.

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Pathophysiology of abnormal GH secretion

• Hyposecretion
• Pre-adolescents
• Decreased GH secretion (or sensitivity) results
  in slow growth and delayed onset of sexual
  maturation. These children also tend to be
  slightly chubby.
• Post-adolescents
• Generally, no serious problems are associated
  with hyposecretion of GH in mature individuals.
  However, in very severe cases there can be
  progeria (rapid and premature aging).

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Hypersecretion

• Pre-adolescents (before closure of epiphyseal
  plates)
• Hypersecretion results in gigantism, where
  affected individuals grow extremely rapidly and
  become abnormally tall (even over 2.4 m). Body
  proportions remain relatively normal. Usually,
  there are cardiovascular complications later in
  life.

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• Post- adolescents (after epiphyseal closure).
• Hypersecretion results in tissue enlargement.
  This is particularly true of the bones, which get
  heavier and thicker. They cannot elongate since
  the epiphyseal plates are closed. A common
  symptom is a coarsening of the facial features
  and enlargement of the hands and feet. This
  condition is known as acromegaly.

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Treatments of GH secretion disorders

• Hypersecretion is usually caused by a tumour in
  the pituitary gland. Treatment consists of
  surgical or radiation ablation of the tumour
  mass.
• Hyposecretion is usually treated in children by
  hormone replacement therapy. This is generally
  not required in adults, unless GH secretion is
  completely abolished.

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Prolactin (PRL)

• Structurally, very similar to growth hormone
  (single peptide chain of 198 amino acids).
• PRL is secreted by mammotrophs (also referred to
  as lactotrophs).
• Secretion of PRL is also under dual control by
  the hypothalamus.

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• Primarily under inhibitory control. This means
  that if there is an injury to the hypophyseal
  portal system which blocks hypothalamic
  regulation of the pituitary gland, PRL levels
  increase. All other pituitary hormone levels
  decrease when this happens.
• Dopamine is secreted by neuroendocrine cells in
  the hypothalamus and inhibits PRL release.
• PRL release is stimulated by thyrotropin
  releasing hormone (TRH), vasoactive intestinal
  peptide (VIP) and at least one other as yet
  unidentified factor.
• PRL activates a tyrosine kinase receptor.

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Functions of PRL

• In humans, the only effects of PRL so far
  identified are on reproduction and nursing.
• PRL is important in stimulating differentiation
  of breast tissue during development.
• Stimulates further development of mammary glands
  during pregnancy.

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• Stimulates milk production (lactation) after
  pregnancy.
• PRL has a role in regulation of the female
  reproductive cycle. However, its precise role
  has not be delineated yet. Excess PRL secretion
  is know to block synthesis and release of
  gonadotropins, disrupting menstruation and
  causing infertility.
• PRL also can regulate male fertility, but how it
  does so remains unclear.

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Pathophysiology of PRL secretion

• Hyposecretion is never seen. However,
  hyperprolactinemia (excess secretion of PRL) is a
  fairly common disorder. Symptoms in women
  usually include amenorrhea (cessation of
  menstruation), galactorrhea (abnormal lactation)
  and infertility. In men, infertility and
  galactorrhea are the most common symptoms.
• Treatment usually consists of administration of a
  dopaminergic agonist, such as bromocriptine.

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Thyroid Stimulating hormone (TSH)

• TSH is a glycoprotein hormone composed of 2
  peptide chains a and b.
• The a subunit is called unspecific because it
  is also incorporated into two other unrelated
  pituitary hormones (LH and FSH).
• The b subunit contains the biologically active
  sites. However, it must be combined with the a
  subunit in order for the hormone to be active.

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• TSH secretion is controlled very tightly by the
  hypothalamus.
• TSH secretion is stimulated by Thyrotropin-releasi
  ng hormone (TRH). TRH is a tripeptide, meaning
  it is composed of three amino acids.
• TRH secretion is stimulated by thermal and
  caloric signals in the brain.

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Control of TSH secretion

• Negative control of TSH secretion occurs in two
  ways
• Triiodothyronien or T3 (which will be discussed
  later) feeds back on the hypothalamus to
  stimulate secretion of dopamine and somatostatin.
  These two factors both function as TSH-release
  inhibiting factors.
• T3 can feed back directly onto the thyrotrophs to
  directly inhibit TSH secretion.

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Function of TSH

• TSH stimulates the follicular cells of the
  thyroid to induce a number of responses
• TSH activates both the cAMP and PIP pathways
• Increased cAMP
• Increased Ca2i
• TSH can stimulate both cell growth (of follicular
  cells) and secretion of T3 and thyroxine ( T4 ).

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Adrenocorticotropic hormone (ACTH)

• ACTH is a single peptide chain which is
  relatively small (30 amino acids).
• ACTH secretion is primarily under stimulatory
  control (i.e. there isnt an ACTH-release
  inhibitory factor).

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• ACTH secretion is stimulated by corticotropin
  releasing hormone (CRH).
• CRH secretion can be stimulated by a large number
  of factors, most of which would be considered
  stress factors.
• Examples infection, trauma, sleep cycle,
  anxiety, depression and others. (Just remember
  stress).

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Functions of ACTH

• ACTH stimulates the adrenal gland to secrete
  cortisol.
• ACTH levels are associated with the sleep cycle.
• ACTH stimulates the cAMP pathway in
  adrenocorticol cells.
• ACTH can directly inhibit CRH secretion (negative
  feedback).

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Follicular-Stimulating hormone (FSH) Luteinizing
Hormone (LH)

• These are generally grouped together and called
  gonadotropines.
• Gonadotropins are secreted by the gonadotrophs,
  which synthesize and secrete both LH and FSH.
• Both LH and FSH are peptide hormones.
• Secretion of gonadotropins is mainly under
  positive control.
• Hypothalamus secretes gonadotropin-releasing
  hormone (GnRH) which stimulates gonadotrophs to
  secrete both LH and FSH.

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Functions of LH and FSH

• LH and FSH stimulate secretion of the sex
  steroids by the gonads. Mainly estrogen in women
  and testosterone in men.
• FSH also stimulates gonadal release of inhibin,
  which serves as a negative feedback factor to
  block release of FSH by pituitary.
• LH and FSH stimulate the gonadal release of
  activin, which can have positive feedback on
  gonadotropin secretion by the pituitary.
• Gonadal secretion of estrogen and testosterone
  can negatively feedback on both the hypothalamus,
  to reduce GnRH secretion, and the gonadotrophs
  directly, to reduce gonadotropin secretions.

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Hormones of the posterior pituitary

• Remember that the neurohypophysis serves as a
  storage organ for hormones produced by
  neurosecretory cells in the hypothalamus.
• There are two hormones secreted by the
  neurohypophysis
• 1) antidiuretic hormone (ADH)
• 2) oxytocin
• Both hormones are peptide hormones containing 9
  amino acid residues.
• They differ in only 2 amino acids, but have very
  different functions.
• Both activate the PIP pathway in the target cells.

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ADH

• Term diuresis ö means production of urine.
• ADH inhibits urine production, i.e. conserves
  water in the body.
• Main target for ADH are the cells in the kidney
  which reabsorb water (will be covered in detail
  in the section on renal physiology).
• ADH secretion is stimulated by either an increase
  in the osmotic concentration of the blood, or by
  a decrease in blood volume
• usually sensed by a decrease in blood pressure.

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• Secretion of ADH causes retention of water, which
  will tend to counteract both an increase in
  blood concentration and/or decrease in blood
  volume.
• cannot overcome serious blood loss.
• Conversely, excess consumption of water will have
  two effects
• increase blood volume (and pressure).
• decrease blood concentration.
• Under these conditions ADH secretion is
  inhibited.
• This results in formation of more urine, which is
  usually fairly dilute.
• Blood loses water and thus volume.

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Oxytocin

• Release of oxytocin is under neural control (like
  with ADH).
• However, unlike ADH, the release of oxytocin is
  largely controlled by emotional state.
• Oxytocin specifically stimulates certain smooth
  muscles to contract.
• Primarily those of the reproductive tract and
  mammary glands.

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• Oxytocin is required for nursing.
• Principally know as the milk letdown factor.
• It is secreted within seconds of the onset of
  suckling.
• Sensory receptors in the nipples generate
  afferent impulses that stimulate the
  hypothalamus, triggering oxytocin secretion.
• Can actually be secreted in response to auditory
  input, i.e. in nursing mothers in response to
  hearing their babies cry.

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Effects of Oxytocin

• Oxytocin stimulation at low doses causes rhythmic
  contractions of the uterus.
• Oxytocin stimulation at high dose causes
  sustained tetanic uterine contractions.
• Oxytocin is often used to induce labour.

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• It is now generally believed that oxytocin
  believed that oxytocin produced by the fetus
  plays a critical role in labour.
• Oxytocin is also used to stop post-partum
  bleeding.
• The number of oxytocin receptors in uterine
  smooth muscles increases towards the end of
  pregnancy.
• Oxytocin affects smooth muscle cells in uterus
  and vagina of non-pregnant women.

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• There is clear evidence that oxytocin is involved
  in sexual arousal and orgasm in both men and
  women.
• What role it plays in men is unknown. However,
  it may play a strong role in reinforcing the
  pair-bond.
• The role in women is only slightly better known.
• Oxytocin is secreted in response to vaginal
  distention during intercourse.
• Oxytocin is also secreted in response to
  stimulation of the nipples.

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Emotional considerations

• Oxytocin secretion during sexual intercourse
  probably serves to reinforce the male-female
  pair-bond.
• Often referred to as the the cuddle hormone or
  the love hormone in the popular press.

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• Secretion of oxytocin during and after labour may
  play an important role in the formation of the
  mother-child pair-bond.
• Oxytocin secreted during suckling may serve to
  reinforce this pair-bond.

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• Recent studies with knock out mice has shown that
  oxytocin is critical in initiating and
  maintaining maternal care.
• Oxytocin secreted in response to suckling can
  cause uterine contractions which may play a role
  in the recovery of uterine muscle tone after
  pregnancy and may serve to shrink the uterus back
  to normal.

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Thyroid Gland

• Location and Structure

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• The largest pure endocrine gland in the body,
  located in the front of the neck, on the trachea
  just below to the larynx.
• Its two lobes are connected by a median tissue
  mass called the isthmus.
• Internally, it is composed of about 1 million of
  round follicles. The walls of each follice are
  formed by cuboidal and squamous epithelial cells
  called follicle cells, which produce
  thyroglobulin (glycoprotein).

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• The lumen of each follicle stores colloid, which
  consists primarily of molecules of thyroglobulin.
• The follicular epithelium also consists of
  parafollicular cells, a separate population of
  endocrine cells that produce calcitonin, a
  hormone involved in calcium homeostasis.

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Thyroid hormones (THs)

• The two THs contain iodine and are called
  thyroxin or T4 and triiodothyronine or T3.
• T4 and T3 have a very similar structure as each
  is made up of two tyrosine amino acids linked
  together and either 4 or 3 atoms of iodine,
  respectively.
• T4 is the main hormone produced by the thyroid
  and T3 has most if not all of biological activity
  as all target tissues rapidly convert T4 to T3.

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• Except for the adult brain, spleen, testes, and
  the thyroid gland itself, THs affect all other
  types of cells in the body where they stimulate
  activity of enzymes especially those involved in
  glucose metabolism
• Increase metabolic rate in target tissues, which
  increases body heat production (calorigenic
  effect).
• THs also are critically important for normal
  growth and development of skeletal and nervous
  systems and maturation of reproductive system.

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Synthesis of thyroid hormones

• Formation and storage of thyroglobulin.
• This process takes place in follicle cells and
  the final product is packed into vesicles, their
  contents are discharged into the lumen of the
  follicle and become a major part of the colloid.

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• Iodide trapping and oxidation to iodine.
• To produce functional iodinated hormones,
  follicle cells accumulate iodide from the blood.
  A protein pump (iodide trap), located on the
  basal surface of follicle cells, actively
  transports iodide into follicle cells where it is
  oxidized and converted to iodine (I2).

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• Iodination.
• Once formed, iodine is attached to tyrosine amino
  acids which are part of the thyroglobulin.
• Iodination of one tyrosine produces
  monoiodotyrosine (MIT), iodination of two
  tyrosines diiodotyrosine (DIT).

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• Coupling.
• Then enzymes within the colloid link MITs and
  DITs in a highly specific fashion, as a result
  two DITs linked together result in T4 , while
  coupling of MIT and DIT produce T3.

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• Coupling (cont.)
• Interactions between two DITs are more frequent
  so more thyroxin.
• At this point both thyroid hormones are still
  attached to thyroglobulin molecules in the
  colloid.

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• Colloid endocytosis.
• Colloid droplets containing iodinated
  thyroglobulin are taken up by follicle cells by
  endocytosis. These combine with lysosomes to
  form phagolysosomes.

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• Cleavage of the hormones for release.
• Within the phagolysosomes, the hormones are
  cleaved from the thyroglobulin by lysosomal
  enzymes. The free hormones then diffuse through
  the basal membrane out of the follicle cell and
  into the blood stream.

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Transport and regulation of release

• Most released T4 and T3 immediately bind to
  plasma proteins, of which the most important is
  thyroxin-binding globulin (TBG) produced by the
  liver.
• Binding proteins protect T4 and T3 from immediate
  degeneration by plasma enzymes, also they allow
  T4 and T3 to reach target tissues, often located
  a significant distance away from the thyroid
  gland.
• Decreasing blood levels of thyroxin trigger
  release of TSH from the anterior pituitary, which
  stimulates the thyroid gland to produce more
  thyroxin.

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Pathology of the thyroid gland function

• Both hypo- and hyperactivity and of the thyroid
  gland can cause severe metabolic disturbances.
• In adults, hypothyroidism is referred to as
• myxedema.
• Symptoms
• Low metabolic rate, poor resistance to cold
  temperatures, constipation, dry skin (especially
  facial), puffy eyes, lethargy and mental
  sluggishness.
• If hypothyroidism results from lack of iodine
  the thyroid gland enlarges to form a goiter.

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• Severe hypothyroidism during the fetal
  development and in infants is called cretinism.
• Symptoms
• A short disproportionate body, a thick tongue and
  neck, and mental retardation.
• The condition is preventable by thyroid hormone
  replacement therapy. However, once developmental
  abnormalities and mental retardation appear,
  they are not reversible.

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Hyperthyroidism

• The most common form of hyperthyroidism is
  Grave's disease, believed to be an autoimmune
  disease.
• The immune system produces antibodies that mimic
  TSH, which bind to TSH receptors and permanently
  switch them on, resulting in continuous release
  of thyroid hormones.
• Typical symptoms include metabolic rate,
  sweating, rapid and irregular heartbeat,
  nervousness, and weight loss despite adequate
  food intake.
• Often, exophthalmos, or protrusion of the
  eyeballs, occurs caused by the edema of tissues
  behind the eyes followed by fibrosis.
• Treatments include surgical removal of the
  thyroid gland (very difficult due to an extremely
  rich blood supply) or ingestion of radioactive
  iodine (131I), which selectively destroys the
  most active thyroid cells.

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Hyperthyroidism and Graves Disease
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Parathyroid Glands

• The parathyroid glands are small in size and are
  found on the posterior aspect of the thyroid
  gland.
• Typically, there are four of them but the actual
  number may vary.

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Histology of the Parathyroid

• The endocrine cells within these glands are
  arranged in thick, branching cords containing
  oxyphil cells of unclear function and most
  importantly large numbers of chief cells that
  secrete parathyroid hormone (PTH).

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PTH

• Small protein
• Single most important hormone controlling calcium
  homeostasis. Its release is triggered by falling
  blood calcium levels and inhibited by
  hypercalcemia (high blood calcium).
• There are three target organs for PTH
• skeleton
• kidneys
• intestine

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PTH stimulates the following on these target
organs

• Osteoclasts (bone absorbing cells) are stimulated
  to digest bone and release ionic calcium and
  phosphates to the blood.
• Kidneys are stimulated to reabsorb calcium and
  excrete phosphate.
• Intestines are stimulated to increase calcium
  absorption.
• Vitamin D is required for absorption of calcium
  from ingested food.
• For vitamin D to exert this effect, it must first
  be converted by the kidneys to its active form
• It is this conversion that is directly stimulated
  by PTH.

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Pathology of the parathyroid glands

• Because calcium is essential for so many
  functions, including transmission of action
  potentials, muscle contraction, pacemaker
  activity in the heart, and blood clotting,
  precise control of ionic calcium levels in body
  fluids is absolutely critical. As a result both
  hyper- and hypoparathyroidism can have severe
  consequences.

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Hyperparathyroidism

• Rare, usually the result of a parathyroid gland
  tumor.
• Results in severe loss of calcium from the bones.
  
• The bones soften and deform as their mineral
  salts are replaced by fibrous connective tissue.
• Results in hypercalcemia
• Leads to, depression of the nervous system
  leading to abnormal reflexes and weakness of the
  skeletal muscles, and formation of kidney stones
  as excess calcium salts are deposited in kidney
  tubules.

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Hypoparathyroidism

• It is a PTH deficiency, which is a common
  consequence of parathyroid trauma or removal
  during thyroid surgery.
• The resulting hypocalcemia increases excitability
  of neurons and may lead to tetany resulting in
  uncontrollable muscle twitches and convulsions,
  which if untreated may progress to spasms of the
  larynx, respiratory paralysis and death.

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ADRENAL GLANDS

• The two adrenal glands are pyramid-shaped organs
  found atop the kidneys.
• Each gland is structurally and functionally two
  endocrine glands in one.

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• The inner adrenal medulla is made up of nervous
  tissue and acts as part of the sympathetic
  nervous system. The outer adrenal cortex forms
  the bulk (about 80) of the gland. Each of these
  regions produces its own set of hormones.

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Adrenal Medulla

• It is made up of chromaffin cells which secrete
  the catecholamines epinephrine (E) (adrenaline)
  and norepinephrine (NE) (noradrenaline) into the
  blood.
• During the fight-or-flight responses, the
  sympathetic nervous system is activated,
  including the chromaffin tissue and large amounts
  of catecholamines (80 of which is E) are
  released.
• In most cases the two hormones have very similar
  effects on their target organs. However, E is the
  more potent stimulator of the heart rate and
  strength of contraction, and metabolic
  activities, such as breakdown of glycogen and
  release of glucose).
• NE has great effect on peripheral
  vasoconstriction and blood pressure.

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Adrenal Cortex

• The cells of the adrenal cortex are arranged in
  three distinct zones, each zone producing
  corticosteroids.
• The Zona glomerulosa is the outer-most layer of
  cells and it produces mineralocorticoids, that
  help control the balance of minerals and water in
  the blood.
• The zona fasciculata is composed of cells that
  secrete glucocorticoids.
• The zona reticularis produce small amounts of
  adrenal sex steroids.

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Hormones of the Adrenal Cortex

• Mineralocorticoids
• Although there are several mineralocorticoids,
  aldosterone is by far the most potent and
  accounts for more than 95 of production. Its
  main function is to maintain sodium balance by
  reducing excretion of this ion from the body.
• The primary target organs of aldosterone are
  kidney tubules where it stimulates reabsorption
  of sodium ions from urine back to the
  bloodstream.
• Aldosterone also enhances sodium absorption from
  sweat, saliva, and gastric juice.

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• Secretion of aldosterone is induced by a number
  of factors such as high blood levels of
  potassium, low blood levels of sodium, and
  decreasing blood volume and pressure.
• The reverse conditions inhibit secretion of
  aldosterone.
• Glucocorticoids
• Glucocorticoids influence metabolism of most body
  cells, help us resist stress, and are considered
  to be absolutely essential to life.

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• The most important glucocorticoid in humans is
  cortisol, but small amounts of cortisone and
  corticosterone are also produced.
• The main effect of cortisol is to promote
  gluconeogenesis or formation of glucose from
  noncarbohydrate molecules, especially fats and
  proteins.
• Cortisol also breaks down adipose (fat) tissue,
  released fatty acids can be then used by many
  tissues as a source of energy and "saving"
  glucose for the brain.
• Blood levels of glucocorticoids increase
  significantly during stress, which helps the body
  to negotiate the crisis.
• Interestingly, chronic excess of cortisol has
  significant anti-inflammatory and anti-immune
  effects and glucocorticoid drugs are often used
  to control symptoms of many chronic inflammatory
  disorders, such as rheumatoid arthritis or
  allergic responses.

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Regulation of glucocorticoid secretion

• It is provided by a typical negative feedback
  system
• increased (hypothalamus) CRH negative
• increased (adenohypophysis) ACTH
• increased (adrenal cortex) cortisol

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• Gonadocorticoids (Sex Hormones)
• The amount of sex steroids produced by zona
  reticularis is insignificant compared to the
  amounts secreted by the gonads.
• These hormones may contribute to the onset of
  puberty and the appearance of axillary and pubic
  hair in both males and females.
• In adult women adrenal androgens (male sex
  hormones, especially testosterone) may be, at
  least partially, responsible for the sex drive.

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Pathology of the adrenal cortex function

• Hyperadrenalism
• It is referred to as Cushing's disease and can be
  caused by a cortisol-secreting tumour in the
  adrenal glands, ACTH-secreting tumour of the
  pituitary, or ACTH secreted by abdominal
  carcinoma.
• However, it most often results from the clinical
  administration of pharmacological (very high)
  doses of glucocorticoid drugs.
• The symptoms include a persistent hyperglycaemia,
  dramatic loss of muscle and bone proteins, and
  water and salt retention, leading to hypertension
  and edema - one of its signs is a swollen "moon"
  face. The only treatment is a surgical removal of
  tumour or discontinuation of the drug.

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• Hypoadrenalism
• It is referred to as Addison's disease and
  involves significant reduction in plasma glucose
  and sodium, very high levels of potassium and
  loss of weight. The usual treatment is
  corticosteroid replacement therapy.

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THE ENDOCRINE PANCREAS

• Located partially behind the stomach, the
  pancreas is a mixed gland composed of both
  endocrine and exocrine cells.
• More than 98 of the gland is made up of acinar
  cells producing an enzyme-rich juice that enters
  a system of ducts and is delivered to the
  duodenum of the small intestine during food
  digestion.

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• The remaining 1-2 of cells form about 1 million
  of islets of Langerhans, tiny cell clusters that
  produce pancreatic hormones.
• The islets have four distinct populations of
  cells, the two most important ones are alpha
  cells that produce hormone glucagon, and more
  numerous beta cells that synthesize insulin. In
  addition, delta cells produce somatostatin and F
  cells secrete pancreatic polypeptide (PP).

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Hormones of the Pancreas

• Glucagon and insulin are directly responsible for
  the regulation of blood glucose levels and their
  effects are exactly opposite
• insulin is hypoglycemic (it decreases blood
  glucose)
• glucagon is hyperglycemic (it increases blood
  glucose).
• Pancreatic somatostatin inhibits the release of
  both insulin and glucagon and slows the activity
  of the digestive tract.
• PP regulates secretion of pancreatic digestive
  enzymes and inhibits release of bile by the
  gallbladder.

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Glucagon

• Glucagon is a 29 amino acid polypeptide with
  extremely potent hyperglycemic properties. One
  molecule of this hormone can induce the release
  of 100 million molecules of glucose into the
  blood.
• The major target organ of glucagon is the liver,
  where it promotes
• Breakdown of glycogen to glucose (glycogenolysis)
• Synthesis of glucose from lactic acid and from
  noncarbohydrate molecules such as fatty acids and
  amino acids (referred to asgluconeogenesis).
• Release of glucose into the blood by the liver
• All these effects blood sugar levels.
• Secretion of glucagon from the alpha cells is
  induced by, most importantly, low blood sugar
  levels but also by high amino acid levels in the
  blood (e.g. following a protein-rich meal).
  Rising blood sugar concentration and somatostatin
  from the delta cells inhibit glucagon release.

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Insulin

• Insulin is a 51 amino acid protein consisting of
  two polypeptide chains linked by disulfide bonds.
  It is synthesized as part of a larger molecule
  called proinsulin and packed into secretory
  vesicles where its middle portion is excised by
  enzymes to produce functional hormone, just
  before insulin is released from the beta cell.
• As mentioned earlier, insulin's main function is
  to lower blood sugar levels but it also affects
  protein and fat metabolism.
• In general, insulin
• Increases membrane transport of glucose into body
  cells, especially muscle and liver cells
• Inhibits the breakdown of glycogen (it should not
  be confused with glucagon!) into glucose,
• Increases the rate of ATP production from
  glucose
• Increases the rate of glycogen synthesis
• Increases the rate of glucose conversion to fat.

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• Insulin binds to tyrosine kinase receptors, but
  mechanism of action, including type(s) and
  specific roles of second messengers, are poorly
  understood.
• The beta cells are stimulated to produce insulin
  primarily by elevated blood sugar levels, but
  also by high blood levels of amino acids and
  fatty acids.
• Several hormones also induce the release of
  insulin, including glucagon, epinephrine, growth
  hormone, thyroid hormones, and glucocorticoids.
• In contrast, somatostatin inhibits insulin
  release.

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