The Endocrine System
Chapter 11
Dr. D. Washington
The Endocrine System
The endocrine system is concerned with the
control of the various metabolic functions
of the body.
It controls the rates of chemical reactions in
the cells, and other aspects of cellular
metabolism such as growth and secretion.
Hormone - Definitions
Classical
Hormones are chemical agents, synthesized in
specialized parts of the body, and
transported by the blood to other parts of
the body where they act on specific target
organs.
Hormone - Definitions
Guillemin
A hormone is any substance released by a cell
and which acts on another cell; (near or far,
regardless of the singularity or ubiquity of
source and regardless of the means of
conveyance; that is; blood stream,
axoplasmic flow, or immediate intracellular
space).
Hormone - Definitions
Fox
Hormones are biologically active chemicals
(in the blood) which combine with specific
receptor proteins in their target cells and
modify the production or action of specific
cellular enzymes and other proteins.
Hormones of the Nervous System
Hypothalamus
ADH
Oxytocin
Releasing Hormones
Synapses - Local Hormones
Acetylcholine
Norepinephrine, etc.
Hormones of the Nervous System (con’t)
Other Neurohormones
Endorphins
Substance P
Brain Renin - Angiotensin System
Brain Calcitonin
Characteristics of Hormones
Arise in tissues specialized for their
production.
Circulate and exert their effects in low serum
concentrations.
Exert their effects on highly specific target
organs.
Reciprocal Action - negative feedback.
Control of Metabolic Activity
Conversion of precursors to active enzymes.
Alter membrane permeability.
Complete with cofactors or coenzymes to
inhibit reactions.
Act as coenzymes to facilitate reactions.
Chemical Nature of Hormones
Neuroectodermal or endodermal
Peptides and Proteins
Modified Amino Acids (thyroxine)
Neurotransmitters
Mesodermal
Steroids
Thyrotropin Releasing Hormone (TRH)
(3 amina acids)
=
O
C
O
N
H
Glutamic acid
Steroids
CD
AB
NH
CH
C
CH2
N
C=O
NH
N
NH2
Histidine
Proline
Thyroxine
I
I
O
HO
I
CH2
CH
COOH
NH2
I
3,5,3’5,’-tetraiodothyronine
HO
CH2
CH
COOH
NH2
Synthesized from two tyrosines
Neurotransmitters
H
H CH3
C
C
N
H
H
CH3
=
O
H3C
C
O
CH3
Acetylcholine
HO
HO
CH2
CH2
Dopamine
NH2
Amino Acid Sequence of HGH
Endocrine Methodologies
I. Surgical Ablation:
a. Berthold’s experiment with chickens.
b. Houssay Animal (pancreatectomizedhypophy-sectomized dog).
Endocrine Methodologies
II. Chemical Ablation (Impairment):
A. Radiothyroidectomy; destroys parts of the
thyroid gland.
B. Anti-thyroid agents:
1. Iodide pump blockers: para-amino benzoic
acid etc.
2. Iodination of tyrosine blockers: Thiourea,
Propylthiouracil, & Sulfonamides.
3. Alloxan Treatment: destroys B-cells of Islets.
Endocrine Methodologies
C. metabolic Inhibitors:
1. Dinitrophenol - uncouples
phosphorylation
2. Cyanide - inhibits the action of
cytochrome oxidase.
Berthold’s Experiment:
the first endocrine experiment
Experimental
Groups
I
X X X X
III
II
X
X
X
X
Methods
Both Testes Removed
Results
Comb & wattles small
No interest in hens
Weak crow
Listless fight behavior
One Testis Replaced
Comb & wattles normal
Interest in hens
Normal crow
Aggressive fight behavior
Testis larger then in controls
One Testis Exchanged
Same as II
III. Replacement Therapy:
Used following surgical ablation or
hypofunction.
Example: Estrogen treatment at
menopause to prevent bone
fracture and overall osteoporosis.
IV. Radioisotopic Tracer Studies
Hormones are labeled (125I, 35S, 32P, etc.)
to determine the: target organs;
uptake by glands;
incorporation into compounds;
half-life;
and sites of breakdown.
Important for studying metabolic pathways
V.Immunochemistry:
Antibodies to peptides and protein
hormones are produced, then
conjugated to a fluorescent dye. This
antibody-dye complex is added to the
tissue sample (gland) and washed off
several times. It binds to the cells that
produce the hormone.
VI.Immunoenzymes:
An anti-body to a hormone is
conjugated to an enzyme (like
peroxidase). The antibody-enzymen
complex is added to tissue slices.
Substrates for the enzyme are added
and the hormone producing cells are
stained & observed with the electron
microscope.
Mechanisms of Hormonal Action
(Signal Transduction)
I. Activation of Cyclic Nucleotides
A. Cyclic AMP
adenosine - 3’, 5’ monophosphate (cAMP)
A. Cyclic GMP
guanosine - 3’, 5’ monophosphate (cAMP)
Mechanisms of Hormonal Action
(Signal Transduction)
II. Activation of Gene
A. Thyroxine (T3 & T4)
B. Steroids
III. Activation of Calmodulin
A. Insulin
ATP
NH
N
N
N
H2 C
O
H
H
OH
O
P
O
=
N
O
=
H
O
O
O
OH
Pyrophosphate Cleavage
P
O
=
H
O
P
O
ATP
NH
N
N
H
N
N
C
O
O
H
P O
OH
O
=
H
O
Cyclic AMP + PP1
Begin
First
messenger
Extracellular
fluid
Receptor
activates
Effector protein
(ion channel
or enzyme)
Plasma
membrane
generates
Cytoplasm
G Protein activates
Second messengers
and/or
change in membrane potential
Beta Adrenergic
Receptor
protein
Hormone
Adenylate
norepinephrine
cyclase
G-proteins
Cell
memebrane
cAMP
Inhibitory subunit
Protein kinase
(inactive)
Activation of
specific enzymes
+ PPi
Inhibitory subunit
cAMP
Protein kinase
(active)
Phosphorylation
of enzymes
Inactivation of
specific enzymes
Alpha adrenergic
Phospholipase C
PLC
G-proteins
Ca++ Ca++
--Binds to calmodulin
--Causes phosphorglation
IP3
Inositol
triphosphate
Endoplasmic
reticulum
cytoplasm
Activates protein kinase
Stimulus
Adrenal medulla
Epinephrine Epinephrine
receptor
blood
Cell membrane
Adenylate cyclase
ATP
cAMP + PP1
Protein kinase
C R
Protein kinase + cAMP
C
(inactive)
ATP +
R
(active)
dephosho-phosphorylase kinase
Phospho-phosphorylase kinase
+ ADP
(active)
(inactive)
ATP + phosphorylase b
(inactive)
phosphorylase + ADP
Glycogen +P1
(active)
Glucose 1-phosphate
Glucose 6-phosphate
Glucose +???
Blood Glucose
Inhibition of Glycogen Synthesis by Epinephrine
Stimulus
Adrenal medulla
Epinephrine Epinephrine
receptor
blood
membrane
Adenylate cyclase
ATP
cAMP + PP1
Protein kinase
C R
(inactive)
Liver cell
Protein kinase + cAMP
C
R
(active)
ATP + Dephosho-glycogen
synthase
(active)
Phospho- glycogen + ADP
synthase
(inactive)
Phosphorylation
of receptor
Binding to
receptor proteins
Dimerization
Signal-molecule activation
Cascade of effects
Steroid Hormone
H
Receptor protein
for steroid hormone
Ligand-binding
domain
Half-sites
DNA-binding
domain
DNA
Hormone-response
element
Homodimer
Dimerization of receptor
steroid
H
hormone
Target gene
steroid
hormone
H
DNA
Genetic transcription
mRNA
Blood
Target cell
Nucleus
Carrier
protein
Cytoplasm
DNA
mRNA
Translocation
mRNA
Receptor
protein
Protein
synthesis
Steroid
hormone
response
T3
T3
T3
T4
T3
T4
T4
RXR Receptor
TR Receptor
(for 9-cisRetinoic acid)
(for Triiodothyronine)
Dimerization
9-cisRetinoic acid
T3
Triiodothyronine
DNA
Hormone-response Genetic transcription
element
mRNA
Effects on
permeability &
transport
Effects on
production of
secretory
proteins
mRNA
Transcription
mRNA
translation
Effects on
metabolism
DNA
Other Effects
Transduction Pathways of Releasing Hormones
Hormone
CRH
TRH
GnRH
AVP
GHRH
Somatostian
PRL
Location of Action
Corticotrope of anterior pituitary
(ACTH)
Thyrotrope of anterior pituitary
(TSH)
Gonadotrope of anterior pituitary
(LH & FSH)
Corticotrope of anterior pituitary
assists CRH in releasing ACTH
Somatomammotrope of anterior
pituitary (GH)
Somatomammotrope of anterior
pituitary (inhibits GH release)
release & inhibitor
Pathway
PKa PIb
+
+c
+
+ (?)
+d
Pineal body
pituitary
Thyroid
Adrenal
Pancreas
Ovary
Testis
Hypothalamus
Cerebrum
Forebrain
Diencephalon
Midbrain
Brainstem
Pons
Cerebellum
Medulla
oblongota
Spinal cord
Pituitary Gland
(Hypophysis)
Adenohpophysis
Neurohypophysis
Pars tuberalis
Pars distalis
Pars intermedia
Median eminence
Infundibular stem
Pars nervosa
(infundibular process)
Chromophobes
Basophil
Acidophil
0.6 grams
Embryonic Development
brain
infundibulum
Rathke’s pouch
Pars tuberalis
Pars
distalis
Pars intermedia
Pars nervosa
Cell body
Axons to primary
capillaries
Primary
capillaries
Superior
hypophyseal
artery
Portal
venules
Secondary
capillaries
Median
eminence
Pituitary
stalk
Posterior
pituitary
Releasing
hormones
Anterior
pituitary
Trophic
hormones