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PHYSIOLOGY
METABOLISM-2017
Lectures 1-2
March 20 2018
Is very small
3 major functions
• Hormone levels
• Temperature
• Sodium
The hypothalamus is involved in many functions
of the autonomic nervous system, as it receives
information from parts of the nervous system.
As such,
it is considered the link between the nervous
system and the endocrine system.
NEUROENDOCRINE RELATIONS
We contrast nervous system
structures with endocrine structures.
2-16
Regulation Mechanisms
• Receiving sensory information from all
areas of the body.
• Anterior
• Middle
• Posterior
Anterior
• Contains the Preoptic Nucleus
• BP
• Blood composition
• Temperature
• Hormones
• Reproductive activity
Middle Overlays the pituitary
stalk . Contains:
• Dorsomedial Nuclei
• Ventromedial Nuclei
• Paraventricular Nuclei
• Supraoptic Nuclei
• Arcuate Nucle
Ventromedial and Dorsomedial Nuclei Regulate
• Growth
• Feeding
• Maturation
• Reproduction
Paraventricular Nucleus –
This nucleus contributes to all 3 functions
1. Parvocellular division anterior pituitary
2. Magnocellular division posterior pituitary
3. Autonomic division descending paths
Paraventricular Nuclei
• Mammillary Body
• Function unknown
• Direct Connection
• Sends neuroendocrine materials from
the posterior pituitary
• Indirect
Embryological Derivation:
• Posterior lobe
– Pars nervosa
Development of the anterior pituitary
2-46
Development of the anterior pituitary1
2. Disorders:
Genetic absence of Pit-1 results in failure of the
somatotropes, lactotropes, and thyrotropes to develop
Absence of prop-1 results in deficiencies of these three
hormones as well as deficiencies in gonadotropin production
Pituitary
Portal System
Hypophyseal arteries
From carotid
Superior
80-90% to adenophysis
Inferior
Posterior pituitary
Posterior lobe
Rich nerve supply
Unmyelinated nerves
Hypothalamus
Anterior
Pituitary
Systemic target
organs
HYPOTHALAMIC HORMONES
+ + + + +
1. CHEMICAL STUCTURE:
GHRH 44 AA Release of GH
Somatostatin 14 AA Inhibition of GH & TSH release
2. Non Poly-polypeptide
DOPAMINE Inhibits prolactin
release
General features of anterior pituitary
hormonesa
1. CHEMICAL STUCTURE:
TSH
FSH
LH
HCG
COMMON FEATURES OF THE
GLYCOPROTEIN HORMONES
PRO-OPIO-MELANO-CORTICOPTROPIN
BETA LIPOTROPIN
PRO-ACTH
GAMMA-LIPOTROPIN + BETA-ENDORPHIN
ACTH
P.
1 convertase
. s
2
.
• NEUROMODULATION BY:
Stress: catecholamines, other
neurotransmitters
& cytokines
Sleep
etc
REGULATION OF SECRETION OF
FSH & LH
STIMULATION BY GnRH
HYPOTHALAMIC NEURONE _
GnRH
_ PITUITARY GONADOTROPES _
FSH LH
Inhibin
Testosterone
TESTES
Seminefeous Leydig
Tubules cells
+
HYPOTHALAMIC NEURONE
_
GnRH
+
_ PITUITARY GONADOTROPES
_
FSH LH
Inhibin
Estradiol
OVARY
Granulosa Thecal
Cells Cells
REGULATION OF SECRETION
OF FSH & LH
STIMULATION BY GnRH
TRH
PITUITARY THYROTROPES _
TSH
T4 & T3
THYROID
HYPOTHALAMIC NEURONE _
Somatostatin TRH
_
PITUITARY THYROTROPES _
TSH
T4 & T3
THYROID
REGULATION OF TSH SECRETION
STIMULATION BY TRH
Inhibition by Somatostatin:
? Physiological importance
REGULATION OF PROLACTIN
SECRETION
Inhibition by Dopamine
Stimulation by TRH
• GROWTH HORMONE
• PROLACTIN
• ACTH
VNEURO-ENDOCRINE
RESPONSE TO STRESS
CRH -ACTH
FSH & LH ADH
TSH GH
Prolactin
THE HYPOTHALAMIC-PITUITARY
RESPONSE TO STRESS
• STIMULATION OF:
CRH-ACTH-CORTISOL
GROWTH HORMONE
PROLACTIN
ADH
• INHIBITION OF:
TSH
FSH & LH
GH & CORTISOL RESPONSE TO HYPOGLYCEMIA
Human Growth Hormone
REGULATION OF GROWTH
HORMONE SECRETION
STIMULATION BY:
GHRH
GHRELIN
INHIBITION BY SOMATOSTATIN
MULTIPLE EFFECTS OF
SOMATOSTATIN
1. As a hypothalamic neuro-hormone:
Inhibition of GH secretion
Inhibition of TSH secretion
2. As a GI hormone:
Inhibition of GI motility & secretion
Inhibition of pancreatic exocrine secretion
3. As a pancreatic hormone:
Inhibition of insulin & glucagon secretion
Ghrelin
A short polypeptide secreted by the stomach,
in response to fasting
• Physiologic stimulants
Sleep
Exercise
Stress (Physical/psychological)
Post-prandial hyperaminoaciduria
Fasting
• Physiologic inhibitors
Hyperglycemia
Elevated free FA
Aging
PHARMACOLOGICAL FACTORS AFFECTING
GROWTH HORMONE SECRETION
• STIMULANTS
Hypoglycemia
• INHIBITORS
Estrogens
GHRH
IGF-1
GHRELIN Somatostatin
Alpha-adrenergic agonists
Glucocorticoids
Beta-adrenergic antagonists
Serotonin Alpha adrenergic
DOPAMINE agonists antagonists
Cholinergic agonists Beta adrenergic agonists
GABA Serotonin antagonists
Cholinergic antagonists
PHATHOLOGICAL FACTORS AFFECTING
GROWTH HORMONE SECRETION
STIMULANTS
Protein depletion &
INHIBITORS
starvation Obesity
Hypothyhroidism
Anorexia nervosa
0
0 100 200 300 400 500 600 IGF 1
SOMATOPAUSE-consequences
2.Measurement of serum
Somatomedin-C (IGF-1)
LABORATORY ASSESMENT OF GH
SECRETION
2. TESTS FOR GH EXCESS
1.Demonstrate autonomy of GH hypersecretion e.g.
After oral glucose tolerance
test
2.Measurement of serum
Somatomedin-C (IGF-1)
GH BINDING PROTEIN
A large protein similar to
the extra-cellular
segment of the GH
receptor
GH receptor
GH receptor — GH acts by binding to a
specific receptor, located mostly in the liver,
and inducing intracellular signaling by a
phosphorylation cascade involving the
JAK/STAT (signal transducing activators of
transcription) pathway. Its predominant action
is to stimulate hepatic synthesis and secretion
of IGF-I, a potent growth and differentiation
factor [1].
GH Receptor
A single GH molecule complexes with two GH receptor
molecules, followed by rapid binding and activation of JAK2
tyrosine kinase, leading to phosphorylation of several
cytoplasmic signaling molecules.
GH-RECEPTOR
GH
GH – GH Receptor Interactions
GH
Dimerization of
2 adjacent receptors
RECEPTOR RECEPTOR
TARGET CELL
The STAT proteins comprise important signaling
components for GH action.
2. METABOLIC EFFECTS:
Anabolic effect on proteins
Anti-insulin effect on carbohydrates & fats
Growth Hormone
Stimulates bone growth
Stimulates muscle growth
Stimulates fat breakdown for energy use
Increases the rate of protein synthesis
Increases blood sugar
Increase blood pressure
Biological Effects of GH
1. INHIBITION BY DOPAMINE
2. STIMULATION BY TRH
Pregnancy
Nursing
Nipple stimulation
Sexual intercourse (women only)
Exercise
Sleep
Stress
Pharmacological factors that
influence prolactin secretion
STIMULATORY INHIBITORY
Estrogen
TRH Glucocorticoids
DOPAMINE antagonists Thyroxine
Catecholamine depletors DOPAMINE agonists
Serotonin Precursors
GABA agonists
Serotonin antagonists
Histamine H2 blockers
Opiates
Pathological factors that increase
prolactin secretion
Liver cirrhosis
Hypothyroidism
(? via TRH)
Intercostal nerve
stimulation:
(similar to nipple stimulation during lactation)
Effects of TSH on the Thyroid
• Few minutes after injection of TSH:
– 1)-increases in iodide binding
– 2)-synthesis of T3, T4, and iodotyrosines;
– 3)-secretion of thyroglobulin into colloid;
– 4)-endocytosis of colloid.
• Chronic TSH injections:
– 1)-cells hypertrophy;
– 2)-increase weight of gland.
• Enlargement thyroid = goiter.
Regulation of Thyroid Secretion
TRH Hypothalamus
-
-
TSH Anterior Pituitary
-
-
TH Thyroid Gland
Control of T3 and T4 Release
TSH Receptors
inhibited by stress
increased by cold
decreased by warmth.
REGULATION OF THYROID
SECRETION
COLD IN
STRESS HYPOTHALAMUS
CHILDREN
- TRH
+
ANTERIOR PITUITARY
TSH
THYROID GLAND
THYROID HORMONE
TARGET ORGANS
Chemistry & Metabolism of TSH
• Glycoprotein: contains 211 amino acid residues, plus hexoses,
hexosamines, and sialic acid.
• Made up of 2 subunits: and .
• Each subunit: product of a separate precursor protein.
• subunits are noncovalently linked in the thyrotropes.
• TSH-: identical in structure to submit of LH FSH and hCG.
• Functional specificity of TSH: conferred by the unit.
• The biologic half-life of human TSH = ~ 60 minutes.
• TSH degradation: in the kidney and to a lesser extent in the liver
Control Mechanisms
Negative feedback effect of thyroid hormones
on TSH secretion: mainly on the pituitary and
partly at the hypothalamic level.
Thyroid hormones inhibit secretion before they
inhibit synthesis of TSH.
Dopamine and somatostatin: (at the pituitary
level) inhibit TSH secretion.
DIURNAL RHYTHM
Circadian Rhythm
ACTH is secreted in irregular bursts throughout the day.
Plasma
ACTH
25 µg/dl
Plasma Cortisol
Sleep
DIURNAL
STRESS HYPOTHALAMUS
RHYTHM
+ - +
CRH
ANTERIOR PITUITARY
INCREASED
BLOOD GLUCOSE ACTH -
BLOOD AA
BLOOD FATTY ACIDS
ADRENAL CORTEX
CORTISOL
TARGET ORGANS
Adrenal Glands
The adrenal
cortex and
medulla are
major factors in
the body's
response to
stress.
CONTROL OF ADRENAL
FUNCTION
The response to Stress
ANTERIOR PITUITARY
INCREASED
BLOOD GLUCOSE ACTH -
BLOOD AA
BLOOD FATTY ACIDS
ADRENAL CORTEX
CORTISOL
TARGET ORGANS
Screening Test
Overnight dexamethasone suppression test (1 mg at
11 pm, cortisol measured at 8 am)
– normal <2 micrograms/dL
Or
24 hour urine free cortisol (>140 nmol/day)
Overnight dexamethasone test
ANSWER:
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