Hypothalamus and
Anterior Pituitary
04
• The “story line” concept: introduction to communication,
“reflex arc” model, neuroendocrinology, hierarchies, integration
• The “hypothalamic - pituitary” unit: neurovascular
hypothesis, hypothalamic and hypophysiotropic neurohormones
to anterior pituitary.
• The “neuroendocrine control”, “hierarchies” and
“integration” sites: the ME as neuroendocrine integration
site, other neuroendocrine integration sites
• The “anterior pituitary”: embriological origin, amplification
unit for hypophysiotropic hypothalamic signals
• Regulators of anterior pituitary secretion: regulators
of ACTH and of GH secretions and their mechanisms of action
• Neurohormones (GnRH, TRH, GHRH, SS, CRH,
DA): a list of hypophysiotropic neurohormones and their effects
The “Story Line” Concept
I suggest you put this information into a table YOU design !!!
Page 1
The “Story Line” Concept
integrator
center
afferent
“story line”
S
S
sensor
E
a “reflex arc”
a base for a
control model
efferent
“story line”
diagram for a control system
as that present in
a refrigerator
negative feedback
“story line”
E
effector
… if story lines are linked through an integrator and
a negative feedback then you have “control”…
The “Story Line” Concept
Blood glucose as example of a multihormonal control
e.g.
Insulin (1)
Glucagon (2)
Cortisol (3)
Epinephrine
SS and GRH
GH
T3 - T4
others ...
()1
()2
()
S
()3
S
S
E
E
Page 2
E
The “Hypothalamic- Pituitary” Unit
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Hypothalamus
Pituitary Stalk
Anterior / Posterior Pit.
Hypothalamic Nuclei
Vascular link to AP
Neuronal link to PP
Stalk transection
Kidney transplant
Neonate pituitary
Harris, Halaz, Yalow,
Shally, Guilleman (NTC)
• Neuroendocrine control
ACTH
LH
pulsatile
GH
circadian
episodic
(pulsatile, circadian, episodic)
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
hypothalamus
NTC =
neuroendocrine
transducer
cells
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•
•
•
•
•
S
variable under
control (t°C /
°F)
thermostat
(set point)
t°C / °F
detector
(feedback)
Integrator ()
common
language
error signal
(on/off)
engine
(amplifier)
NTC
long
loop
negative
feedback
AP
short and
ultrashort
negative
feedbacks
hierarchies:
gonadal
adrenal
TARGET
thyroid
others
E
FINAL ENDOCRINE EFFECT
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The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
CS
feedback
detector
•
•
•
•
•
•
•
S
variable under
control (t°C /
°F)
thermostat
(set point)
t°C / °F
detector
(feedback)
Integrator ()
common
language
error signal
(on/off)
engine
(amplifier)
Integrator ()
Error signal (NTC)
negative
feedback
loop
AP
gland
E
controlled hormone
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
CS
E2
P4
receptor
Cortisol.
receptor
GnRH
N TC
gonadal
hierarchy
S
CS
E
AP
CS
T3
receptor
CRH
adrenal
hierarchy
AP
TRH
thyroid
hierarchy
AP
gonad
adrenal
thyroid
E2 / P4
cortisol
T3 / T4
Page 4
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
ARN-ME and PVN, two hypothalamic integration center
ARN-ME
S
PVN
E
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
ARN-ME and PVN, two hypothalamic integration center
POA
PVN
The PVN has outputs:
to ARN-ME area
to posterior pituitary
to midbrain (ANS)
ME
S
E
Page 5
GnRH
TRH, GHRH
SRIF / SS
DA, CRH, VIP
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
ARN-ME and PVN, two hypothalamic integration center
What are integrators for, and from where do their inputs
came from, and where do their outputs go to ??
ARN-ME
S
AP
PVN
PP ANS
E
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
ARN-ME and PVN, two hypothalamic integration center
What are integrators for, and from where do their inputs
came from, and where do their outputs go to ??
S
E
Page 6
The “Neuroendocrine Control”,
“Hierarchies” and “Integrators”
ARN-ME and PVN, two hypothalamic integration center
What are integrators for, and from where do their inputs
came from, and where do their outputs go to ??
S
E
The “Anterior Pituitary”
Anterior Pituitary Hormones
AP function and “story lines”
Hormone
TSH
FSH
LH
GH
PRL
ACTH
POMC
Page 7
Target
Major Action
The “Anterior Pituitary”
• Embriological
origin
• Anatomical /
functional
links to the
brain
• Hypophysiotropic neurohormones
• Hormone
RIAs
anterior pituitary
roof of the mouth
Rathk’es pouch
adenohypophysis
vascular link
posterior pituitary
hypothalamic projection
axonal transport
neurohypophysis
neuronal link
The pituitary gland is located in a depression of
the basiesphenoid bone called the “sella turcica”
The “Anterior Pituitary”
• Embriological
origin
• Anatomical /
functional
links to the
brain
Lesion
1
• Hypophysiotropic neurohormones
• Hormone
RIAs
Page 8
The “Anterior Pituitary”
Hypophysiotropic Hormones
• Embriological
origin
• Anatomical /
functional
links to the
brain
• Hypophysiotropic neurohormones
this
lecture
(vascular link)
• Hormone
RIAs
next
lecture
(neuronal link)
The “Anterior Pituitary”
• Embriological
origin
• Anatomical /
functional
links to the
brain
• Hypophysiotropic neurohormones
• Hormone
RIAs
Hypophysiotropic Hormones
Hormone
Aminoacids
CRH
GnRH
GHRH
Ghrelin
SS
5HT
DA
TRH
AVP
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Hypothalamic
Source
Pituitary Action
The “Anterior Pituitary”
Hypophysiotropic Hormones
• Embriological
origin
• Anatomical /
functional
links to the
brain
• Hypophysiotropic neurohormones
• Hormone
RIAs
TRH
GnRH
SS
CRH
GHRH
Grhelin
VP
The “Anterior Pituitary”
• Embriological
origin
How to measure Hormones
• Anatomical /
functional
links to the
brain
• Hypophysiotropic neurohormones
• Hormone
RIAs
Page 10
Regulators of AP secretion
The
hypothalamic –
pituitary –
adrenal
hierarchy
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
S
E
Regulators of AP secretion
• Regulators of
ACTH
secretion
Regulation of ACTH secretion
• Regulators of
GH secretion
S
E
ACTH --->
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Regulators of AP secretion
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
Feedback associated
with control of ACTH
POMC and
biosynthesis
of ACTH
(Addisson’s disease ???)
S
E
Regulators of AP secretion
• Regulators of
ACTH
secretion
CS
Basal
release
of ACTH
Cortisol.
receptor
• Regulators of
GH secretion
CRH
adrenal
hierarchy
S
E
What does this
profile suggest
about the control
of ACTH ???
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AP
adrenal
cortisol
Regulators of AP secretion
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
(more
Info in
glucocorticoid
lectures)
S
E
Regulators of AP secretion
• Regulators of
ACTH
secretion
Mechanism of action
• Regulators of
GH secretion
S
E
Page 13
Regulators of AP secretion
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
S
E
(more info on steroids, gluco and mineralocorticoids lectures)
Regulators of AP secretion
• Regulators of
ACTH
secretion
the
growth
hierarchy
• Regulators of
GH secretion
S
E
Page 14
Regulators of AP secretion
Regulation of GH secretion
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
S
E
Regulators of AP secretion
(last lecture)
• Regulators of
ACTH
secretion
(this
lecture)
• Regulators of
GH secretion
(-Fb)
(lecture
on
growth)
S
E
Page 15
Regulators of AP secretion
• Regulators of
ACTH
secretion
day
vs
night
GH
basal
release
• Regulators of
GH secretion
S
E
What does this experimental profile suggests ?
Regulators of AP secretion
• Regulators of
ACTH
secretion
More on
growth and
metabolic
actions
of hormones
in later
lectures on
metabilism of:
• Regulators of
GH secretion
a) water
b) glucose
c) mineral
d) growth
S
E
GH endocrine effects are also the reason why it
is abused as drug to enhance sport performance.
Page 16
Regulators of AP secretion
GH and exercise performance
force
• Regulators of
GH secretion
More on
growth and
metabolic
actions
of hormones
in later
lectures on
metabilism of:
workload
• Regulators of
ACTH
secretion
a) water
b) glucose
c) mineral
d) growth
time in months
S
E
GH endocrine effects are also the reason why it
is abused as drug to enhance sport performance.
(+)
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
S
E
(-)
Page 17
Regulators of AP secretion
• Regulators of
ACTH
secretion
Mechanism of action
• Regulators of
GH secretion
S
E
Regulators of AP secretion
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
S
E
2.3 meters
(7’ 6”)
1.6 meters
GH hypersecretion
before and
after the
closure of
epiphyseal
growth plate
at puberty
Page 18
Gigantism
Regulators of AP secretion
• Regulators of
ACTH
secretion
Acromegaly
• Regulators of
GH secretion
S
E
Regulators of AP secretion
• Regulators of
ACTH
secretion
• Regulators of
GH secretion
S
E
Acromegaly
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Hypophysiotropic
neurohormones
• anatomy, embryology, and hierarchies
(gonadal, thyroid, GH, adrenal, Prl,
intermedin).
• GnRH: structure, gene expression,
receptor, secretion, action, Kallman
syndrome, clinical use.
• TRH: structure, receptor, secreting cells,
regulation, actions, clinical use.
• GHRH: structure, receptor, secretion,
patophysiology, clinical use.
• SRIF: structure, receptor, secretion,
analogs.
• CRH: structure, receptors, regulation,
secretion and patophysiology, clinical
use.
• DA: synthesis and DA neurons,
regulation of Prl, receptors,
hyperprolactinemia and D2R agonists.
• gases as neural messengers
(neurohormones).
GnRH
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decapeptide derived from a
92 aa precursor encoded by
one gene which also encodes
GAP
its receptor has 7transmembrane domains,
characteristic of G protein linked receptors. Its AP
content changes with
physiological states. Constant
GnRH infusion downregulates
the GnRH- receptor
GnRH regulates LH / FSH
synthesis and release by a Ca
- dependent mechanism
involving phosphoinosi-tide
hydrolysis, PKC activation,
and calmodulin
Kallman syndrome,
precocious puberty, hpg
mouse
sexual behavior, prostate
cancer, endometriosis
GnRH
LHRH
TRH
GRH
SS
LH / FSH
TSH
GH
P4, T, E2
T3, T4
IGFs
CRH
DA
VIP
MSH - RF
5HT
ACTH
Prl
MSH
cortisol
TRH
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is a tripeptide amide
synthesized as part of a
large prohormone termed
prepro-TRH which
contains 6 TRH copies
encoded by one gene
its receptor has 7transmembrane domains,
characteristic of G protein
- linked receptors
TRH actions are mediated
by the phosphoinositol /
Ca system (IP3, DAG,
calmodulin, PKC)
distribution of TRH
receptors in brain suggest
TRH is also a
neurotransmitter /
neuromodulator
TRH appears to function
as neurotrophic factor
used in stimulation tests
prior to new TSH assays
Page 20
GHRH
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44 aa in more than a
isoform coded in a large
prohormone. Hypothalamic
gene expression is under
the control of GH, is
sexually dimorphic and
regulated by gonadal
steroids (up by DHT)
its receptor has 7transmembrane domains,
characteristic of G protein linked receptors
several second messenger
systems mediate effects of
GHRH: AC/cAMP, PLC/IP2,
PLA/PGE
GHRH neurons have SS
receptors, GH pulses
half of human GH secreting tumors have point
mutations of Gs gene that
interferes with intrinsic
GTPase activity and lead to
constitutive activation
SS
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a tetradecapeptide whose gene
sequence is well conserved in
evolution. Post-translational
processing of proSS by
peptidases / convertases is also
conserved and determine the SS
tissue specificity
its five receptor subtypes have 7transmembrane domains, typical
of G protein - linked receptors
SS inhibits AC activity on binding
to its receptor by stimulating Gi.
Additional SS open K channels hyperpolarizing the cell and
decreasing Ca influx through
voltage sensitive channels
since many tumors expressed SSreceptors, SS agonists are used in
their detection and treatment. SS
antagonists are of potential use to
increase GH
CRH
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a 41 aa, synthesized as part of
a prohormone which is
processed enzymatically. The
CRH gene is expressed widely.
CRH-BP decreases its synaptic
concentration and
bioavailability
its receptor has homology to
the G - protein - coupled
receptor superfamily, and has
been linked to GC and to an
increase in Ca by cAMP
CRH is the primary hormonal
regulator of the body’s stress
response. It has a reciprocal
positive interaction with AVP at
the ME (?)
CRH is used in stimulation
tests, antagonists in
depression, anorexia nervosa,
anxiety, drug withdrawal. CRHBP antagonists increase CRH
Page 21
DA
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is a catecholamine
synthesized by
hydroxylation of tyrosine
and subsequent
decarboxylation of LDopa
D2 receptors regulate Prl.
They have 7 transmembrane domains, typical of
G protein- linked
receptors
DA decreases cAMP (Gi)
and ICF-Ca. Prl release is
inhibited by low Ca and
by Ca channel blockers
hyperprolactinemia due to
uncoupling of lactotrophs
from hypothalamic DA.
hyperprolactinemia
causes hypo-gonadism,
low libido & galactorrhea.
It is treated by DA
agonists. Prl response to
haloperidol is a very good
predictor of its
antipsychotic effects