Endocrine System

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Endocrine System
Huiping Wang (???), PhD Department of
Physiology Rm C516, Block C, Research Building,
School of Medicine Tel [phone] Email
wanghuiping_at_zju.edu.cn
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• RECOMMENDED TEXTBOOK Widmaier EP, Raff H,
  Strang KT (2006) Vanders Human Physiology The
  Mechanisms of Body Function, Tenth Edition.
  McGraw-Hill.
• SUPPLEMENTARY READING Stephan Sanders (2003)
  Endocrine and Reproductive systems, Second
  Edition. Mosby.
• COURSE WEBSITERS http//www.endocrineweb.com/
• http//arbl.cvmbs.colostate.edu/hbooks/pat
  hphys/endocrine/index.html
• http//medical.physiology.uab.edu/cardio.h
  tm
• http//www.mhhe.com/biosci/ap/foxhumphys/s
  tudent/olc/index.htm

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Endocrine System

• General Principles of Endocrine Physiology
• Hypothalamus and pituitary gland
• Thyroid gland
• Endocrine Regulation of Calcium and Phosphate
  Metabolism
• Adrenal gland
• Pancreatic hormones

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General Principles of Endocrine Physiology
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Outline

• Endocrine system and Hormone
• Hormone types
• Hormone synthesis, storage, release, transport,
  clearance and action modes
• Characteristics of hormones
• Regulation of Hormone Secretion
• Mechanisms of hormone action

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Endocrine System

• One of the two major communication systems in the
  body
• Have much longer delays
• Last for much greater lengths of time
• Integrate stimuli and responses to changes in
  external and internal environment
• crucial to coordinated functions of highly
  differentiated cells, tissues and organs

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Endocrine gland (ductless) is a group of cells
that produce and secret a hormone

• Endocrine Glands
• Hypothalamus
• Pituitary (Anterior and Posterior)
• Thyroid / Parathyroid
• Endocrine Pancreas (islets)
• Adrenal Cortex and Medulla
• Gonad (Ovary and Testis)

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Endocrine System

• The endocrine system broadcasts its hormonal
  messages to target cells by secretion into blood
  and extracellular fluid. Like a radio broadcast,
  it requires a receiver to get the message - in
  the case of endocrine messages, cells must bear a
  receptor for the hormone being broadcast in order
  to respond.

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What is a hormone?

• Chemical messenger synthesized by specific
  endocrine cells in response to certain stimuli
  and secreted into the blood
• Travel via the circulation to affect one or more
  groups of different cells (target cells) to
  elicit a physiological response

Hormones are primarily information transferring
molecules
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Types of Hormones
Types Amines Steroids Protein and peptides
Example T4, T3, catecholamine Hormones from adrenal cortex and gonads Most of hormones insulin, oxytocin, GH
Synthesis Tyrosine Cholesterol DNA mRNA Preprohormone - Prohormone
Feature lipid insoluble lipid soluble lipid insoluble
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Synthesis of peptide hormones
NUCLEUS The DNA code is transcribed into
mRNA. RIBOSOMES The mRNA is translated to
give instructions for proteins synthesis.
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Typical synthesis of peptide hormones

• Preprohormones- larger hormones produced on the
  ribosomes of the endocrine cells
• Prohormones- cleavage of preprohormones by
  proteolytic enzymes in rER
• Prohormones- packaged into secretory vesicles by
  the Golgi apparatus
• Prohormones- cleaved to give active hormone and
  pro-fragments

pre-pro-insulin pro-insulin insulin
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Synthesis of steroid hormones
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Hormone Storage and Release

• Thyroid and steroid hormones
• Not stored as secretory granules
• Transferring through plasma membrane
• Protein and catecholamine hormones
• Stored as secretory granules
• Released by exocytosis

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Hormones are not secreted at auniform rate

• In a pulsatile pattern
• Diurnal (circadian) rhythm
• linked to sleep-wake cycles (cortisol, growth
  hormone)
• Be aware of the pulsatile nature and rhythmic
  pattern of hormone secretion when relating the
  serum hormone measurements to normal values

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Hormones are not secreted at auniform rate

• Rhythmic secretion
• Cyclic
• oestrogen, progesterone, LH

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Modes of Action

• Endocrine transmission of a signal from a
  classic endocrine cell through bloodstream to a
  distant target cell e.g. testosterone
• Neurocrine hormone is released from a neuron
  down its axon and then travels via the
  bloodstream to target cell
• Paracrine - hormone acts on adjacent cells e.g.
  histamine released at site of injury to constrict
  blood vessel walls and stop bleeding
• Autocrine hormone is released and acts on the
  cell that secreted it. e.g. norepinephrine itself
  inhibits further release by that cell in the
  adrenal medulla

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A secretion may have several sites of action
simultaneously

• Example
• Norepinephrine
• - Autocrine action causes negative
  feedback on secretion.
• - Simultaneously, endocrine action causes
  respiration rate to increase, peripheral blood
  vessels to constrict, etc.

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Hormone Transport

• Peptides and catecholamine
• water soluble
• dissolve in blood
• circulate in blood mainly in free form
• Steroid and thyroid hormones
• circulate in blood mainly bound to plasma
  proteins
• the free form is biologically active
• the greater binding, the longer half-life

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Hormone Clearance

• The half-life of a hormone in blood
• is the period of time needed for its
  concentration to be reduced by half.
• Free min
• Binding mins, hrs, days
• e.g. T4 (6 days) Insulin (0.006 days)
• Hormone concentration in blood is determined by
• secretion rate
• clearance rate
• Ways of Clearance
• target cell uptake
• metabolic degradation
• urinary or biliary excretion

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The metabolic fate of a given hormone molecule
in the blood
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Characteristics of Hormones

• Regulates rate of reaction
• Do not initiate
• Very specific
• Amplification effect
• Present in very small quantity
• pg/mL ?g/mL

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Characteristics of Hormones

• Interaction between hormones
• Synergistic action
• Antagonistic action
• Permissive action
• Hormone A must be present for the full strength
  of hormone Bs effect.
• Up-regulation of one hormones receptors by
  another hormone
• the facilitation of the action of one hormone by
  another

• e.g. the ability of TH to permit
  epinephrine-induced release of fatty acids from
  adipose tissue cells (TH causes an ? no. of
  epinephrine receptors on the cell)

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Regulation of Hormone Secretion
Three types of inputs to endocrine cells that
stimulate or inhibit hormone secretion.
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Regulation of Hormone Secretion

• Negative feedback
• Most common
• Occurs when a hormone produces a biologic effect
  that, on attaining sufficient magnitude, inhibits
  further secretion
• Positive feedback
• Less common
• Amplify the initial biological effect of the
  hormone

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Negative Feedback

• Characteristic of control systems in which
  systems response opposes the original change in
  the system.
• Hormone itself feeds back to inhibit its own
  synthesis.
• Regulated product (metabolite) feeds back to
  inhibit hormone synthesis.
• Important for homeostatic control.
• Example Control of blood glucose by insulin

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Positive Feedback

• Characteristic of control systems in which an
  initial disturbance sets off train of events that
  increases the disturbance even further.
• Amplifies the deviation from the normal levels
• Example Oxytocin (suckling)
• Important for amplification of level for action

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Mechanisms of hormone actions

• Hormone action mediated by the specific receptors
• Most hormones circulate in blood, coming into
  contact with essentially all cells. However, a
  given hormone usually affects only a limited
  number of cells, which are called target cells. A
  target cell responds to a hormone because it
  bears receptors for the hormone.

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Hormone Receptors
The receptor provides link between a specific
extracellular hormoneand the activation of a
specific signal-transduction system

• Structure
• Recognition domain binds hormone
• Coupling domain generates signal
• Location
• cell membrane (e.g. for insulin)
• cytoplasm (for steroids)
• nucleus (e.g. for thyroid hormone)
• Receptor capacity
• exposure to excess hormone down-regulates
  capacity
• low hormone concentration up-regulates capacity

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Two general mechanisms ofhormone action

• Second messengers enzyme activity ??(rapid,
  cytosolic effects)
• Gene expression - enzymes synthesis ??(slow,
  nuclear effects)

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Mechanisms of Peptide Hormone Action

• G proteins
• are GTP-binding proteins
• couple hormone receptors to adjacent effector
  molecule
• have intrinsic GTPase activity
• have three subunits a, ß, ?
• a subunit bound to GDP ? inactive G protein
• a subunit bound to GTP ? active G protein
• the effect can be either stimulatory (Gs) or
  inhibitory (Gi)
• Second messengers
• cAMP second message system
• IP3 mechanism
• Ca2-calmodulin mechanism

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Signal transduction pathway involving adenylate
cyclase
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Cyclic AMP signaling-sequence of events

• The hormone (1st messenger) binds to the membrane
  receptor the membrane receptor changes shape and
  bind to G protein (GTP-binding protein)
• G protein is activated binds to GTP (Guanosine
  5- triphosphate) and release GDP
• Activated G protein moves to membrane and binds
  and activates adenylate cyclase (GTP is
  hydrolysed by GTPase activity of G protein)
• Activated adenylate cyclase converts ATP to cAMP
  (second messenger) (if inhibited, no catalysed
  reaction by AC)
• cAMP is free to circulate inside the cell
  triggers activation of one to several protein
  kinase molecules protein kinase phosphorylates
  many proteins
• The phosphorylated proteins may either be
  activated or inhibited by phosphorylation

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Adenylyl cyclase forms cAMP, a second messenger
that activates enzymes used in cellular
responses.
The phosphodiesterase enzymes terminate
the second messenger cAMP.
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Amplification effect
Each protein kinase can catalyse hundreds of
reactions
The cAMP system rapidly amplifies the
response capacity of cells here, one first
messenger led to the formation of one million
product molecules.
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PIP-calcium signaling mechanism
This receptor-G-protein complex is linked to and
activates phospholipase C, leading to an increase
in IP3 and DAG, which work together to activate
enzymes and to increase intracellular calcium
levels.
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PIP-calcium signaling mechanism

• A hormone (first messenger) binding to its
  receptor causes the receptor to bind inactive G
  protein
• G protein is activated binds GTP releases GDP
• Activated G protein binds activates a
  membrane-bound phospholipase enzyme
• G protein becomes inactive
• Phospholipase splits phosphatidyl inositol
  biphosphate (PIP2) to diacylglycerol (DAG)
  inositol triphosphate (IP3)
• DAG activates protein kinases on the plasma
  membrane IP3 triggers calcium ion release from
  the ER
• Released calcium ions (second messengers) alter
  activity specific enzymes activity and ion
  channels or bind to the regulatory protein
  calmodulin
• Calmodulin also activates specific enzymes to
  amplify the cellular response

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Ca-calmodulin system
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Mechanisms of steroid Hormone Action

• Modulation of gene expression
• Steroid hormones bind to intracellular receptors
• The steroid-receptor complex binds to DNA,
  turning specific genes on or off

Steroid hormone receptor
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Sequence of events for steroid hormone binding

• Steroids are lipid-based and can diffuse into
  cells easily
• No need for intracellular second messenger
• Mobile receptors
• Some steroids bind to a cytoplasmic receptor,
  which then translocates to the nucleus
• Other receptors for steroids are located in the
  nucleus or are nuclear receptor proteins
• In both cases, the steroid-receptor complex
  formed can then bind to specific regions of DNA
  and activate specific genes
• Activated genes transcribe into messenger RNA and
  instruct the cell to synthesize specific enzyme
  proteins that change the metabolism of the target
  cell

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Radioimmunoassay (RIA)

• (from the Nobel lecture by Dr. Rosalyn Yalow,
  1977)

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The main difference between the modes of action
of peptide hormones and steroid hormones is that
QUIZ

• a. peptide hormones bind to intracellular
  receptors whereas steroid hormones bind to
  receptors on the cell surface.
• b. peptide hormones bind to receptors in the
  nucleus whereas steroid hormones bind to
  receptors in the cytosol.
• c. peptide hormones bind to receptors on the
  cell surface whereas steroid hormones act as
  second messengers.
• d. peptide hormones bind to receptors on the
  cell surface whereas steroid hormones bind to
  intracellular receptors.
• e. there are no differences both act by binding
  to receptors on the cell surface.

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The main difference between the modes of action
of peptide hormones and steroid hormones is that
QUIZ

• a. peptide hormones bind to intracellular
  receptors whereas steroid hormones bind to
  receptors on the cell surface.
• b. peptide hormones bind to receptors in the
  nucleus whereas steroid hormones bind to
  receptors in the cytosol.
• c. peptide hormones bind to receptors on the
  cell surface whereas steroid hormones act as
  second messengers.
• d. peptide hormones bind to receptors on the
  cell surface whereas steroid hormones bind to
  intracellular receptors.
• e. there are no differences both act by binding
  to receptors on the cell surface.

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In the absence of thyroid hormone, epinephrine
stimulates release of a small amount of fatty
acids from adipose cells. In the presence of
thyroid hormone (which has no effect by itself),
epinephrine causes a much more substantial
release of fatty acids from the cells. The effect
of thyroid hormone on epinephrine's actions is
called
QUIZ

• a. antagonistic.
• b. agonistic.
• c. permissive.
• d. direct.
• e. paracrine.

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In the absence of thyroid hormone, epinephrine
stimulates release of a small amount of fatty
acids from adipose cells. In the presence of
thyroid hormone (which has no effect by itself),
epinephrine causes a much more substantial
release of fatty acids from the cells. The effect
of thyroid hormone on epinephrine's actions is
called
QUIZ

• a. antagonistic.
• b. agonistic.
• c. permissive.
• d. direct.
• e. paracrine.

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Summary

• Hormone
• Primarily information transferring molecules
• Transfer information from one set of cells to
  another
• Travel via the circulation to affect one or more
  groups of different cells to elicit a
  physiological response
• Hormone types
• Protein and peptides
• Amines
• Steroids
• Action modes of hormones
• Endocrine
• Paracrine
• Autocrine
• Neurocrine

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Summary

• Regulation of Hormone Secretion
• Negative feedback
• Positive feedback
• Mechanisms of hormone action
• Mechanisms of Peptide Hormone Action
• Second messenger signaling pathway
• cAMP second message system
• IP3 mechanism
• Ca2-calmodulin mechanism
• Mechanisms of Steroid Hormone Action
• Modification of gene expression