Wingfield 2

Wingfield 2 - NPB
101,
Autumn
2008
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Unformatted text preview: NPB
101,
Autumn
2008
 Endocrinology
2
 Hypothalamo‐pituitary
unit
 Anterior
pituitary
 Neurosecretory neurons Hypothalamus Systemic arterial inflow Hypothalamic-hypophyseal portal system Anterior pituitary System venous outflow = Hypophysiotropic =
Anterior Posterior pituitary pituitary hormone Fig.
18‐9,
p.
667
 Hormones of the Pars distalis Growth hormone and prolactin (polypeptides) Glycoproteins: thyroid-stimulating hormone (TSH), luteinizing hormone (LH) follicle-stimulating hormone (FSH) Proopiomelanocortin (POMC): adrenocorticotropin (ACTH), melanocyte-stimulating hormone (MSH) and endorphin Growth hormone Immunocytochemical staining of pituitary cells ACTH ProlacDn
 Growth
hormone
 FSH
 LH
 GH and PRL comparisons. Both have considerable overlap in amino acids. GH has two disulphide bonds and PRL has three Growth hormone Prolactin Prolactin Prolactin is synthesized as a prohormone. Following cleavage of the signal peptide, the length of the mature hormone is between 194 and 199 amino acids, depending on species Structure is stabilized by three intramolecular disulfide bonds It is secreted by so-called lactotrophs in the anterior pituitary Prolactin is secreted by a broad range of other cells in the body, most prominently various immune cells, the brain and the decidua of the pregnant uterus AcDons
of
prolacDn
 Over
300
known
 Actions related to reproduction Somatotropic effects (e.g. growth) Osmoregulation Actions on the integument and its derivatives Interactions with steroid hormones Interactions with the immune system Signal transduction pathways involved in prolactin regulation Positive regulators of prolactin release include vasoactive intestinal peptide (VIP), estrogen, and thyrotropinreleasing hormone (TRH) VIP exerts its effects by G-protein mediated activation of adenylate cyclase (AC) and its downstream effectors cAMP and protein kinase A (PKA). These activate a protein kinase cascade that culminates in gene expression and subsequent release of prolactin. TRH induces prolactin secretion through activation of the phospholipase C (PLC) signaling pathway. Activation of PLC cleaves phosphatidylinositol 4,5-phosphate (PIP) to form diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). These release intracellular calcium from endoplasmic reticulum (ER) and release of prolactin by exocytosis. Signal transduction pathways involved in prolactin regulation Negative regulators include dopamine and thyroid hormone Dopamine binds to the D2 dopamine receptor and decreases AC activity. Thyroid hormone can directly inhibit the prolactin promotor again through a genomic receptor. Growth, growth hormone and growth factors S GO G1 M The
mammalian
cell
cycle.
Go
=
a
fully
mature
cell
(specialized
or
resDng),
not

 dividing.
G1
is
the
growth
phase
preparatory
to
S,
the
syntheDc
stage

 when
DNA
is
duplicated.
G2
is
of
short
duraDon
(only
3
‐
4
hours
and
involving

 protein
synthesis),
and
M
is
the
mitoDc
phase.
Cells
then
may
re‐enter
the
 proliferaDon
cycle
or
may
become
resDng
or
specialized
Go
cells.
The
control
point

 appears
to
be
the
transiDon
from
Go
to
G1
phases
(both
direcDons).

 G2 Types
of
growth
 Cells
may
enlarge
(hypertrophy)
and
intracellular
products
may

 
change
as
a
result
 Cells
may
increase
in
number
(hyperplasia),
e.g.
organ
formaDon,

 
growth
in
size
 ProducDon
of
inter‐cellular
structures,
i.e.
the
extracellular
matrix
 

‐
membranes,
bone,
carDlage
 Metamorphosis,
i.e.
changes
in
cell
types
including
structure,

 
funcDon
and
products.
Note
that
some
cells
may
be
lost
and

 
resorbed,
an
apparent
paradox,
but
nevertheless
a
part
of
growth

 
and
differenDaDon
 Wounding
‐
growth
and
differenDaDon
to
repair
and
replace

 
destroyed
Dssue
 Growth
effects
 Metabolic
effects:
 Decrease
glucose
clearance
 Hypercalcemia
increase

 uptake
of
fat
by
liver
and

 muscles
 Fig.
18‐10,
p.
669
 ArDcular
 carDlage
 Bone
of
epiphysis
 Epiphyseal
plate
 Bone
of
diaphysis
 Marrow
cavity
 CarDlage
 Calcified
carDlage
 Bone
 Fig.
18‐11a,
p.
671
 These
girls
are
sisters.
The
girl
on
the
le]
lacked

 growth
hormone.
In
this
picture
she
was
18cm

 shorter
than
her
sister,
despite
being
one
and
a

 half
years
older.
 Excess
growth
hormone
before
 puberty
produces
excessively

 tall
stature.
In
the
past,
these

 people
typically
were

 crippled
by
nerve,
muscle,

 and
joint
problems,

 acquired
acromegalic
 features
as
they
got

 older,
and
died
young

 of
complicaDons
of
their

 diabetes.

 Features
of
agromegaly
 Growth
hormone
release
from
the
pituitary
is
controlled
by
inhibitory
 
effects
of
somatostaDn
and
sDmulatory
effect
of
growth
hormone

 
releasing
hormone.
Growth
hormone
mediates
its
effects
in
the

 
body
through
insulin‐like
growth
factor
(or
IGF‐1).
 Daily Rhythm [GH] 0 4 8 12 16 20 24 Time of Day, hours Episodic Release [GH] 0 4 8 12 16 20 24 Time of Day, hours Increase




 Decrease




 Note
that
GH
had
two
receptor
binding
sites
resulDng
in
one
 GH
and
a
dimer
of
receptors
 Mechanism
of
GH
acDon
on
post‐natal
growth
 Daughaday
and
Salmon
used
the
incorporaDon
of
S35
into

 rat
carDlage
as
an
indicator
of
growth
 GH
does
not
act
in
vitro!
 An
addiDonal
blood
factor
was
clearly
required
‐
called

 "sulphaDon
factor",
now
known
as
somatomedin,
or
more

 accurately
as
a
family
of
pepDdes
called
insulin‐like
growth

 factors
(IGFs,
because
of
their
similarity
in
structure
to
insulin).

 IGFs
are
absent
from
the
blood
of
hypophysectomized
rats,

 but
reappear
when
GH
injecDons
are
given
 IGFs
are
produced
in
the
liver
and
muscle
within
an
hour
or

 so
of
GH
sDmulaDon
 Insulin‐like
growth
factor
or
 Somatomedin
C
 They
are
about
3,900
‐
12,400
Daltons
in
size
 They
circulate
bound
to
carrier
proteins
 They
have
all
the
effects
on
growth
processes
that
were
at
first

 ascribed
directly
to
GH
 Growth
factors
‐
a
short
list
 Nerve
growth
factors
‐
neurotropins
 Epidermal
growth
factor
 Platelet
derived
growth
factors
 Angiogenic
factors
 Fibroblast
growth
factors
 Transforming
growth
factors
 HematopoeiDc
growth
factors
 Thymic
hormone
 Cytokines
 Chalones
 Placental
lactogen
 Neurotropins
 Four
families
of
neurotropins:
 Nerve
growth
factor
(NGF)
 BDNF
 Neurotropin
3
(NT‐3)
 Neurotropin
4
(NT‐4)
 Two
molecules
of
NGF
bind
to
their
receptor
(tyrosine
kinase),
dimerize
and
 become
phosphorylated.
Then
they
can
adract
other
signaling
proteins.
The
newly
 formed
complex
of
proteins
acDvates
several
kinase
pathways.
TranscripDon
factors
 are
phosphorylated,
move
into
the
nucleus,
and
iniDate
the
transcripDon
of
genes.
 Products
of
transcripDon
may
be
ion
channels.
In
this
example,
increased
 intracellular
levels
of
the
second
messenger,
Ca++.

 This
magnified
image
shows
rat
nerve

 This
magnified
image
shows
rat
nerve
fibers
 fibers
and
Schwann
cells
a]er
72
hours

 
(white
arrows)
and
Schwann
cells
a]er
72
 in
a
culture
with
IGF‐I.
Most
cells
have

 
hours
in
a
culture
without
IGF‐I.
Only
a
few

 already
moved
to
the
fiber
and
adached
 of
the
Schwann
cells
have
moved
toward
or

 to
it;
many
are
beginning
to
wrap
around

adached
to
the
fibers.

 and
spread
along
the
fiber.
 

 Neurotropin
AcDons
 EssenDal
for
central
and
autonomic
neuron
development,
 including
myelinizaDon
and
projecDons
to
other
neurons
 Acts
in
brain
(e.g.
BDNF)
as
well
as
peripherally
‐
e.g.
the

 inervaDon
of
Dssues
 NGF
plays
a
role
in
the
repair,
regeneraDon,
and
protecDon

 of
neurons
 AcDons
in
adults
as
well
as
fetus,
i.e
to
promote
survival

 of
neurons,
learning
and
memory
 Play
a
role
in
other
physiological
systems
and
Dssues
such

 as
the
immune
system
 Epidermal
growth
factor
 Regulates
opening
of
eyelids
 Triggers
erupDon
of
teeth
 SDmulates
proliferaDon
and
keraDnizaDon
of
epidermal
Dssues
 SDmulates
proliferaDon
of
skin
cells
in
neonates
and
embryos
 Regulates
development
and
differenDaDon
of
epithelial
cells
 Protein
Sequence
of
Human
Epidermal
Growth
Factor

 Epidermal
growth
factor
and
wound
healing
 EGF
is
also
involved
in
healing
of
wounds
 It
acts
to
increase
nutrient
uptake,
ion
fluxes
and

 phosphorylaDon
of
membrane
proteins
 This
is
followed
by
an
increase
in
RNA
and
protein

 synthesis
and
finally
DNA
synthesis
prior
to
cell
division
 First
characterized
in
mouse
submaxillary
glands
of


 newborn
pups.
Known
to
be
in
saliva
 Control
of
epidermal
growth
factor
 Synthesis
of
EGF
is
enhanced
by
androgens
(as
is
NGF
synthesis)
 May
also
be
under
direct
alpha
adrenergic
control
that
elevates

 blood
levels
of
EGF
 Electrical
sDmulaDon
of
the
superior
cervical
ganglion
also
 results
in
an
increase
of
EGF
secreDon
 Thyroxine
elevates
EGF
in
salivary
glands,
skin,
ocular
Dssue

 and
kidney,
but
not
the
liver
 Estradiol
promotes
EGF
secreDon
in
kidney
and
uterus
 HematopoieDc
Growth
Factors
 These
factors
sDmulate
erythropoiesis
(producDon
of
red
blood
cells)
 They
are
produced
primarily
by
the
kidney
but
are
known
to
also
be

 produced
by
other
Dssues
 HematopoieDc
factors
are
thought
to
be
responsible
for

 erythropoiesis
in
people
at
high
alDtudes
 Liver
is
a
primary
source
of
erythropoieDn
in
the
fetus
 Hormones of the Pars distalis Growth hormone and prolactin (polypeptides) Glycoproteins: thyroid-stimulating hormone (TSH), luteinizing hormone (LH) follicle-stimulating hormone (FSH) Proopiomelanocortin (POMC): adrenocorticotropin (ACTH), melanocyte-stimulating hormone (MSH) and endorphin Thyroid‐
 SDmulaDng
 Hormone

 Luteinizing
 Hormone

 Follicle‐
 SDmulaDng
 Hormone

 Regulates
synthesis
 and
secreDon
of

 thyroid
hormones
 Regulates
synthesis
 and
secreDon
of
sex
 steroids,
ovulaDon
 Regulates
ovarian
 development,

 spermatogenesis
 Thyroid
sDmulaDng
hormone
α‐subunit
is
92
amino
acids
and
is

 
glycosylated
(two
oligosaccharides).
 Thyroid
sDmulaDng
hormone
β‐subunit
is
112
amino
acids
and
 
is
synthesized
separately
from
the
α‐subunit.
It
has
one
 
oligosaccharide
chain
 TSH
in
situ,

 anterior
pituitary
 CNS
 Dopamine
 SomatostaDn
 HYPOTHALAMUS
 MAMMALS
 ‐ve
 THYROTROPIN‐RELEASING
 HORMONE 
 ANTERIOR
PITUITARY
 THYROID
STIMULATING
 HORMONE
 +ve
 THYROID
 TRIODOTHYRONINE
 MONODEIODINASE
 THYROXINE
 Thyroid
 gland
 Right
lobe
 Trachea
 Isthmus
 Le]
lobe
 Fig.
19‐1a,
p.
684
 Normal
appearance
of
the
thyroid

 gland
on
the
anterior
trachea
of

 the
neck.
The
thyroid
gland
has
a

 right
lobe
and
a
le]
lobe

 connected
by
a
narrow
isthmus.

 Human
Thyroid
 Thyroid
 Trachea
 Esophagus
 Fig.
19‐1b,
p.
684
 Capillary
network
 around
follicles
 Fig.
12
 Thyroxine (T4) I 3' I 3 O CH2-CH-C-OH NH2 HO I 5' O I 5 Tri-iodothyronine (T3) I 3' I 3 O CH2-CH-C-OH NH2 HO O I 5 Thyroid
hormones
have
effects
on
development,
metabolism,
and
 
interact
with
many
other
hormones
(permissive
acDons).
 Major
steps
of
thyroid
hormone
synthesis
 Iodine
Trapping
‐
transporDng
iodine
into
the
follicular
cells
from

 
the
extracellular
fluid
 AcDvaDon
of
iodine
‐
iodine
is
made
more
reacDve
inside
the
cell
 
by
peroxidase
cycle
 OrganificaDon
‐
addiDon
of
iodine
to
tyrosine
residues
on

 
thyroid‐binding
globulin
(TGB)
 Coupling
of
tyrosines
‐
combining
iodinated
tyrosines
within

 
the
TGB
 Pinocytosis
of
TGB
in
colloid
and
fusion
with
lysosomes
 ProteolyDc
cleavage
of
TGB
to
release
hormones
 Blood
 Colloid
 Thyroid
follicular
cell
 *Endoplasmic
 

reDculum/Golgi
 

complex
 Lysosome
 TGB
=
Thyroglobulin
 





I
=
Iodine
 

MIT
=
Monoiodotyrosine
 DIT
=
Di‐iodotyrosine
 


T3
=
Tri‐iodothyronine
 


T4
=
Tetraiodothyronine
(thyroxine)
 Fig.
19‐2,
p.
685
 CharacterisDcs
of
thyroid
hormone
transport
 T4
is
usually
produced
by
the
thyroid
in
greater
quanDty
than
T3
 Mono‐iodinaDon
in
the
blood
or
at
a
target
cell
can
form
more
T3
 Mono‐deiodinase,
synthesized
in
liver,

may
be
a
criDcal
point

 
of
regulaDon
of
thyroid
hormone
acDon
 In
general
it
is
thought
that
T3
is
more
potent
than
T4
 There
is
a
specialized
thyroid
hormone
binding
carrier
called

 
thyroxine
binding
globulin
(ThyBG),
which
binds
to
about
70%

 
of
both
thyroid
hormones
 The
rest
of
the
hormone
binds
to
albumin
and
transthyreDn

 
(formerly
known
as
pre‐albumin)
 Receptors
(thyroid
hormone
receptors)
and
transporters
(amino
acid

 transporters)
interact
to
modulate
thyroid
hormone
uptake
into
target

 Dssues
and
it's
importance
in
controlling
thyroid
hormone
delivery
to
the

 cell
nucleus.
 Roles
of
Thyroid
Hormones,
growth
and
 development
 Thyroidectomy
results
in
severe
growth
retardaDon

 Growth
hormone
secreDon
is
decreased
as
a
result
of
low

 
T3
and
T4,
but
is
restored
is
thyroid
hormones
are
injected
 Note,
however,
that
growth
hormone
injecDons
do
not
restore

 
growth
in
thyroidectomized
animals
 Thus
T3
and
T4
are
required
for
both
growth
hormone
secreDon

 
and
systemic
acDons
 Effects
on
growth
and
development
include
linear

 
development/growth
and
bone
growth
 MyelinaDon
of
nerves
‐
increase
in
protein
synthesis
 Thyroid
hormones
can
increase
nerve
growth
factor
in
brain
 Disrupted
skeletal
development
following
deleDon
of
the
thyroid
hormone
receptor

 gene;
the
structure
of
the
growth
plate
is
disorganized
and
chondrocytes
lay
down

 immature
bone
that
is
poorly
mineralized.
 MRC
Clinical
Sciences
Centre,
Faculty
of
Medicine,
Imperial
College
London,
 Thyroid
hormone
is
essenDal
for

 normal
brain
development
 TRa1
mRNA
in
rat
fetal
brain.
 This
is
the
period
before
the
onset

 of
fetal
thyroid
funcDon,
which

 clearly
demonstrates
that
thyroid

 hormone
of
maternal
origin
can

 affect
fetal
brain
development
 Roles
of
Thyroid
Hormones,
thermogenesis
 EvoluDon
of
homeothermy
resulted
in
a
need
for
heat
producDon
 Thyroid
hormones
increase
mitochondrial
oxygen
consumpDon

 
and
producDon
of
ATP
 Increase
the
number
of
membrane
sodium
pumps
that
use
up
to

 
20
or
45%
of
total
cell
energy
supplies
(ATP)
 InhibiDon
of
Na+/K+ATPase
acDvity
by,
for
example
ouabain,

 
reduces
the
acDon
of
thyroid
hormones
on
heat
producDon
and
 
oxygen
consumpDon
 Increased
cardiac
output
‐
elevated
heart
rate/contracDon
 UpregulaDon
of
β‐1
adrenergic
receptor
number
and
acDvity
 Increased
metabolism
‐
heightened
lipolysis
–
increased
carbohydrate

 
usage
‐
greater
appeDte
‐
higher
protein
turnover
rate

 Increased
gut
movement
and
muscle
excitability
 OxidaDve
cycles
 The
respiratory
chain
and
ATP
synthase.


Electrons
are
transferred
from
NADH

 dehydrogenase
to
cytochrome
c
oxidase
by
coenzyme
Q
(Q),
cytochrome
bc1
complex

 and
cytochrome
c.
The
established
proton
gradient
across
the
inner
mitochondrial

 membrane
drives
the
proton
flow
in
ATP
synthase
that
accompanies
ATP
synthesis.

 Structures
are
taken
from:
cytochrome
bc1
complex;
cytochrome
c
oxidase;
the

 F1
part
of
ATP
synthase;
and
the
Fo
part
of
ATP
synthase.

 Roles
of
thyroid
hormones
–
permissive
acDons
 Thyroid
hormones
synergize
with
other
other
hormones
to
enhance

 
their
effects.
In
some
cases
they
may
inhibit
their
effects.
 In
synergy
with
glucocorDcosteroids,
thyroid
hormones
elevate

 
growth
hormone
secreDon
and
increase
lipolysis.
 Thyroid
hormones
synergize
with
reproducDve
hormones
to
regulate
 
reproducDve
funcDon.
 In
some
mammals
and
many
other
vertebrates,
thyroid
hormones

 
regulate
molDng
and
other
funcDons
of
the
integument.
 Enhancement
of
sympatheDc
acDvity
 Effects
of
iodine
insufficiency
 Massive
goiter
 Endemic
goiter
 thioruea
 propylthiouracil
 methimazole
 tolbutamide
 metahexanamide
 chlorpropamide
 2‐4‐dinitrophenol
 acetylsalicylic
 acid
 Para‐aminosalicylic
acid
 resorcinol
 chlorpromazine
 Diphenyl
hydontoin
Na
 Structural
formulas
of
some
drugs
that
affect
the
thyroid.
 Thyroid
Atrophy:
The
large

 dark
staining
structures
are

 parathyroid
glands
separated

 by
loose
fibrous
connecDve

 Dssue.

Follicles
are
absent.
 Note
several
clusters
of

 atrophic
follicles
scadered

 within
loose
connecDve
Dssue.
 Hypothyroidism
due
to
lack
of
thyroid
hormone
 (no
TSH
receptor
etc.)
 Expressionless
face
 Coarseness
and
loss
of
hair
 Dry
skin
 Cold
intolerance
 Weight
gain
 FaDgue
 ConsDpaDon
 Memory
and
mental
 
impairment
 Decreased
concentraDon
 Yellow
skin
 depression
 Hypothyroidism
can
lead
to
 creDnism
 18
month
old
boxer
dog
with

 congenital
hypothyroidism.
 Note
sparse
hair,
large
head,
 wrinkled
skin,
femur
is

 short
and
widened,
epiphyses
 are
under‐ossified
and
inter‐
 vertebral
spaces
are
wider
 A
cat
with
severe
weight
loss

 due
to
hyperthyroidism
 Hair
loss
following
 hyperthyroidism
 Grave’s
disease
 Bulging
eyes
in
hyperthyroidism
 “thyroid
stare”
 Autoimmune
disease
–
LATS
targets
TSH
 receptors
and
promotes
T4
release
 Fig.
19‐4,
p.
688
 Thyroid
hormones
receptors
 Hormones of the Pars distalis Growth hormone and prolactin (polypeptides) Glycoproteins: thyroid-stimulating hormone (TSH), luteinizing hormone (LH) follicle-stimulating hormone (FSH) Proopiomelanocortin (POMC): adrenocorticotropin (ACTH), melanocyte-stimulating hormone (MSH) and endorphin The Pro-opiomelanocortin derived hormones: Adrenocorticotropic hormone α-Melanocyte-stimulating Hormone Endorphins POMC‐derived
pep-des
 Opiate
pepDdes:
β‐endorphin,
met‐enkephalin
 MelanocorDns:
adrenocorDcotropin
(ACTH),
α‐Melanocyte‐
 
sDmulaDng
Hormone
(a‐MSH),
ß‐MSH,
γ‐MSH
 Lipotropic
Hormones:
α‐
LPH
and
ß‐
LPH
are
known
to
have

 
acDons
to
increase
fat
deposiDon
in
some
vertebrates
 CorDcotropin‐like
pepDde
(CLIP),
has
no
known
biological

 
funcDon
 AcDons
of
α‐Melanocyte‐sDmulaDng
Hormone
 Increase
synthesis
of
melanin
(many
vertebrates)
 Regulate
dispersion
of
melanin
granules
(melanosomes)
 
in
skin
cells
(fish
and
amphibians)
 Regulates
other
chromatophores
and
color
in
general
 May
mimic
adrenocorDcotropin
in
development
(fetus)
 Role
in
memory
as
a
brain
pepDde
 Thermoregulatory
role
‐
e.g.
in
lizards,
dark
in
morning
and
pale

 
during
heat
of
the
day
 May
be
involved
with
fever
regulaDon
 Suppresses
appeDte
 MelanocorDn
Receptors
 A
family
of
five
melanocorDn
receptors
(MC1‐R
‐
MC5‐R)
 MC2‐R
is
expressed
in
adrenal
cortex
and
is
involved
in
the

 
stress
response
 MC3‐R
and
MC4‐R
mRNA
in
regions
in
rat
brain
indicated
both

 
receptors
may
funcDon
in
neuroendocrine,
cardiovascular,
 
and
food
and
water
intake
regulaDon
 MC5‐R
appears
to
be
involved
in
the
regulaDon
of
exocrine
gland

 
funcDon
 The Pro-opiomelanocortin derived hormones: Adrenocorticotropic hormone and the adrenal cortex α-Melanocyte-stimulating hormone Endorphins CNS
 HYPOTHALAMUS
 
VASOPRESSIN
 OXYTOCIN
 CORTICOTROPIN‐RELEASING
 HORMONE 
 POMC
 ANTERIOR
PITUITARY
 α-MELANOCYTE STIMULATING HORMONE
 ADRENOCORTICOTROPIN
 ADRENAL
 CORTEX
 ENDORPHIN
 CORTISOL
 Human
adrenal
glands.
Each
adult

 adrenal
gland
weighs
from
4
to
6
grams.
 Zona
glomerulosa
 Zona
fasciculata
 Cortex
 Zona
reDcularis
 Medulla
 Zona
glomerulosa
cell
(mammal)
 Zona
fasciculata
cell
(mammal)
 SER
=
smooth
endoplasmic
reDculum



ER
=
rough
endoplasmic
reDculum
 M
=
mitochondria 
 








 





Ly
=
lysosome
 LD
=
lipid
droplets 
 





LPG
=
lipofuchsin
pigment
granules
 BL
=
basement
lamina 
 






FL
=
nuclear
internal
lamina
 Smooth
endoplasmic
 reDculum
is
the
site
 of
steroid
synthesis
 CRH
 Oxytocin
 R
 Vasopressin
 AcDon
of
ACTH
on
adrenal
cortex
 R
 cyclopentanoperhydrophenanthrene
nuclei

 21 COOH 20 C=O 12 18 11 1 2 19 10 9 17 C 8 7 6 13 14 D 16 15 A 3 4 B 5 Steroid
Hormones
 AromaDzaDon
of
ring
A
gives
rise
to
the
C‐18
steroids

 
(i.e.
18
carbon
atoms
‐
estrogens)
 Androgens
are
C‐19
steroids

 Steroid
molecules
with
a
side
chain
at
carbon
17
are
the

 
C‐21
steroids
(corDcosteroids
and
progesDns
 GlucocorDcosteroids
have
=O
or
‐OH
groups
at
carbon
11
 3β‐DH
is
3β‐dehydrogenase
 P450c11
is
11β‐hydroxylase
 P450c17
is
17α‐hydroxylase
 P450c21
is
21β‐hydroxylase
 Important
enzymes
etc.
in
steroid
synthesis
 P450,
side
chain
cleavage
or
desmolase
 3b‐DH
or
3b‐hydroxysteroid
dehydrogenase
 P450c17
or
17a‐hydroxylase
 P450c21
or
21b‐hydroxylase
 P450c11
or
11b‐hydroxylase
 Steroidogenic
Acute
Regulatory
or
StAR
protein
has
been
shown
to

 
be
instrumental
in
the
acute
regulaDon
of
steroid
hormone

 
biosynthesis

 AcDon
in
mediaDng
cholesterol
transfer
to
the
inner
mitochondrial

 
membrane
and
the
cholesterol
side
chain
cleavage
enzyme
system
 FuncDons
of
GlucocorDcosteroids.
 Metabolism,
increase
gluconeogenesis
(the
breakdown
of

 
proteins
and
fats
to
give
carbohydrates
 In
the
liver,
corDsol
increases
the
conversion
of
glucose
to
glycogen

 
and
at
the
same
Dme
decreases
enzymes
involved
in
glycogenolysis
 Proteins
can
be
broken
down
from
liver,
skeletal
muscle
and

 
lymphoid
Dssue
 CorDsol
mobilizes
fady
acids
and
decreases
glucose
uptake
by

 
adipose
Dssue
 Decreases
uptake
of
amino
acids
and
nucleoDdes
in
fibroblasts,
 
leukocytes,
skin
and
bone
 GlucocorDcosteroids
provide
energy
in
the
form
of
usable

 
carbohydrate
(glucose/glycogen)
at
the
expense
of
anabolic

 
acDviDes
 Chronic
stress
or
Cushing's
syndrome
results
in
thin
skin
and

 
characterisDc
purple
striae.
 Cushing’s
syndrome
(result
of
excess
CRH
or
ACTH
release
and
 
hypersecreDon
of
glucocorDcosteroids
 Fig.
19‐9,
p.
694
 FuncDons
of
GlucocorDcosteroids.
 Development
 CorDsol
is
acDve
in
the
differenDaDon
of
pulmonary
epithelial

 
cells
in
the
fetal
lung
 It
is
involved
in
the
synthesis
and
secreDon
of
pulmonary

 
surfactant
by
these
cells
 CorDsol
levels
in
blood
increase
during
the
last
trimester
of

 
pregnancy
and
culminate
the
inducDon
of
birth
 GlucocorDcosteroids
have
effects
on
the
mammary
gland

 
(i.e.
differenDaDon
during
development)
 FuncDons
of
GlucocorDcosteroids.
 OsmoregulaDon
 GlucocorDcosteroids
are
essenDal
for
protein
synthesis
related

 
to
sodium
pump
acDvity
in
cell
membranes
 CorDcosterone
can
acDvate
the
acDon
of
nasal
salt
glands
in

 
birds
and
mammals;
decrease
Ca2+
uptake
by
the
gut
 GlucocorDcosteroids
also
influence
inflammaDon
by
decreasing

 
arachidonic
acid
synthesis
and
histamine
producDon
 FuncDons
of
GlucocorDcosteroids.
 Behavior
 CorDcosterone
is
important
for
the
acDon
of
nor‐epinephrine

 
to
increase
feeding
behavior

 CorDcosterone
increases
acDvity
and
"escape"
hyperacDvity

 
(note
that
CRH
also
has
these
effects)
 GlucocorDcosteroids
can
result
in
suppression
of
reproducDve

 
behavior
in
general
 Stress
effects
‐
very
complex

 1.
Steroid
enters
cell
 2.
Binds
receptor
 3.
Heat
shock
proteins
 



dissociate
 4.
Hormone
receptor

 dimerizes
and
enters

 nucleus
 5.
Receptor/hormone

 complex
binds
DNA
 6.
mRNA
enters
cytosol,
 protein
synthesis
begins
 Stress, and Coping Styles Emergency
Life
History
Stage
and
its
Sub‐stages
 Fight
or
flight
response
 InfecDon/
 wounding
 Sickness
behavior
 and
fever
 Stressors
 ProacDve/ReacDve
coping
styles.
 InfecDon/
 wounding
 FacultaDve
behavioral
and
 physiological
responses
 Autonomic nervous system Epinephrine (adrenalin) from adrenal medulla ProacDve/reacDve
coping
styles
 to
direct
and
indirect
LPFs
 ReacDve
 Behavioral
immobility,
low
aggression
 ProacDve
 AcDve
behavioral
response
to
social
challenge,
 high
aggression
 Koolhaas
et
al.,
1999
 Effects
of
glucocorDcosteroids
 at
baseline
levels

 Regulate
immune
system
 Increase
gluconeogenesis,
fat
storage
 Permissive
for
foraging
and
related
acDvity
 Regulate
ion
transport
 Provide
negaDve
feedback
 Short
Term
Effects
of
Elevated

 GlucocorDcosteroids
in
Response
to
 Direct
LPFs
 1.

Suppress
"unnecessary"
physiological
and
 
behavioral
funcDons.
 2.

AcDvate
facultaDve
behavioral
paderns
that 

 
promote
survival
(i.e.
temporary
emergency
 
behavior).
 3.
Prepare
immune
system
for
possible

 
infecDon/wounding
(and
sickness
behavior)
 4.

Increase
gluconeogenesis.
 5.

Avoid
the
long‐term
effects
of
stress‐induced 

 
high
levels
of
glucocorDcosteroids.
 Sickness
behavior
 LPFs, infection, wounding Macrophages, T lymphocytes Interleukin-1 Cortisol Cacechtin, (Tumor necrosis factor) Adrenal cortex Hypothalamus
 ACTH Anterior pituitary gland CRH
 Interleukin-1 Prostaglandins Sickness behavior Lethargy, sleep Pain - aching joints etc. Loss of appetite, adypsia Decline in appearance Lack of interest in surroundings Decline in libido Fever Hart,
1988
 Kent
et
al.,
1992
 Brebner
et
al.,
2000
 Components
of
the
Behavioral/Physiological

 Strategies
in
Response
to
Stress
 1.
Movements
away
from
the
source
of
the
stress
"leave‐it"

 
strategy
 2.
Seek
a
refuge
"take‐it"
strategy
 3.
Seek
a
refuge
first
and
then
move
away
if
condiDons
do
not

 
improve
"take‐it
at
first
and
then
leave‐it"
strategy
 4.
MobilizaDon
of
stored
energy
sources
such
as
fat,
glycogen
 
 
and
protein
to
fuel
movement
away
from
the
source
of
the

 
stress,
or
to
provide
energy
while
sheltering
in
a
refuge
 5.
Sedle
in
alternate
habitat
once
an
appropriate
site
is

 
idenDfied,
or
return
to
the
original
site
and
resume

 
the
normal
sequence
of
life
cycle

 Effects
of
GlucocorDcosteroids
on
FacultaDve
 Behavioral
and
 Physiological
Strategies
of
the
Emergency
Life
 History
Stage
 Chronic
(days
to
weeks)
 Inhibit
reproducDve
system
 Suppress
immune
system
 Promote
severe
protein
loss
 Neuronal
cell
death
 Suppress
growth
 Rapid
(mins
to
hours)
 Suppress
reproducDve
behavior
 Regulate
immune
system
 Increase
gluconeogenesis
 Promote
escape
(irrupDve)
 behavior
during
day
 Promote
night
reszulness
 Promote
recovery
on
return
 to
normal
life
history
stage
 Disrupt
second
cell
messengers
 Increase
foraging
behavior
 (a)
 (b)
 (c)
 (d)
 Osteo‐
 Chronic
 Hyper‐
 Cervical
 arthriDs
 disease
 tension
 cancer
 b
 25
 20
 15
 10
 5
 150
 125
 100
 75
 50
 16
 14
 12
 10
 8
 30
 25
 20
 15
 10
 1
 2
 Highest
 3
 4
 5
 6
 7
 Lowest
 c
 a
 d
 From
McEwen,
2000
 Socioeconomic
Status
 ...
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This note was uploaded on 01/06/2010 for the course NPB idk taught by Professor Wingfield during the Spring '09 term at UC Davis.

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