ENDOCRINE SYSTEM
PHYSIOLOGY
Hormones
• A chemical secreted by a cell or groups of cells
into the blood for transport to a distant target
where it exerts its effect at very low
concentrations
• Types
– Peptide Hormones
• Growth Hormone, Insulin, Vasopressin
– Steroid Hormones
• Cortisol, Testosterone, Estrogen
– Tyrosine Derivatives
• Thyroxine and Epinephrine
Endocrine vs. Nervous System
• Major communication systems in the
body
• Integrate stimuli and responses to
changes in external and internal
environment
• Both are crucial to coordinated functions
of highly differentiated cells, tissues and
organs
• Unlike the nervous system, the
endocrine system is anatomically
discontinuous.
Nervous system
•The nervous system exerts
point-to-point control through
nerves, similar to sending
messages by conventional
telephone. Nervous control is
electrical in nature and fast.
Hormones travel via the
bloodstream to target cells
•The endocrine system broadcasts its
hormonal messages to essentially all
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.
A cell is a target because is has a specific
receptor for the hormone
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.
Mechanisms of Secretion
Ca++
Neuron
Ca++
Neurosecretory cell
Ca++
Simple Endocrine Cell
Ca++
Intracellular Ca stores
Capillary
Hormones
•
Types of Secretion
1.
2.
3.
4.
Autocrine – affects the secreting cell
Paracrine – affects neighbouring cell
Endocrine – secreted into bloodstream
Exocrine – secreted onto body surface,
including surface of gut
Response vs. Distance Traveled
Endocrine action: the hormone is distributed in blood and binds to
distant target cells.
Paracrine action: the hormone acts locally by diffusing from its
source to target cells in the neighborhood.
Autocrine action: the hormone acts on the same cell that produced
it.
Types of hormones
• Hormones are categorized into four
structural groups, with members of
each group having many properties
in common:
– Steroids
– Thyroid Hormones
– Peptides and proteins
– Amino acid derivatives= Catecholamines
– Fatty acid derivatives - Eicosanoids
Two types of hormones
• Lipid Soluble
– Steroid hormones (eg estrogen, testosterone)
– Thyroid hormones
• Lipid Insoluble
– Peptides and Proteins (eg insulin)
– Catecholamines (eg adrenalin)
Two types of hormones
1. Lipid-soluble
Carrier molecule
Hormone molecule
Cytoplasmic receptor
Nuclear receptor
Transcription &
Translation
long lasting effects
Nucleus
Two types of hormones
2. Lipid-insoluble
Hormone molecule
Plasma membrane receptor
Second Messenger
Effector Protein
Cellular effects
Peptide/protein hormones
Range from 3 amino acids to hundreds
of amino acids in size.
Often produced as larger molecular
weight
precursors
that
are
proteolytically cleaved to the active form
of the hormone.
Peptide/protein hormones are water
soluble.
Comprise the largest number of
hormones– perhaps in thousands
Peptide/protein hormones
• Are encoded by a specific gene which is transcribed
into mRNA and translated into a protein precursor
called a preprohormone
• Preprohormones are often post-translationally
modified in the ER to contain carbohydrates
(glycosylation)
• Preprohormones
contain
signal
peptides
(hydrophobic amino acids) which targets them to the
golgi where signal sequence is removed to form
prohormone
• Prohormone is processed into active hormone and
packaged into secretory vessicles
Amine hormones
There are two groups of hormones derived from
the amino acid tyrosine
Thyroid hormones and Catecholamines
Hypothalamus and pituitary gland
Hypothalamus and pituitary gland
Hypothalamus and
posterior pituitary
Midsagital view
illustrates that
magnocellular neurons
paraventricular and
supraoptic nuclei secrete
oxytocin and
vasopressin directly into
capillaries in the
posterior lobe
Pituitary gland
• Master gland
– Secretes 9 hormones that control other
glands
• 2 distinct parts
– Anterior pituitary (adenohypophysis)
– Posterior pituitary (neurohypophysis)
• Both parts controlled by neurosecretory
cells of the hypothalamus (part of the
brain!)
Anterior pituitary:
Adenohypophysis
• Anterior pituitary: connected to the
hypothalamus by the superior hypophyseal
artery.
• The antererior pituitary is an amalgam of
hormone producing glandular cells.
• The anterior pituitary produces six peptide
hormones: prolactin, growth hormone
(GH), thyroid stimulating hormone (TSH),
adrenocorticotropic hormone (ACTH),
follicle-stimulating hormone (FSH), and
luteinizing hormone (LH).
Anterior Pituitary
Hypothalamus
Hormone 1
Portal blood vessels
Hormone 1
Target Tissue
Anterior Pituitary
Hormone 2
Posterior Pituitary
Hypothalamus
Hormone 1
Portal blood vessels
Target Tissue
Posterior Pituitary
• Neurosecretory neurons  Anterior
Pituitary
– Secrete hormones into portal blood vessels
– Regulate secretion of other hormones from
anterior pituitary
• Neurosecretory neurons  Posterior
Pituitary
– Secrete hormones directly into capillaries
Anterior Pituitary
• 2 hormone system
• 1st hormone stimulates or inhibits release
of other hormones from anterior pituitary
• 2nd hormone has effect on target tissue
Examples:
• 1st hormone
• 2nd hormone
– Corticotropin-releasing
hormone (CRH)
– Adrenocorticotropin
hormone (ACTH)
– Thyroid hormone
releasing hormone (TRH)
– Thyroid stimulating
hormone (TSH)
– Prolactin-inhibiting
hormone (PIH)
– Prolactin
Posterior Pituitary
•
•
Neurosecretory cells secrete hormones
directly onto capillaries
Only 2 hormones:
1. Antidiuretic hormone (ADH, also called
vasopressin)
•
Water retention by the kidney
2. Oxytocin
•
•
Uterine contractions during childbirth
Milk ejection during breast feeding
Hypothalamic releasing hormones
Hypothalamic releasing hormone
Effect on pituitary
Corticotropin releasing hormone
(CRH)
Thyrotropin releasing hormone
(TRH)
Growth hormone releasing
hormone (GHRH)
Somatostatin
Stimulates ACTH secretion
Gonadotropin releasing hormone
(GnRH)
Prolactin releasing hormone (PRH)
Prolactin inhibiting hormone
(dopamine)
Stimulates TSH and Prolactin
secretion
Stimulates GH secretion
Inhibits GH (and other hormone)
secretion
Stimulates LH and FSH
secretion
Stimulates PRL secretion
Inhibits PRL secretion
Thyroid
Thyroid Hormone
 Thyroid hormones are basically a "double" tyrosine
with the critical incorporation of 3 or 4 iodine atoms.
 Thyroid hormone is produced by the thyroid gland
and is lipid soluble
 Thyroid hormones are produced by modification of a
tyrosine residue contained in thyroglobulin, posttranslationally modified to bind iodine, then
proteolytically cleaved and released as T4 and T3.
T3 and T4 then bind to thyroxin binding globulin for
transport in the blood
• Thyroid Hormones
– Produced in the follicle cells of the thyroid
– T3 triiodothyronine
– T4 thyroxine
• Both require iodine to be produced
• Thyroid hormones increase metabolic rate
in brain, muscle, heart, liver, kidney, etc.
– Produces heat as a by-product
Thyroid hormones
Hypothyroid
• Lack of iodine during fetal development
Stunted growth, called cretinism
Hypothyroid
• Lack of Iodine in diet
• Lack of selenium in diet
• Genetic defect on chromosome 15
– 15q25.3-26.1
• Receptor insensitivity
• Increased Antibody levels
– Due to Environmental Factors?
• Decreased Adrenal Function
Enlargement of the thyroid, called goiter
Due to lack of thyroid hormones and
overstimulation of the thyroid gland by TSH
Because no negative feedback
Thyroxine
Triiodothyronine feedback on the Anterior
Pituitary and Hypothalamus to decrease TSH
levels
If TSH levels are high then there is a lack of
negative feedback
A lack of negative feedback means low T4,
T3 levels in the circulation.
Hoshimoto’s Thyroiditis
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Increased sensitivity to cold
Constipation
Pale, dry skin
A puffy face
Hoarse voice
An elevated blood cholesterol level
Unexplained weight gain — occurring infrequently and rarely more
than 10 to 20 pounds, most of which is fluid
Muscle aches, tenderness and stiffness, especially in your shoulders
and hips
Pain and stiffness in your joints and swelling in your knees or the
small joints in your hands and feet
Muscle weakness, especially in your lower extremities
Excessive or prolonged menstrual bleeding (menorrhagia)
Depression
Control of Thyroid
Cold
If –’ve feedback lost
Too much TSH
Get goiter
Hypothalamic neurons
Thyroid releasing hormone (TRH)
Anterior Pituitary
Thyroid Stimulating Hormone (TSH)
Thyroid
Release of thyroid hormones – T3 and T4
Hyperthyroid
• Also known as Graves’ Disease
• Excessive secretion of T4
• An antibody called thyrotropin receptor
antibody (TRAb) stimulates the thyroid to
make excessive amounts of thyroid
hormone.
Graves’ Disease
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Anxiety
Irritability
Difficulty sleeping
Fatigue
A rapid or irregular heartbeat
A fine tremor of your hands or fingers
An increase in perspiration
Sensitivity to heat
Weight loss, despite normal food intake
Brittle hair
Enlargement of your thyroid gland (goiter)
Light menstrual periods
Frequent bowel movements
Control of extracellular Calcium
•
Two hormones
1. Parathyroid hormone
2. Calcitonin
Parathyroid Gland
Parathyroid
• Low blood Ca++
stimulates release of
parathyroid hormones
• Act to increase blood
Ca++ by
–  Ca++ release from bone
–  Ca++ absorption in gut
–  Ca++ reabsorption in
kidney
Calcitonin
• Produced in parafollicular cells of
the thyroid gland
• High Blood Ca++ stimulates
release of calcitonin
• Act to decrease blood Ca++ by
– ↓ Ca++ release from bone
– ↓ Ca++ reabsorption in kidney
High Ca++
Low Ca++
Calcitonin
Mobilize Ca
From Bone
Parathyroid hormone
Reabsorb Ca
In the kidney
Increase absorption
of Ca from intestine
Hormones
• Robert Wadlow
– 8’-11” tall
– 496 pounds
– Size 37 shoe
• Too much growth
hormone
Growth Hormone:
Somatostatin
•
•
Direct effects are the result of
growth hormone binding its
receptor on target cells. Fat cells
(adipocytes), for example, have
growth hormone receptors, and
growth hormone stimulates them
to break down triglyceride and
suppresses their ability to take up
and accumulate circulating lipids.
Indirect effects are mediated
primarily by a insulin-like growth
factor-I (IGF-I), a hormone that is
secreted from the liver and other
tissues in response to growth
hormone. A majority of the growth
promoting effects of growth
hormone is actually due to IGF-I
acting on its target cells.
• Growth hormone-releasing hormone (GHRH) is a hypothalamic
peptide that stimulates both the synthesis and secretion of growth
hormone.
• Somatostatin (SS) is a peptide produced by several tissues in the
body, including the hypothalamus. Somatostatin inhibits growth
hormone release in response to GHRH and to other stimulatory
factors such as low blood glucose concentration.
• Ghrelin is a peptide hormone secreted from the stomach. Ghrelin
binds to receptors on somatotrophs and potently stimulates
secretion of growth hormone.
• Growth hormone secretion is also part of a negative feedback loop
involving IGF-I. High blood levels of IGF-I lead to decreased
secretion of growth hormone not only by directly suppressing the
somatotroph, but by stimulating release of somatostatin from the
hypothalamus.
• Growth hormone also feeds back to inhibit GHRH secretion and
probably has a direct (autocrine) inhibitory effect on secretion from
the somatotroph.
Gigantism v Acromegaly
The Adrenal Glands
• An example of Pituitary control over other
endocrine tissue
• One gland attached to the top of each
kidney
Adrenal Medulla
Adrenal Cortex
Kidney
Adrenal Cortex
• Steroid hormones
– Mineralcorticoids
• Aldosterone
– Glucocorticoids
• Cortisol
– Small amounts of
estrogen,
testosterone,
progesterone
Adrenal Medulla
• Catecholamine
– Epinipherine
(adrenalin)
– Norepinipherine
(noradrenalin)
Control of Adrenal Cortex
Stress, circadian rhythm
and other neural input
Hypothalamic neurons
Corticotropin releasing hormone (CRH)
Anterior Pituitary
Adrenocorticotropic hormone (ACTH)
Adrenal cortex
Release of steroid hormones
Adrenal Cortex
• Glucocorticoids; cortisol is the major
representative in most mammals
• Mineralocorticoids; aldosterone being
most prominent
• Androgens such as testosterone
• Estrogens, including estradiol and
estrone
• Progestogens (also known a progestins)
such as progesterone
Adrenal Cortical Steroids
• Mineralocorticoids
– eg. aldosterone
– Controls ion transport
in the kidney function
– Regulates expression
of a Na+ Channel
– Important for water
reabsorption
• Glucocorticoids
– eg. cortisol
– Important for
metabolism esp.
glucose
– Activate enzymes (in
liver) that increase
glucose production
–  blood glucose
Cortex
Medulla
Zona
Glomerulosa
mineralocorticoids (aldosterone)
Zona
fasiculata
glucocorticoids (cortisol)
Zona
reticularis
sex steroids (androgens)
catecholamines (epinephrine and norepinephrine)
Adrenal Medulla
• Catecholamines stored in large vesicles
within chromaffin cells of the adrenal
medulla
• Chromaffin cells innervated by neurons of
the sympathetic nervous system
• ‘Fight or flight’ response
Sympathetic nerve terminal
Acetycholine synapse
Ca++
Adrenal medulla
Catecholamine
containing vesicles
Chromaffin cell
Blood vessel
Adrenal Medulla
• Ach depolarizes chromaffin cell by
activating nicotinic Ach receptors
• Opens voltage-gated Ca++ channels
• Ca++ causes fusion of vesicles
• Release of catecholamine into blood
stream
Catecholamines
• Catecholamines released by adrenal
medulla:
– epinipherine 80%
– norepiniphrine 20%
– Also neurotransmitter
• Norepinephrine primary SNS
Effects of Catecholamines depend
upon receptor type
• Activate adrenoreceptors
– Two types:  and 
1
Phospholipase C
IP3 & DAG
2
1
2
Adenylate cyclase
cAMP
Potential effects of catecholamine
receptor activation
• Heart
– , mediated -  contraction, HR
• Smooth Muscle (Blood vessels and lungs)
–  contraction
–  relaxation
• Metabolism
–  -  glycogenolysis  glucose
• Neural
–  -  K+ channel conductance
Some clinical stuff
•  adrenoreceptor agonists used to treat
asthma
•  blockers used to treat high blood
pressure
Addison’s Disease
• Severe or total deficiency of the hormones made in the
adrenal cortex, caused by the destruction of the cortex
• Symptoms
– steadily worsening fatigue
– a loss of appetite, and some weight loss
– Blood pressure is low and falls further when a person is
standing, producing lightheadedness
– Nausea, sometimes with vomiting, and diarrhea are common
– The muscles are weak and often go into spasm
– There are often emotional changes, particularly irritability and
depression
– Because of salt loss, a craving for salty foods is common
– Finally, the increase in ACTH due to the loss of cortisol will
usually produce a darkening of the skin that may look like an
inappropriate tan on a person who feels very sick.
Cushing’s Disease/Syndrome
•
Cushing's Syndrome is a disease caused by
an excess of cortisol production or by excessive
use of cortisol or other similar steroid
(glucocorticoid) hormones.
• Symptoms
– General physical features include a tendency to gain
weight, especially on the abdomen, face (moon face),
neck and upper back (buffalo hump)
– fatigue, weakness, depression, mood swings,
increased thirst and urination, and lack of menstrual
periods in women.
Blood Glucose Regulation
• Endocrine pancreas
– Only 2% of entire pancreas,
– the rest produces digestive enzymes
(exocrine)
– Islets of Langerhans
• Insulin ( cells)
• Glucagon ( cells)
• Somatostatin ( cells)
Islets of Langerhans
• Alpha cells (A cells)
secrete the hormone
glucagon.
• Beta cells (B cells)
produce insulin and are
the most abundant of the
islet cells.
• Delta cells (D cells)
secrete the hormone
somatostatin, which is
also produced by a
number of other
endocrine cells in the
body.
Diabetes
• Diabetes
– 2 million Canadians
– $9 billion per year health care costs
– Insulin isolated by Banting & Best 1922, U of T Dept of
Physiology (1923 Nobel Prize)
• Type 1
– No or very little insulin produced
• Type 2
– Reduced cellular response to insulin
• Consequences
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–
–
–
Death
Blindness
Kidney disease
Limb amputation
Hormonal control of blood glucose
In the GI tract, 80% of all carbohydrate is digested to glucose
Basically:
Glucose
Used for ATP production
Glycogen
Used for glucose storage
Insulin
• Stimulus for secretion is high blood
glucose
• Secreted by  cells
• Leads to glucose uptake and storage in
liver, muscle and fat tissue.
• Effect is to  blood glucose
• Danger of Diabetes is hyperglycemia
Insulin Effects on Muscle and Fat
Tissue
• Insulin initiates transfer of glucose
transporters to cell membrane
•  blood glucose
•  production of glycogen
Effects in Muscle & Fat
Glycogen synthesis
Glucose
transporter
glucose
SNARE dependent
transport
Glucose
transporter
Insulin
storage
vesicle
In the Liver
• Insulin stimulates the synthesis of an
enzyme (glucokinase)
• Required to ‘trap’ glucose in the cell
• initiates glycogen production
Effects in Liver
GLUT2
Glycogen synthesis
Glucose
transporter
glucose
X
glucose
Glucose 6-phosphate
glucokinase
‘trapped’
Hemoglobin
• Hemoglobin is the oxygen-carrying pigment that gives
blood its red color and also the predominant protein in
red blood cells.
• About 90% of hemoglobin is hemoglobin A. (The "A"
stands for adult type.) Although one chemical component
accounts for 92% of hemoglobin A, approximately 8% of
hemoglobin A is made up of minor components that are
chemically slightly different.
• These minor components include hemoglobin A1c, A1b,
A1a1, and A1a2. Hemoglobin A1c (HbA1c) is a minor
component of hemoglobin to which glucose is bound.
HbA1c also is referred to as glycosylated or glucosylated
hemoglobin.
Hemoglobin A1c
• Sugar sticks, and when it's around for a long time, it's
harder to get it off. In the body sugar sticks particularly to
proteins.
• The red blood cells that circulate in the body live for
about 3 months before they die off.
• When sugar sticks to these cells, it gives us an idea of
how much sugar is around for the preceding 3 months.
In most labs, the normal range is 4-5.9 %.
• In poorly controlled diabetes, its 8.0% or above, and in
well controlled patients it's less than 7.0%. The benefits
of measuring A1c is that is gives a more reasonable view
of what's happening over the course of time (3 months)
ADA’s Goal is Less than 7%
• A1c(%)
Mean blood sugar (mg/dl)
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135
170
205
240
275
310
345
6
7
8
9
10
11
12
Other hormones
• Glucagon
– Secretion stimulated by low blood glucose
– Activates enzymes for gluconeogenesis and
glycogenolysis
– Leads to  blood glucose levels
• Somatostatin
– Regulates secretion of insulin and glucagon
Glucose Regulation Summary
• Endocrine pancreas
• Secretion of several hormones important
for blood glucose regulation
• Insulin  glucose uptake and storage
– Different effects on liver and muscle & fat
• Glucagon  glucose production
What hormone increases
intestinal calcium absorption?
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A.
B.
C.
D.
E.
Parathyroid Hormone
Calcitonin
Glucagon
Cortisol
Heparin
The Target Tissue of ACTH is?
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•
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A.
B.
C.
D.
E.
Hypothalamus
Pituitary Gland
Thyroid Gland
Adrenal Cortex
Adrenal Medulla
Which of the following are NOT
a catecholamine?
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•
•
•
A. Epinephrine
B. Dopamine
C. Cortisol
D. Norepinephrine
Which of the following are called
a second messenger?
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•
•
•
A.
B.
C.
D.
PIP
DAG
cGMP
cAMP
Which disease results from over production
of Growth Hormone before the epiphyseal
plates close?
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A.
B.
C.
D.
Gigantism
Acromegaly
Dwarfism
Obesity
Which hormone is secreted
from the neurohypophysis?
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A.
B.
C.
D.
E.
LH
FSH
TSH
ADH
ACTH
Addison’s Disease is caused by
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•
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A.
B.
C.
D.
an increase in Aldosterone secretion
a decrease in Aldosterone secretion
an increase in ACTH secretion
a decrease in ACTH secretion
The following type of hormonal release affects
the cell next to the cell that secreted the
hormone.
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A.
B.
C.
D.
E.
Autocrine release
Paracrine release
Endocrine release
Steroidal release
None of the Above
Which test is best to use for a
patient with Diabetes?
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•
•
A.
B.
C.
D
E.
Glucose Tolerance Test
Glucose Infusion Test
Hemoglobin A1c Test
Urinalysis
None of the Above
If you ate 25 sugar cubes and followed them with a
chaser of Mountain Dew, which hormone might be
secreted in large amounts?
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•
•
•
•
A. Glucagon
B. Insulin
C. Cortisol
D. Somatastatin
E. ACTH
Signal Transduction
Signal
Reception, Transduction
Amplification
Second Messengers
Regulators
Specific Effectors
Cellular Response