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endocrinology
The study of hormones
overview
Comparison of n.s. & endocrine as control/signaling systems
Nervous system
Fast response
Detects external events
(mostly), but also internal
events
Controls muscle effectors that
operate on external
environment (mostly), but also
directly controls internal
functions (heart rate,
breathing, exocrine gland
secretion)
Controls endocrine system!
Endocrine system
Slower response (mostly) &
longer term action
Detects internal events
(external if include
pheromones!)
Controls organ function
Supervises growth &
development
Controls nervous system!
Nervous system control of
endocrine system:
Hypothalamic brain neurons
release synaptic vesicles
containing “neuro-hormones”1
Endocrine control of nervous
system:
At different times in the
organism’s life, certain
neurons make receptors for
hormones.
NH’s travel “synaptically” or via
blood to endocrine target tissue in Neuron binding of a hormone
the brain (ant. or post. pituitary).
can change growth,
development of neuron, and
Target tissue stimulated to release activity level of neuron.
its own set of hormones.
Some neurons have
The latter travel via blood to many permanent hormone receptors
tissues/organs.
(e.g. those that respond to
(also called releasing hormones or releasing factors)
epinephrine)
1
Two broad functional grouping of hormones:
1. Steroids & thyroid hormones & prostaglandins are lipid
soluble - travel through cell membranes. Bind to cytosol
receptors. Typically the receptor-hormone complex then
moves through the nuclear membrane & acts as
transcription regulator.
2. Amino acid derivatives & peptides bind to transmembrane
chemoreceptor proteins. The binding activates intracellular
2nd messenger systems (G-proteins, various
phosphorylation events). Can also lead to transcription
regulation.
Chemical (not functional!) classes of hormones
NOT Lipid soluble
Lipid soluble
In all cases, there is an internal messenger system
to activate intracellular processes.
Internal messenger system for lipid soluble steroid
hormone…
Internal messenger
system for non-lipid
soluble hormones.
Example: Epinephrine
(an amino acid
derivative)
To activate the target
cell it must bind to a
membrane receptor
protein.
Cells may have receptors for more than one type
of hormone.
Two different hormones activate liver cells.
Glucagon
Epinephrine
(adrenalin)
They bind to different
receptors.
Liver cell
Both hormones cause liver cells to break down
glycogen & release glucose to blood…
but effects are not additive.
Glucagon
Epinephrine
(adrenalin)
Liver cell
If saturate with glycogen, can’t get further
increase with epinephrine  same internal 2nd
messenger (non-additive).
So why does liver cell make receptors for 2
different hormones that do the same thing?
Diagram modified from Hadley, Endocrinology
Epinephrine: Stress hormone. Causes increased
blood flow to muscles, increased respiration, etc
AND breakdown of glycogen (fight/flight response)
Glucagon: Regulator of blood sugar; monitoring
of hypoglycemia under non-stress conditions.
So: Two different physiological control
mechanisms need to activate the same
cellular process.
As earlier, hormone binding mechanism depends
on the type of chemical. So does the hormone
release mechanism:
Thyroid hormones: Diffuse out of lysosome,
through cell membrane, into blood.
Steroid hormones & prostaglandins:
Diffuse out of cytoplasm, through cell
membrane, into blood.
All other hormones: Packaged into
secretory vesicles. Held in cell until vesicle
release triggered.
Previous
slides
How hormones get into cells 
How hormones get out of cells 
But how do hormones get to cells?
endocrine
To blood –
classic
definition of
hormone.
Neuroendocrine
Neuron
releases
hormone
to blood.
paracrine
Diffusion
to nearby
cells
neurocrine
autocrine
Hormone
released
at synaptic
cleft.
Diffusion
to same
cell.
Diagram modified from Hadley, Endocrinology
These are all broadcast
chemical communication
systems.
What is or is not part of the
“endocrine” system gets
fuzzy.
Note: Not all chemical signaling systems
involve hormones!
Non-hormonal chemical signals:
1. Pheromones – transmission of specific
chemical signal through medium outside
of organism.
2. Synaptic Transmission – almost the same
thing as “neurocrine”.
Pheromones.
Specific molecules
released by one
individual typically to
attract a conspecific.
Extreme sensitivity – in
some cases a
behavioral response to
detection of a single
molecule.
Serious pheromone detector – can detect
a single molecule of pheromone
Another serious
pheromone detector
Released by elephant
Synaptic transmission is short distance, short
duration, private chemical communication but
endocrine signals are broadcast.
… but the fact that synaptic chemical signals are
not broadcast and endocrine signals are
broadcast -- is not a sufficient criterion. Other
broadcast chemicals may still not be endocrine.
The original
experiments showing
the presence of
chemical
communication
systems within
organisms.
Easy read for U.
… so we will skip in
lecture.
Steroid Hormones
Types of steroid hormones
Glucocorticoids Example: cortisol
Mineralocorticoids Example: aldosterone
Androgens such as testosterone
Estrogens, including estradiol and estrone
Progestogens (also known a progestins) such as
progesterone
Steroid hormones…
… are not packaged, but synthesized and
immediately released.
… are all derived from Cholesterol.
… are produced by enzymes in mitochondria
and smooth ER.
… (as mentioned already) are lipid soluble,
freely permeable to membranes, so not
stored in cells.
Consequence of lipid solubility….
NOT water soluble!!!
So steroids are carried in the blood complexed to specific
binding globulins.
Examples:
• Corticosteroid binding globulin carries cortisol.
• Sex steroid binding globulin carries testosterone and
estradiol.
Steroids vs Peptides
Peptide hormones encoded by specific genes (steroid
hormones are synthesized from the enzymatic modification of
cholesterol)
SO…
There is no gene which encodes aldosterone, for example!
SO …
• Far fewer different types of steroid hormones re peptide
hormones.
• Steroid structures are the same across taxa.
• Regulation of steroid production (Steroidogenesis) involves
control of the enzymes which modify cholesterol into the
particular steroid hormone.
Overview of human
endocrine system
Part of the brain
The pituitary is two completely
separate glands (anterior &
posterior) that grow together
during development
Skin of most
mammals can
synthesize
vitamin D (really
a hormone)
Coming up next: Revisit stress hormone
response as an example system of how
hormones work in general.
1. Epinephrine (= Adrenalin). Gets body ready
for fast muscle action. Expect changes in heart
rate, blood pressure, making glucose available.
Experiment to document one of the
expected effects: to mobilize glucose.
Inject saline
control or 3
different
chemicals into
volunteers.
Can show that
epinephrine is
necessary and
sufficient to cause
expected change
in blood glucose
concentration.
Note use of two negative controls: saline
and phenyephrine.
Epi & Nor-epi have
effect on blood
glucose, negative
controls do not.
Other experiments show epi & nor-epi do affect pulse rate,
blood pressure and O2 consumption by brain.
So… the perfect task for the endocrine system - multiple
processes (4 of them) controlled at the same time:
1
2
3
Mobilize glucose
0.4 mEq
1.1 mEq
4
Release epinephrine (adrenaline) – the
appropriate target tissues will respond to it.
The specificity of the response is a function of
which tissues are “tuned in” to the signal.
… but what causes release of epinephrine
Epi produced by the adrenal medulla…
How do the post-ganglionic fibers
control adrenal medulla cells?
The epinephrine release example
shows how the nervous system can
control the endocrine system
We have to specify an adrenal gland chromaffin cell,
because often endocrine tissue contains multiple cell types
that release different sorts of hormones.
The chromaffin
cell is
controlled by a
neuron, but it
could just as
well have been
controlled by a
hormone from
some other
endocrine
tissue.
The half-life of a hormone is set by degradative
processes.
Epinephrine controls 3 different processes.
How does it do that?
Ans: The target tissues have specific
receptors for epinephrine, and the
receptors can be tuned to produce just the
right response.
4. Skeletal muscle
B2 receptors bind E
vasodilation
Increase blood flow
Overall, epinephrine release increases blood
pressure.
Which is why “ß-blockers” treat hypertension (ßadrenergic receptor antagonists)
Next:
Simple examples of how negative feedback
regulation works using two different
example hormone systems…
Negative feedback
Set-point /comparator element
regulation
Tissue sensor: pancreatic islet cell monitors glucose level
(Not)
Too much glucose bound to
receptors?
Incr. insulin secretion
Less blood glucose
Insulin binds to receptors
on most cells
Increase transport of
glucose from blood to cells
Neural sensor:
brain neuron osmosensor
(Not)
Osmotic concentration too
high? (implies dehydration)
Neuro-secretion
ADH release
Water retention,
thirst … drinking
Example of feedback regulation with an
adjustable set-point:
Cortisol levels….
Cortisol  long-term
stress-related hormone.
Less acute than EPI.
Also circadian control.
A class of steroid hormones that binds to the
glucocorticoid receptor (GCR).
Cortisol levels sensed by anterior pituitary
Hypothalamus is set point adjuster:
(1) Last 3 months pregnancy,
or (2) extreme athletes – set
point moved higher.
Plasma Cortisol
concentration
Circadian effect:
Time of Day
Immune system cells (but not just) have
glucocorticoid receptors, so taking hydrocortisone,
prednesone (say for arthritis)  antiinflammatory…
But too much for too long -- or if have set-point
problem: Cushing’s disease 
High blood pressure & blood glucose, anxiety,
thirst & other problems.
In many endocrine systems there is also negative
feedback control based on receptor abundance
Long-term
adaptive
change
(change in
transcription)
Down-regulate
receptors
Anterior
pituitary
cell
Anterior
pituitary
cell
Genetic control
(+/- individual
variation) of the
number of
cortisol
receptors
Up-regulate receptors
Anterior
pituitary
cell
Genetic control occurs relative to
transcription levels for the production of
hormones…
and also for the production of hormone
receptors!
How can you tell which is happening?
Figure 47.09 diabetic and obese mice
Here is how it works
(I’ve changed the nomenclature a bit, and split experiment
into two parts….
OB gene
Normal: OB-L (lean)
Mutant 1: OB-F (fat)
Wild-type OB-L/OB-L
Normal weight (lean)
Heterozygote OB-L/OB-F
Normal weight
Homozygous OB-F/OB-F
Lethargic; eats way
too much
Consider heterozygote result. This implies lean is
dominant. In other words, there must be a ‘lean’ gene
product. If you don’t have it, you are fat.
If there is a gene product that determines ‘lean’,
is it a hormone?
Make parabiotic mice:
OB-L/OB-L
OB-F/OB-F
Implies the OB-L
mouse of the pair
Less
food
Normal
makes something
intake
than
food
that moves in
expected
for
intake
blood to OB-F
the fat
mouse and
phenotype
reduces food
intake…
…and moreover, that OB-F mice have the necessary receptor.
OB gene
OB-L/OB-L
Stops eating
& dies of
starvation
Normal: OB-L
Mutant 2: OB-D (diabetic)
OB-D/OB-D
Eats normally
OB-F/OB-F
Stops eating & dies of
starvation
Diabetic mouse
causes wt or
fat mouse to
stop eating
OB-D/OB-D
Eats normally
Interpretation: Both the wt and fat mice have the receptor for the lean
gene product, but the diabetic mice don’t.
The diabetic mice do make the gene product, but not the receptor for
it!
The diabetic mouse keeps eating (no lean receptor), but does not gain
weight: diabetes => cells don’t take up glucose. Despite high blood
sugar levels cells are still malnourished.
The ever-eating diabetic mouse makes more and more lean hormone,
but does not know it.
The parabiotic fat or wt mice do have the receptor, and get the high
levels of the gene product from the OB-D parabiotic buddy. This shuts
down appetite in the OB-F or OB-L mouse.
The previous examples (Epi, ACTH) showed a
hormone system that responded to an external
variable: acute or chronic stress detected by the
nervous system. The n.s. then controlled the
endocrine system.
Internal variables are also detected and
controlled by the endocrine system: the previous
example of pancreatic islet cells.
Here is another example of internal variable
control…
Endocrine cells of the thyroid & parathyroid are both signal
detectors and set point comparators.
Parathyroids  parathormone (PTH), a peptide.
osteoblast cells in bone
marrow  cytokines 
osteoclast cells 
resorb/demineralize bone
 incr. blood Ca2+.
Cells of distal renal
tubule  incr. absorption
of Ca2+ from gut  incr.
blood Ca2+.
Other effects on phosphate
metabolism, biosynthesis of
“vitamin” D  incr. gut
absorption of Ca2+.
Thyroid gland produces thyroxine… but
embedded in thyroid are “C” for clear cells or
parafollicular cells.
C cells produce calcitonin (CT), a peptide
hormone.
So thyroid is two glands in one!
Calcitonin  satiety signal. Stop eating… too
much calcium in blood.
Vitamin D3 = cholecalciferol. A steroid-like hormone.
U.V. light
------ skin -----7-dehydrocholesterol
------ skin -----Vitamin D3
Cholecalciferol-Binding protein
blood
25-hydroxyvitamin D3
liver
Absence of sunlight (e.g. Forks, WA)
No absorption of calcium from gut
Bone demineralization
(Too much 25-OH-D3: Ca2+ feedback via PTH 
conversion to 25-(OH)2-D3 (inactive))
Hormones that control hormones
The anterior and posterior pituitary each
produce a number of hormones that stimulate
other endocrine tissues.
The release mechanism is slightly different for
the two glands.
Note that these
neurons have long
axons that project all
the way to the
posterior pituitary.
More on oxytocin later.
Here a portal
blood system is
used instead of
long axons.
Like cortisol
Hypothalamic hormones are all “releasing hormones”
All are peptides, and released in spurts.
(Replacement therapy also has to be in spurts!)
4 major releasing hormones, cause anterior
pituitary to secrete 6 “controlling” hormones…
4
1. Thyrotropin releasing hormone (TRH)
(tripeptide: Glu-His-Pro)
 Thyroid stimulating hormone (TSH)
 prolactin: mammary growth, lactation
(there may be a role in males)
2. Gonadotropin releasing hormone (GnRH)
(10 aa)
 Follicle stimulating hormone (FSH)
 Luteinizing hormone (LH)
Release starts at the onset of puberty, and for
the rest of life in spurts every 1-2 hours.
Secreted in both males and females.
GnRH agonists used to treat prostate cancer:
High persistent level of agonist  reduction in
GnRH receptors in pituitary  reduced FSH, LH
 reduced testosterone  less stim of prostate.
3. Growth Hormone Releasing Hormone (GHRH)
(mixture of 2 similar 40 amino acid peptides)
 growth hormone
4. Corticotropin Releasing Hormone (CRH)
(41 amino acid peptide)
 adrenocorticotropic hormone (ACTH)
(ACTH  adrenal cortex  cortisol)
Interesting: dramatic circadian rhythm in ACTH
production.
… but only in individuals with regular sleep habits!
• Sharp increase 3-5 hours after sleep
• Increase reaches max 1 hour after
awakening
• Minimum level 3 hours before sleep
This cycle cannot be synchronized by external
light.
Oxytocin
Widespread neuropeptide, found in all vertebrates
-- modulation of neuro-endocrine reflexes
-- affects social/bonding behaviors, care of offspring
-- species differences in use
Steroid regulation of oxytocin
Human Oxytocin Receptor
G-protein coupled receptor (GPCR) 
phospholipase C …
Oxytocin (OT)  uterine contractions
Progesterone  uterine quiescence
Progesterone may bind directly to the OT
receptor, but good evidence that it also blocks
intracellular signaling of OT GPCR.
So 2 hormones balance physiological
processes.
At end of pregnancy, uterus up-regulates OT
receptor mRNA. So no increase in OT
production, but increase in sensitivity to OT.
OT release in the CNS is independent of
OT release in the general circulation
because OT does not cross the bloodbrain barrier.
Brain release  behavior changes
In rats – lordosis (female), penile erection (males)
is facilitated by brain neuron release of OT.
In general, parental care, pair bonding, mate
guarding & territorial aggression have been linked
to OT. Studied extensively in Prairie Voles. (see
article by Gimpl & Fahrenholz pg 665-666 for more
info)
Humans – mixed CNS/peripheral effects post-partum:
After birth, suckling  tactile receptors  spinal
cord  oxytocinergic neurons of the
hypothalamus.
Hypothalamic OT neurons: 3-4 second bursts of
APs Huge OT release to blood  contraction of
myoepithelial cells in the walls of lactiferous
ducts… “let-down” response occurs ½ - 1 min after
tactile stimulation.
Acoustic stimuli (crying baby sounds!) also
activate hypothalamic neurons.
Hormones used by the meat and dairy industries
Six steroids approved by FDA: estradiol, progesterone, testosterone,
zeranol, trenbolone acetate, and melengestrol acetate.
Zeranol, trenbolone acetate and melengesterol acetate are synthetic
growth promoters (hormone-like chemicals that can make animals
grow faster).
Currently, federal regulations allow these hormones to be used on
growing cattle and sheep, but not on poultry. (They are not so
effective on birds)
The synthetic hormone rbGH used to increase milk production in
dairy cattle; not used on beef cattle.
Some key points from this chapter
• Animals use at least six major types of chemical signals.
Hormones are chemical signals that are present in tiny
concentrations and travel throughout the body to affect target
cells.
• The information in hormonal signals helps animals respond
to environmental change, develop as embryos, undergo
sexual maturation, and achieve homeostasis.
• The information in hormonal signals helps animals respond
to environmental change, develop as embryos, undergo
sexual maturation, and achieve homeostasis.
• The production of a hormone is tightly regulated by input
from the nervous system and by other hormones.