Endocrine System
Huiping Wang (王会平), PhD
Department of Physiology
Rm C516, Block C, Research Building, School of Medicine
Tel: 88208252
Email: wanghuiping@zju.edu.cn
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RECOMMENDED TEXTBOOK:
Widmaier EP, Raff H, Strang KT (2006) Vander’s Human Physiology: The Mechanisms of Body Function, Tenth
Edition. McGraw-Hill.
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SUPPLEMENTARY READING:
Stephan Sanders (2003) Endocrine and Reproductive systems, Second Edition. Mosby.
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COURSE WEBSITERS:
http://www.endocrineweb.com/
http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.html
http://medical.physiology.uab.edu/cardio.htm
http://www.mhhe.com/biosci/ap/foxhumphys/student/olc/index.htm
Endocrine System
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General Principles of Endocrine Physiology
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Hypothalamus and pituitary gland
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Thyroid gland
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Endocrine Regulation of Calcium and Phosphate
Metabolism
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Adrenal gland
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Pancreatic hormones
General Principles
of Endocrine Physiology
Outline
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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
Endocrine System
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One of the two major communication systems in
the body
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Have much longer delays
Last for much greater lengths of time
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Integrate stimuli and responses to changes in
external and internal environment
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crucial to coordinated functions of highly
differentiated cells, tissues and organs
Endocrine Glands
Hypothalamus
Pituitary (Anterior and Posterior)
Thyroid / Parathyroid
Endocrine Pancreas (islets)
Adrenal Cortex and Medulla
Gonad (Ovary and Testis)
Endocrine gland (ductless) is a
group of cells that produce and
secret a hormone
Endocrine System
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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.
What is a hormone?
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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
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
Synthesis of peptide hormones
NUCLEUS
The DNA code is
“transcribed” into
mRNA.
RIBOSOMES
The mRNA is
“translated” to
give instructions
for proteins
synthesis.
Typical synthesis of peptide hormones
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Preprohormones- larger hormones
produced on the ribosomes of the
endocrine cells
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Prohormones- cleavage of
preprohormones by proteolytic
enzymes in rER
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Prohormones- packaged into
secretory vesicles by the Golgi
apparatus
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Prohormones- cleaved to give
active hormone and pro-fragments
pre-pro-insulin
pro-insulin
insulin
Synthesis of steroid hormones
Hormone Storage and Release
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Thyroid and steroid hormones
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Not stored as secretory granules
Transferring through plasma membrane
Protein and catecholamine hormones
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Stored as secretory granules
Released by exocytosis
Hormones are not secreted at a
uniform rate
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In a pulsatile pattern
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Diurnal (circadian) rhythm:
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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
Hormones are not secreted at a
uniform rate
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Rhythmic secretion
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Cyclic
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oestrogen,
progesterone, LH
Modes of Action
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Endocrine – transmission of a signal
from a classic endocrine cell
through bloodstream to a distant
target cell e.g. testosterone
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Neurocrine – hormone is released
from a neuron down its axon and
then travels via the bloodstream to
target cell
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Paracrine - hormone acts on
adjacent cells e.g. histamine
released at site of injury to constrict
blood vessel walls and stop bleeding
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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
A secretion may have
several sites of action
simultaneously
Example:
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Norepinephrine
- Autocrine action
causes negative
feedback on
secretion.
- Simultaneously,
endocrine action
causes respiration
rate to increase,
peripheral blood
vessels to constrict,
etc.
Hormone Transport
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Peptides and catecholamine
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water soluble
dissolve in blood
circulate in blood mainly in free form
Steroid and thyroid hormones
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circulate in blood mainly bound to plasma proteins
the free form is biologically active
the greater binding, the longer half-life
Hormone Clearance
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The half-life of a hormone in blood
is the period of time needed for its concentration to be reduced by
half.
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Free: min
Binding: mins, hrs, days
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Hormone concentration in blood is determined by
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e.g. T4 (6 days); Insulin (0.006 days)
secretion rate
clearance rate
Ways of Clearance
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target cell uptake
metabolic degradation
urinary or biliary excretion
The “metabolic fate” of a given hormone
molecule in the blood
Characteristics of Hormones
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Regulates rate of reaction
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Do not initiate
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Very specific
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Amplification effect
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Present in very small quantity
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pg/mL ~ g/mL
Characteristics of Hormones
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Interaction between hormones
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Synergistic action
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Antagonistic action
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Permissive action
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Hormone A must be present for the
full strength of hormone B’s effect.
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Up-regulation of one hormone’s
receptors by another hormone
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the facilitation of the action of one
hormone by another
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e.g. the ability of TH to “permit” epinephrineinduced release of fatty acids from adipose
tissue cells (TH causes an  no. of
epinephrine receptors on the cell)
Regulation of Hormone Secretion
Three types of inputs to endocrine cells that
stimulate or inhibit hormone secretion.
Regulation of Hormone Secretion
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Negative feedback
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Most common
Occurs when a hormone
produces a biologic effect
that, on attaining sufficient
magnitude, inhibits further
secretion
Positive feedback
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Less common
Amplify the initial biological
effect of the hormone
Negative Feedback
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Characteristic of control systems in which system’s
response opposes the original change in the system.
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Hormone itself feeds back to inhibit its own synthesis.
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Regulated product (metabolite) feeds back to inhibit
hormone synthesis.
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Important for homeostatic control.
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Example: Control of blood glucose by insulin
Positive Feedback
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Characteristic of control systems in which an
initial disturbance sets off train of events that
increases the disturbance even further.
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Amplifies the deviation from the normal levels
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Example: Oxytocin (suckling)
Important for amplification of level for action
Mechanisms of hormone actions
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Hormone action mediated by the specific receptors
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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.
Hormone Receptors
The receptor provides link between a specific extracellular hormone
and the activation of a specific signal-transduction system
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Structure
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Location
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Recognition domain binds hormone
Coupling domain generates signal
cell membrane (e.g. for insulin)
cytoplasm (for steroids)
nucleus (e.g. for thyroid hormone)
Receptor capacity
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exposure to excess hormone down-regulates capacity
low hormone concentration up-regulates capacity
Two general mechanisms of
hormone action
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Second messengers – enzyme activity
↑↓(rapid, cytosolic effects)
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Gene expression - enzymes synthesis
↑↓(slow, nuclear effects)
Mechanisms of Peptide Hormone Action
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G proteins
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are GTP-binding proteins
couple hormone receptors to adjacent effector molecule
have intrinsic GTPase activity
have three subunits: α, β, γ
α subunit bound to GDP → inactive G protein
α subunit bound to GTP → active G protein
the effect can be either stimulatory (Gs) or inhibitory (Gi)
Second messengers
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cAMP second message system
IP3 mechanism
Ca2+-calmodulin mechanism
Signal transduction pathway involving adenylate cyclase
Cyclic AMP signaling-sequence of events
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The hormone (1st messenger) binds to the membrane receptor; the
membrane receptor changes shape and bind to G protein (GTP-binding
protein)
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G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and
release GDP
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Activated G protein moves to membrane and binds and activates
adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)
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Activated adenylate cyclase converts ATP to cAMP (second
messenger) (if inhibited, no catalysed reaction by AC)
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cAMP is free to circulate inside the cell; triggers activation of one to
several protein kinase molecules; protein kinase phosphorylates many
proteins
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The phosphorylated proteins may either be activated or inhibited by
phosphorylation
Adenylyl cyclase forms cAMP,
a “second messenger”
that activates enzymes
used in cellular responses.
The phosphodiesterase
enzymes “terminate” the
second messenger cAMP.
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.
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.
PIP-calcium signaling mechanism
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A hormone (first messenger) binding to its receptor causes the receptor to
bind inactive G protein
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G protein is activated; binds GTP & releases GDP
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Activated G protein binds & activates a membrane-bound phospholipase
enzyme;
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G protein becomes inactive
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Phospholipase splits phosphatidyl inositol biphosphate (PIP2) to
diacylglycerol (DAG) & inositol triphosphate (IP3);
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DAG activates protein kinases on the plasma membrane; IP3 triggers calcium
ion release from the ER
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Released calcium ions (second messengers) alter activity specific enzymes’
activity and ion channels or bind to the regulatory protein calmodulin;
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Calmodulin also activates specific enzymes to amplify the cellular response
Ca-calmodulin system
Mechanisms of steroid Hormone Action
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Modulation of gene
expression
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Steroid hormones bind to
intracellular receptors
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The steroid-receptor complex
binds to DNA, turning specific
genes on or off
Steroid hormone receptor
Sequence of events for steroid
hormone binding
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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
Radioimmunoassay (RIA)
(from the Nobel lecture by Dr. Rosalyn Yalow, 1977)
QUIZ
The main difference between the modes of action of
peptide hormones and steroid hormones is that
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.
QUIZ
The main difference between the modes of action of
peptide hormones and steroid hormones is that
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.
QUIZ
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
a.
b.
c.
d.
e.
antagonistic.
agonistic.
permissive.
direct.
paracrine.
QUIZ
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
a.
b.
c.
d.
e.
antagonistic.
agonistic.
permissive.
direct.
paracrine.
Summary
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Hormone

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Hormone types




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
Protein and peptides
Amines
Steroids
Action modes of hormones




Endocrine
Paracrine
Autocrine
Neurocrine
Summary
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Regulation of Hormone Secretion

Negative feedback
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Positive feedback
Mechanisms of hormone action

Mechanisms of Peptide Hormone Action
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Second messenger signaling pathway
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cAMP second message system
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IP3 mechanism
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Ca2+-calmodulin mechanism
Mechanisms of Steroid Hormone Action
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Modification of gene expression