HYPOTHLAMIC-PITUITARY

PHYSIOLOGY

Mona Abou Chebl MD.

METABOLISM-2017

Lectures 1-2
March 20 2018
 Is very small

Weighs only about 4 grams

Brain=1400 grams

Contains a variety of specialized

structures.
Functional Zones
A. Periventricular zone
- a thin nuclei bordering the 3rd ventricle.
- regulates release of endocrine hormones from
anterior pituitary gland
-uses neurosecretion as a portal vein system, rather
than a neurotransmitter across a synapse.
B. Middle zone
- regulates hormone release from posterior pituitary.
- regulates ANS.
C. Lateral zone
- integration and transmission of info from limbic
system structures (important in emotional regulation
– will view next lecture (limbic system).
 The Hypothalamus Essentials

The portion of the brain that maintains the body’s

internal balance (homeostasis).

The hypothalamus is the link between the endocrine

& nervous systems

The hypothalamus produces releasing &inhibiting

hormones, stopping & starting the production of
other hormones throughout the body
 A crucial part of the CNS that takes
some part in regulating most organs

3 major functions

1. Regulating release of hormones from pituitary gland.

2. Regulating the ANS; general visceral motor function.

3. Regulating the “appetitive behaviors” (eating, drinking,

mating.
The hypothalamus helps stimulate or inhibit key processes

Heart rate and blood pressure

Body temperature
Fluid & electrolyte balance, thirst
Appetite & body weight /Energy metabolism
Reproduction
Glandular secretions of the stomach and intestines
Sleep cycles
Emergency response to stress
 The main function of the hypothalamus

maintain the body's status quo.

Blood pressure, temperature, fluid electrolyte

balance, & body weight are held to a precise value
called the set-point which is fixed.
The hypothalamus receives inputs about the state of the
body & must be able to initiate compensatory changes
Some Set Points
• Blood sugar

• 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.

...But certain nervous system cells act as endocrine

cells and certain endocrine tissues are derived from
neural ectoderm.

Nerve cells that produce hormones and secrete them

into the bloodstream are called NEUROSECRETORY
CELLS.
 HYPOTHALAMUS & PITUITARY GLAND

Innervation: Part of brain or very close to it in case of

pituitary. Some hypothalamic neurons secrete
neurohormones – they pass down connecting stalk to
terminate close to the capillaries serving posterior pituitary.

Arterial Supply: circulosus artriosus cerebri

Venous Drainage: cavernous venous sinus

Hypothalamus and pituitary

2-16
Regulation Mechanisms
• Receiving sensory information from all
areas of the body.

• Comparing sensory information with

biological set points.

• Adjusting the system to restore the

body balance when deviations from
biological set points occur.
The inputs include:

Nucleus of the solitary tract - this nucleus collects all of

the visceral sensory information from the vagus and relays it
to the hypothalamus and other targets. Information includes
blood pressure and gut distension.

Reticular formation - this catchall nucleus in the

brainstem receives a variety of inputs from the spinal cord.
Among them is information about skin temperature, which is
relayed to the hypothalamus.
 Retina - fibers from the optic nerve directly reaching
the suprachiasmatic nucleus. This nucleus regulates circadian
rhythms, and the rhythms to the light/dark cycles.

Circumventricular organs - Nuclei are located along the

ventricles, project to the hypothalamus uniquely lack a
blood-brain barrier. They monitor changes in osmolarity.
The area postrema, is sensitive to toxins in the blood and
induces vomiting

Limbic & Olfactory systems - the amygdala,hippocampus,

and the olfactory cortex project to the hypothalamus, probably
regulate behaviors such as eating and reproduction.
 HYPOTHALAMUS HORMONES
(FUNCTION)

•Hypothalamic hormones enclosed in vesicles that move down

axon and accumulate near terminal ends that are close to the
posterior pituitary’s capillaries.

•In response to an action potential– hormones are released from

vesicles (much like a neurotransmitter), in this case into venous
capillaries.
 HYPOTHALAMUS HORMONES (FUNCTION)

Most hormonal interactions of the hypothalamus-pituitary

complex follow a common pattern:

A hypothalamic hormone effects control over the secretion of an

anterior pituitary hormone;

The corresponding anterior pituitary hormone controls secretion

of the hormone of another endocrine gland; and

That secretion of that gland affects other target tissues/organs.

So...
Hypothalamic hormones can have
effect of stimulating or inhibiting
the release of anterior pituitary
hormones.

Called RELEASING HORMONES

(“RH”) or INHIBITING
HORMONES (“IH”) respectively.
Hypothalamic Regions
divided into three regions

• Anterior

• Middle

• Posterior
 Anterior
• Contains the Preoptic Nucleus

• Is concerned with the integration of sensory stimuli

that is related to setpoints
Anterior hypothalamus
Note the preoptic region
Preoptic Nuclei Control

• 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

• Includes magnocellular and

parvocellular components

• Controls the Pituitary Gland

• Contains neurons that innervate

sympathetic and parasympathetic
neurons in the Medulla and Spinal Cord.

• Regulates autonomic responses

B. Magnocellular system and the posterior pituitary.

- Here, peptide hormones are produced by large-

diameter hypothalamic neurons from same nuclei
of the middle zone.

- Axons deliver these hormones down the

infundibular stalk and terminate on fenestral
capillaries (“leaky”) of the posterior pit - this is
1 place lacking a BBB.
Is Between the Medial Forebrain Bundle

• MFB are long pathways

• Runs through the lateral hypothalamus
• Connects the hypothalamus with the
• Brain Stem
• Basal Forebrain
• Amygdala
• Cortex
Function
• Help organize behaviors
• Autonomic functioning
• Highly involved with the
addiction
process
• Heavily loaded with Dopamine
Neurons
Posterior Third

• Mammillary Body

• Function unknown

• Posterior hypothalamic Nuclei

• Contains Tuberoamammillary Nucleus

• Regulates wakefulness and arousal

 Endocrine System
• Regulated by the Hypothalamus

• Direct Connection
• Sends neuroendocrine materials from
the posterior pituitary

• Indirect

• Sends hormones to the ant pituitary

• Regulates the production and release of

pituitary hormones into circulation
Nomenclature
 Pituitary
 Greek
ptuo (to spit)
 Latin
Pituita (mucus)
 Mucus was produced by
the brain and was excreted
through the nose by the pituitary
The Normal Pituitary
 HYPOTHALAMUS & PITUITARY GLAND

Embryological Derivation:

• Hypothalamus is an outgrowth of brain, neural

ectoderm.

•Posterior Pituitary is an outgrowth of hypothalamus,

neural ectoderm.

•Anterior Pituitary develops as a superiorly directed

outgrowth of roof of mouth, endoderm.
 Pituitary Development

• Evagination of the stromodeal ectoderm from buccal cavity

• Infundibulum, neural stalk and posterior lobe from diencephalon
• Development 3rd to the 15th week gestation
 Pituitary Anatomy
Gross
 Sits in sella turcica
 Surrounded by dura
 Sphenoid
 Lateral and inferior
 Lateral
 Cavernous sinus
 Internal carotid artery
 CN III, IV, VI, V1 and V2
Pituitary Anatomy
Microscopic
 Anterior lobe
 80% of gland
 Brown color
 Posterior lobe
 Gray/brown color
 Pituitary Anatomy
Microscopic
• Anterior lobe 3 divisions
– Pars distalis
• Largest
• Hormone producing cells
– Pars intermedia
• Poorly defined in the human
– Pars tuberalis
• Upward extension to the anterior lobe
and attached to pituitary stalk

• Posterior lobe
– Pars nervosa
Development of the anterior pituitary

2-46
Development of the anterior pituitary1

1. Several transcription factors determine the

different cellular lineages .
A. Corticotropes lineage
B. GH, PRL, and TSH lineage
C. Gonadotropes lineage

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

Hormone Target cells Action

TRH Thyrotrope TSH release
Lactotrope Prolactin release

CRH Corticotrope ACTH & related

polypeptides release
GHRH Somatotrope GH release
GnRH Gonadotrope FSH & LH release

SOMATOSTATIN Somatotrope Inhibition of GH release

Thyrotrope Inhibition of TSH release
DOPAMINE Lactotrope Inhibition of Prolactin
release
 Control of anterior pituitary hormone
secretion
CRH, GnRH GHRH
ADH
TRH

+ + + + +

ACTH PROLACTIN TSH FSH &LH G.H.

- - -
DOPAMINE Somatostatin
Common features Pituitary &
Hypothalamic Hormones
1. Chemical Structure
2. Pulsatile Secretion Pattern
3. Feedback control
4. Circadian Rhythm
General features of
hypothalamic hormones

1. CHEMICAL STUCTURE:

All ( except DOPAMINE ) are

polypeptides of varying sizes
Hypothalamic Hormones
1. Polypeptides
Hormone Size Function
TRH 3 AA Release of TSH & Prolactin

GnRH 10 AA Release of FSH & LH

GHRH 44 AA Release of GH
Somatostatin 14 AA Inhibition of GH & TSH release

CRH 41 Release of ACTH & related PP

2. Non Poly-polypeptide
DOPAMINE Inhibits prolactin
release
General features of anterior pituitary
hormonesa
1. CHEMICAL STUCTURE:

- All are polypeptides of varying sizes

General features of anterior pituitary
hormones
1. CHEMICAL STUCTURE:

- All are polypeptides of varying sizes

- Some are composed of double chains esp. the glyco-

protein ( i.e carbohydrate rich ) hormones
GLYCOPROTEIN HORMONES
High Carbohydrate Content

TSH
FSH
LH
HCG
COMMON FEATURES OF THE
GLYCOPROTEIN HORMONES

TSH, FSH, LH & HCG ALL HAVE:

- A double polypeptide chain structure

- The same alpha chain in all 4 hormones
- The biological specificity of the hormone
is in the Beta chain
- The Beta chains of LH & HCG are very
similar, hence their similar biological and
immuno-chemical features
General features of hypothalamic &
anterior pituitary hormones
3. PULSATILE SECRETION
EFFECT OF GnRH Super-agonist
General features of hypothalamic &
anterior pituitary hormones

2. FEED BACK CONTROL

 REGULATION OF SECRETION OF
ACTH & RELATED POLYPEPTIDES

PRO-OPIO-MELANO-CORTICOPTROPIN

BETA LIPOTROPIN
PRO-ACTH
GAMMA-LIPOTROPIN + BETA-ENDORPHIN

ACTH

BETA-MSH ALPHA MSH + CLIP

 Pro-opiomelanocortin (POMC), a
gene, products

P.
1 convertase
. s

2
.

3. Melanocyte-stimulating hormone (MSH)

Corticotropin-like intermediate lobe peptide (CLIP)
2-69
 ACTH & POMC
1. ACTH (adrenal corticotropic hormone)
regulates hormone secretion by the cortex of
the adrenal glands.
2. The gene produces ACTH is called POMC (pro-
opiomelanocortin) in corticotropes and other
cells by prohormone convertases.
 (Corticotropes) ACTH is the only one has an
established physiological role in humans
 (melanocytes and keratinocytes)– pigmentation by
MSH
 (Melanotrope in arcuate neurons)– food intake
2-70
 REGULATION OF SECRETION
OF ACTH & RELATED
POLYPEPTIDES
1. STIMULATION BY CRH
and by ADH
 REGULATION OF SECRETION
OF ACTH & RELATED
POLYPEPTIDES
 STIMULATION BY CRH & ADH

 FEEDBACK INHIBITION BY CORTISOL

 REGULATION OF SECRETION OF
ACTH & RELATED POLYPEPTIDES

• STIMULATION BY CRH & BY ADH

• FEEDBACK INHIBITION BY CORTISOL

• NEUROMODULATION BY:
Stress: catecholamines, other
neurotransmitters
& cytokines
Sleep
etc
 REGULATION OF SECRETION OF
FSH & LH

 STIMULATION BY GnRH

 FEEDBACK INHIBITION BY SEX HORMONES ( Estradiol &

Testosterone ) and by INHIBIN
 Another example of feedback control

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

 FEEDBACK INHIBITION BY SEX HORMONES ( Estradiol &

Testosterone ) and by INHIBIN
 Positive feedback by estradiol in females
 REGULATION OF TSH SECRETION
 STIMULATION BY TRH

 FEEDBACK INHIBITION BY T4 & T3

HYPOTHALAMIC NEURONE _

TRH

PITUITARY THYROTROPES _
TSH

T4 & T3
THYROID
 HYPOTHALAMIC NEURONE _
Somatostatin TRH
_
PITUITARY THYROTROPES _
TSH

T4 & T3
THYROID
 REGULATION OF TSH SECRETION

 STIMULATION BY TRH

 FEEDBACK INHIBITION BY T4 & T3

 Inhibition by Somatostatin:
? Physiological importance
 REGULATION OF PROLACTIN
SECRETION

 Inhibition by Dopamine

 Stimulation by TRH

 Stimulation by estrogens ( a direct effect on the lactotropes)

General features of hypothalamic &
anterior pituitary hormones
4. CIRCADIAN RHYTHM

A nocturnal sleep related surge in secretion

Plasma cortisol circadian rhythm
GH CIRCADIAN RHYTHM
PITUITARY HORMONES AFFECTED
BY SLEEP

• 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

- Has 2 main effects;

- Stimulation of appetite
- Stimulation of GH secretion
PHYSIOLOGICAL FACTORS AFFECTING Growth
Hormone secretion

• 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

Chronic renal failure

 Growth hormone secretion at different ages

Birth Childhood Puberty Adulthood Old Age

AGE RELATED CHANGES IN GH
- GH & IGF-1 levels increase gradually to reach
their maximum with puberty

- After ~ 40 y, GH levels (basal & after stimuli)

fall gradually with age due to decreased GHRH
secretion and in response of pituitary
somatotropes: ( SOMATOPAUSE)

There is a corresponding age-related ~ 50%

fall in IGF-1
Cumulative Frequency Distributions
For Circulating Levels of IGF-I
100
healthy old <
men
80
Percent

60 healthy young <

men
40
institutionalized <
old men
20

0
0 100 200 300 400 500 600 IGF 1
SOMATOPAUSE-consequences

1. A decrease in lean body mass & bone

density & an increase in fat mass

2. Decreased physical fitness

The above are partly reversed by GH treatment

Hence the increasing use of GH as an anti-aging treatment

 LABORATORY ASSESMENT OF GH
SECRETION
1. TESTS FOR GH DEFICIENCY

- GHRH Stimulation test

- Insulin-induced hypoglycemia
- Arginine stiumulation test
- Measurement of GH during sleep
- Clonidine stimulation test
- L-DOPA stimulation test
- Exercise test
- Measurement of IGF-1
 LABORATORY ASSESMENT OF GH
SECRETION
1. TEST FOR GH DEFICIENCY
- GHRH Stimulation test
- Insulin-induced hypoglycemia
- Arginine stimulation test
- Measurement of GH during sleep
- Clonidine stimulation test
- L-DOPA stimulation test
- Exercise test
- Measurement of IGF-1
GH RESPONSE TO HYPOGLYCEMIA
 LABORATORY ASSESMENT OF GH
SECRETION
1. TEST FOR GH DEFICIENCY
- GHRH Stimulation test
- Insulin-induced hypoglycemia
- Arginine stiumulation test
- Measurement of GH during sleep
- Clonidine stimulation test
- L-DOPA stimulation test
- Exercise test
- Measurement of IGF-1
 LABORATORY ASSESMENT OF GH
SECRETION
1. TEST FOR GH DEFICIENCY

- GHRH Stimulation test

- Insulin-induced hypoglycemia
- Arginine stiumulation test
- Measurement of GH during sleep
- Clonidine stimulation test
- L-DOPA stimulation test
- Exercise test
- Measurement of 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)
 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.

These cytoplasmic proteins are phosphorylated

by JAK2 & directly translocated to the cell nucleus,
where they elicit GH-specific target gene effects
by binding to nuclear DNA .

Alternatively, STAT proteins 1 and 5 may interact

more directly with the GH receptor molecule .
BIOLOGICAL EFFECTS OF GH

Two main effects:

1. SOMATIC GROWTH: involves all organs

except the brain

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- Somatomedin C (IGF-1) mediated :

Anabolic effect: increased protein

synthesis, cell growth & cell division

An increase in lean body mass i.e. bone,

cartilage, muscle and fibrous tissue.
 
Biological Effects of GH-continued
2. Effects directly mediated by GH
(i.e IGF-1-independent):
 
 Insulin resistance  hyperinsulinemia. Tendency to
hyperglycemia
 Hyperinsulinism
 Lipolysis release of FFA, decrease in total & % body
fat
 Ketogenesis
 Sodium /water retention
 A positive calcium and phosphate balance
 
 Insulin-Like growth factor
• IGF-I is the major mediator of (GH)-stimulated
somatic growth, & GH-independent anabolic
responses in many cells and tissues.
• IGF-1 is a small peptide, circulates bound to
high affinity binding proteins. > 99% protein-
bound.
• IGF-I is synthesized in the liver & secreted
under GH control
• Autocrine/paracrine IGF-I synthesized in peripheral tissues as
bone & cartilage (wound healing & growth of contralateral kidney
IGF1
 
Receptors
 The IGF-I receptor is widespread presence
accounts for the ability to stimulate growth &
is regulated by GH &Thyroxine

 IGF BP (6 high-affinity proteins )>IGF-I and -II

have greateraffinity. present in all extracellular
fluids < 1% total IGF-I in plasma is unbound

 Variables that regulate synthesis and release by

the liver & GH
Factors affecting IGF-1
production
1. Nutritional status
2. Integrity of liver & kidney function
3. Integrity of GH receptor
IGF1
 Plasma IGF-I levels rise sevenfold from very low
concentrations at birth (20 -60 ng/mL) to peak values at
puberty . This falls rapidly in the 2 nd decade, to values that
half of the maximum pubertal levels then declines slowly by
an additional 50 % up to age 60. Part of this change is due to
age-dependent changes in GH secretion.
EFFECT OF AGE ON IGF-1
GENERAL FEATURES OF
PROLACTIN
- A long polypeptide chain:

Some similarity to GH and

to Placental Lactogen

- Prolactin receptor has some

similarity to GH receptor
Mechanism of action of Prolactin
Prolactin PROLACTIN
BIOLOGICAL EFFECTS OF
PROLACTIN
1. Breast milk production:

- Effect starts during pregnancy in preparation

for normal lactation after delivery

Sustained by nipple stimulation

- Breast milk production without pregnancy (Galactorrhea)

is abnormal and
results from non-pregnancy hyperprolactinemia
BIOLOGICAL EFFECTS OF
PROLACTIN
2. On the hypothalamus

Loss of pulsatile GnRH secretion:

a. In females
 menstrual irregularity or amenorrhea
 infertility
b. In males:
Partial hypogonadism
EFFECT OF PROLACTIN ON GnRH, FSH & LH
BIOLOGICAL EFFECTS OF
PROLACTIN
3. On the gonads

Interference with the effect of FSH & LH on the gonads

Results in impaired sex hormone production & contributes

to hypogonadism
BIOLOGICAL EFFECTS OF
PROLACTIN
4. On the adrenals

Increased adrenal androgen production in hyper-

prolactinemic states

Apparently a minor effect

Might contribute to hirsutism in some hyperprolactinemic
females
REGULATION OF PROLACTIN
SECRETION

1. INHIBITION BY DOPAMINE

Physiologically the most important

Factors influencing secretion
by the lactotropes
REGULATION OF PROLACTIN
SECRETION
1. INHIBITION BY DOPAMINE

Physiologically the dominant effect

2. STIMULATION BY TRH

Physiologically not important

May be important in pathological states e.g.
hypothyroidism
3. DIRECT STIMULATION OF LACTOTROPES BY ESTROGENS
Physiological factors that
stimulate prolactin secretion

 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

Chronic renal failure

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

 Made up of a glycoprotein bound to a ganglioside.

 Activation of adenylate cyclase =>increase in intracellular

cyclic AMP =>TSH effects.

 Stimulation of metabolism of phospholipids in membrane

=> thyroid hypertrophy.
 REGULATION OF TSH SECRETION
 
TSH secretion:
 increased by the TRH

 inhibited by free T4 (and T3 ) negative feedback

 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.

 The burst are most frequent in the early morning and

least frequent in the evening
HPA AXIS
Hypothalamic pituitary hormones
 Action of ACTH
 
• ACTH binds to high-affinity receptors.
– This activates adenylate cyclase, and the resultant
increase in intracellular cyclic AMP activates
phosphoprotein kinases.
– The net result is increased conversion of cholesterol
to pregnenolone.
• Other effects of ACTH include:
– increased binding of cholesterol to the enzyme
cytochrome P-450 in the mitochondria
– increased uptake of LDL from the circulation.
 24 h Plasma ACTH & Cortisol

Plasma
ACTH
25 µg/dl

Plasma Cortisol

Sleep

Acute Stress: Increases up to 60-90 or more µg/dl

Chronic stress: Increases basal secretion
 REGULATION OF SECRETION
OF ACTH & RELATED
POLYPEPTIDES
1. STIMULATION BY CRH
and by ADH
REGULATION OF CORTISOL SECRETION

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

 Increase in ACTH secretion to meet emergency situations are

mediated almost exclusively through the hypothalamus.
 Release of CRH from the hypothalamus to the anterior pituitary
stimulates ACTH secretion.
GH & CORTISOL RESPONSE TO HYPOGLYCEMIA
 REGULATION OF CORTISOL
SECRETION
HYPOTHALAMUS DIURNAL
STRESS RHYTHM
+ - +
CRH

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

1 mg of dexamethasone at midnight- collect 8 am cortisol

Cushing’s patients resistant to glucocorticoid feedback.

New cut-off 1.8, 2 or 3 mg/dL. Value greater than that

consistent with Cushing’s syndrome.
Cortisol assay isn’t that good at low values
May get falsely high values if on oral estrogens.
50% classic Cushing’s patients have the genetic defects
leading to resistance to dexamethasone-probably lower in
mild/episodic patients
Clinical Correlate
When the pituitary stalk is injured after head trauma:
What happens to the different pituitary hormones ?

ANSWER:

All ( including ADH and oxytocin ) will be deficient

EXCEPT :

Polactin which will be hypersecreted due to loss of inhibition by

Dopamine
Dynamic Tests of Pituitary
Function
 
TRH stimulation test *
GHRH stimulation test *
CRH stimulation test*
GnRH stimulation test*
Provocative tests for GH:
insulin–induced hypoglycemia, arginine,
exercise, sleep, L-DOPA

Provocative tests for ACTH:

insulin-hypoglycemia, metapyrone test.
===============================================
•      Denotes tests that can distinguish
hypothalamic from pituitary hypopituitarism.
Hyper-secretion of pituitary
hormones

I. Compensatory ( adaptive ) due to loss of negative feedback

II. Amplified physiologic response

III. Autonomous hypersecretion

Compensatory (adaptive) hyper-secretion of
pituitary hormones due to loss of negative feed-
back inhibition
Examples:

1. Hyper-secretion of TSH in primary hypothyroidism

• A very sensitive test of primary hypothyroidism
• May lead to thyroid enlargement e.g. in enzyme defects
2. Hypersecretion of FSH & LH in primary gonadal failure
 May be related to menopausal flushes
3. Hypersecretion of ACTH & MSH in primary adrenocortical
failure
 Leads to skin and mucous membrane hyper-pigmentation
Hyper-secretion of pituitary
hormones

I. Compensatory ( adaptive ) due to loss of negative feedback

II. Amplified physiologic response

III. Autonomous hypersecretion Usually Due to Pituitary

Tumors
END