Endocrinology

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Endocrinology
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Major endocrine glands in the body
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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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MODES OF HORMONE DELIVERY

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

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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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• cAMP IP3

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Pituitary Gland
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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.
• 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).
• 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 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.
• Oxytocin specifically stimulates certain smooth
  muscles to contract.
• Primarily those of the reproductive tract and
  mammary glands.

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Effects of Oxytocin

• Oxytocin stimulation at low doses causes rhythmic
  contractions of the uterus.
• ö Oxytocin stimulation at high dose causes
  sustained tetanic uterine contractions.
• ö Oxytocin is often used to induce labour.
• ö It is now generally believed that oxytocin
  believed that oxytocin produced by the fetus
  plays a critical role in labour.
• ö Oxytocin is also used to stop post-partum
  bleeding.

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• 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.
• 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.
• 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.
• 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.