2. Endocrine System: OverviewEndocrine System: Overview
• Endocrine system – the body’s second great
controlling system which influences metabolic
activities of cells by means of hormones
• Endocrine glands – pituitary, thyroid, parathyroid,
adrenal, pineal, and thymus glands
• The pancreas and gonads produce both hormones
and exocrine products
• The hypothalamus has both neural functions and
releases hormones
• Other tissues and organs that produce hormones –
adipose cells, pockets of cells in the walls of the
small intestine, stomach, kidneys, and heart
3. HormonesHormones
• Hormones – chemical substances secreted by cells
into the extracellular fluids
• Regulate the metabolic function of other cells
• Have lag times ranging from seconds to hours
• Tend to have prolonged effects
• Are classified as amino acid-based hormones, or
steroids
• Eicosanoids – biologically active lipids with local
hormone–like activity
4. Types of HormonesTypes of Hormones
• Amino acid–based – most hormones belong to this
class, including:
• Amines, thyroxine, peptide, and protein hormones
• Steroids – gonadal and adrenocortical hormones
• Eicosanoids – leukotrienes and prostaglandins
5. Hormone ActionHormone Action
• Hormones alter cell activity by one of the following
mechanisms:
• Direct changes in cell membrane permeability
• Second messengers involving:
• Regulatory G proteins (amino acid–based hormones)
• Direct gene activation involving steroid hormones
• The precise response depends on the type of the
target cell and its receptor
6. Mechanism of Hormone ActionMechanism of Hormone Action
• Hormones produce one or more of the
following cellular changes:
• Alter plasma membrane permeability
• Stimulate protein synthesis
• Activate or deactivate enzyme systems
• Induce secretory activity
• Stimulate mitosis
7. • Hormone (first messenger) binds to its receptor,
which then binds to a G protein
• The G protein is then activated as it binds GTP,
displacing GDP
• Activated G protein activates the effector enzyme
adenylate cyclase
• Adenylate cyclase generates cyclic AMP (cAMP)
(second messenger ) from ATP
• cAMP activates protein kinases, which then cause
cellular effects
Amino Acid–Based Hormone Action: cAMPAmino Acid–Based Hormone Action: cAMP
8. An Increase in cAMP Leads to:An Increase in cAMP Leads to:
Activation of PKA which may cause :
• Activation or deactivation of numerous enzymes
• CREB→CREB-P + transcription factor 1→add to CRE
• Stimulation or inhibition of RNA polymerase
• Transcription of genes
• cAMP finally hydrolyzed by phosphodiestrase (PD)
• Activity of PD is also modulated by hormones via a G
protein( dual regulation)
• Two hormones can function antagonistically of one
stimulates AC and the other stimulates PD
9. Figure 15.1a
Amino Acid–Based Hormone Action:Amino Acid–Based Hormone Action:
cAMP Second MessengercAMP Second Messenger
10.
11. • H binds to the receptor and activates G protein
• G protein binds and activates a PLC enzyme
• PLC splits the PIP2 into DAG and IP3 (both act as second
messengers)
• DAG activates protein kinase C; IP3 triggers release of
Ca2+
stores (PKC is Ca2+
dependent)
• Ca2+
(third messenger) alters cellular responses
• Arachidonic acid is derived from hydrolysis of DAG
serve as a substrate of prostaglandins (PG)
• The PGs are also modulators of hormonal response
Amino Acid–Based Hormone Action:Amino Acid–Based Hormone Action:
PIP–CalciumPIP–Calcium
14. Other types ofOther types of Signal transductionSignal transduction ((STST))
• 2 other mechanisms of ST from surface R are known in
which the transducers lie in the cytoplasmic tail of the R
• In one of these, H+R→ autophosphorylation of R→ the R
itself becomes a tyrosine kinase and P the tyrosine residues
on intracellular protein. Tyrosine P initiates a cascade of
serine and threonine P of enzymes
• Causes multiple intracellular events (Metabolism,
proliferation and differentiation), e.g. Insulin
• In the second one H+R→ conformational changes in R
which attracts and docks tyrosine kinases e.g. GH
• Another second messenger is cGMP→ activates PKG
16. Steroid HormonesSteroid Hormones
• Steroid hormones and thyroid hormone diffuse
easily into their target cells
• Once inside, they bind and activate a specific
intracellular receptor
• The hormone-receptor complex travels to the
nucleus and binds a DNA-associated receptor
• This interaction prompts DNA transcription to
produce mRNA
• The mRNA is translated into proteins, which bring
about a cellular effect
18. Intracellular receptors (Intracellular receptors (steroidsteroid))
• These R are large oligomeric and usually phosphorylated
• Related to cis-oncogens family and contain 3 domains :
• Variable C-terminus binds the H and is unique to each R
• middle domain contains a DNA site formed by 2 fingers
• N-terminus domain is variable in length( transactivating)
• Unoccupied R is inactive or blocked by a molecule
• H binding displaces the blocking molecule and translocates
into the nucleus, undergo dimerization, binds to a specific
site on DNA (HRE) → activates the RNA polymerase
• Negative regulatory elements also exist in DNA molecules
• These are characteristic of adrenal steroid hormones
19. Intracellular receptors (Intracellular receptors (thyroxinthyroxin))
• In another general model of activation which is
characteristic of thyroid hormones and Vit D the
unoccupied R is already attached to DNA binding sites
and prevents gene transcription
• H binds R and relieves the suppressive effect of the R
• In a variant of this model, H binding causes dissociation
of the two identical receptor monomers constituting the
homodimer, formation of heterodimer which activates
the gene transcription
21. Hormone–Target Cell SpecificityHormone–Target Cell Specificity
• Hormones circulate to all tissues but only activate
cells referred to as target cells
• Target cells must have specific receptors to which
the hormone binds
• These receptors may be intracellular or located on
the plasma membrane
• Examples of hormone activity
• ACTH receptors are only found on certain cells of
the adrenal cortex
• Thyroxin receptors are found on nearly all cells of
the body
22. Target Cell ActivationTarget Cell Activation
• Target cell activation depends upon three factors
• Blood levels of the hormone
• Relative number of receptors on the target cell
• The affinity of those receptors for the hormone
• Up-regulation – target cells form more receptors in
response to the hormone
• Down-regulation – target cells lose receptors in
response to the hormone
24. Schatchard plot for HR kineticSchatchard plot for HR kinetic
A linear plot results
when the H reacts
with a single R class
and no cooperativity
is present. The
negative of the K
equals the slope of
the line. The R
number,R0, equals
the intercept with the
X axis.
25. Schatchard plot for HR kineticSchatchard plot for HR kinetic
An exponential
plot results when
the H occupancy
of one R
molecule alters
the local affinity
of a second
nearby molecule
for the H. This
phenomenon
called negative
cooperativity.
26. A, The general
shape of a H dose-
response curve.
Sensitivity is
expressed as the
concentration of
the H that
produces half-max
response.
B, Alterations in
dose-response
curve results from
changes in max
responsiveness,
sensitivity, or both.
27. Hormone Concentrations in the BloodHormone Concentrations in the Blood
• Concentrations of circulating hormone reflect:
• Rate of release
• Speed of inactivation and removal from the body
• Hormones are removed from the blood by:
• Degrading enzymes
• The kidneys
• Liver enzyme systems
28. Control of Hormonal SecretionControl of Hormonal Secretion
• Feedback control
• Positive feedback:
• Stimulus detected, H released, H reaches target cell, H binds
R, Effect produced, Feedback to endocrine structure, More H
released
• Negative feedback:
• Stimulus detected, H released, reaches target cell, binds R,
Effect produced, Feedback to endocrine structure, Hormone
release shut down
• Direct nerve control
• Autonomic nervous system
• Inhibiting hormones or Releasing hormones
• Chronotropic control
30. Control of Hormone Synthesis and ReleaseControl of Hormone Synthesis and Release
• Blood levels of hormones:
• Are controlled by negative feedback systems
• by positive feedback systems (seldom)
• Vary only within a narrow desirable range
• Hormones are synthesized and released in response to:
• Humoral stimuli (substrate or mineral- hormone)
• Neural stimuli
• Hormonal stimuli (hormone- hormone)
31. Humoral StimuliHumoral Stimuli
• Humoral stimuli – secretion of
hormones in direct response to
changing blood levels of ions and
nutrients
• Example: Declining blood Ca2+
concentration stimulates the
parathyroid glands to secrete
PTH (parathyroid hormone)
• PTH causes Ca2+
concentrations
to rise and the stimulus is
removed Figure 17.3a
32. Neural StimuliNeural Stimuli
• Neural stimuli – nerve fibers
stimulate hormone release
• Preganglionic sympathetic
nervous system (SNS) fibers
stimulate the adrenal medulla to
secrete catecholamines
Figure 15.3b
33. Hormonal StimuliHormonal Stimuli
• Hormonal stimuli – release of
hormones in response to
hormones produced by other
endocrine organs
• The hypothalamic hormones
stimulate the anterior pituitary
• In turn, pituitary hormones
stimulate targets to secrete still
more hormones Figure 15.3c
34. Nervous System ModulationNervous System Modulation
• The nervous system modifies the stimulation of endocrine
glands and their negative feedback mechanisms
• The nervous system can override normal endocrine controls
For example, control of blood glucose levels
• Normally the endocrine system maintains blood glucose
• Under stress, the body needs more glucose
• The hypothalamus and the sympathetic nervous
system are activated to supply ample glucose
35. Chronal control (the circadian rhythms=CR)Chronal control (the circadian rhythms=CR)
The origin of CR in H
secretion, behavioral
and metabolic activity.
A clock with a 24-25h
cycle is located in the
SCN, this free running
clock is entrained by
environmental light
signals to the external
24h day.
It has bidirectional
relationship with the
sleep-wake cycle,too.
36. Type of cell to cell signalingType of cell to cell signaling
• Endocrine: hormone enters the blood stream
• Neurocrine (neuroendocrine): also enters the blood
• Paracrine:through Int. fluid or GJ to another cell type
• Autocrine: through Int. fluid or gap junction and act on
neighboring identical cells or back to the cell of origin
• Juxtacrine ?
38. Types of hormone synthesisTypes of hormone synthesis
• Protein or peptide hormone synthesis
• Aminoacid based hormone synthesis
• Steroid hormone synthesis
• Eicosanoids synthesis
39.
40. Hormone releaseHormone release
• Release of protein and catecholamine hormones
• Release of Thyroid and steroid hormones
• Other forms of hormone release
• Two adjacent cell types in a single gland may interact so
that Hormone A (androgen) from cell A is modified in
cell B to produce Hormone B (estrogens)
• Modification of a precursor molecule of low activity to
one of higher activity by successive steps (calcitriol)
• Peptide Hormone can be produced in the circulation itself
from a protein precursor (angiotensin)
43. Hormone DisposalHormone Disposal
• Irreversible removal of H is a result of:
• Target cell uptake
• Metabolic degradation
• Urinary excretion
• Biliary excretion
• The sum of all removal processes is expressed as
Metabolic Clearance Rate (MCR)
• MCR= mg/min removed / mg/ml of plasma
• K= MCR / volume of distribution
• K is the fractional turnover rate
• The plasma half-life is inversely related to K
45. Hormone measurementHormone measurement
• The most common and useful method for measuring
hormones is RIA (radioimmunoassay)
• Estimate of hormone secretion rate
• (V con – A con) × blood flow
• This is useful in animal modal but not in human
• Production Rate (PR) is suitable in human
• PR is the total amount of the H entering the
circulation per unit time
• PR = Plasma con × MCR
• Plasma levels is a valid index of Hormone PR
46. Location of the Major Endocrine GlandsLocation of the Major Endocrine Glands
• The major endocrine glands
include:
• Pineal gland,
hypothalamus, and pituitary
• Thyroid, parathyroid, and
thymus
• Adrenal glands and
pancreas
• Gonads – male testes and
female ovaries
Figure 15.4
