ESR [002] The

hypothalamo-pituitary axis
Prof. Dr. Sandra Younan
Professor of Physiology
Kasr el Aini faculty of Medicine
New Giza school of Medicine
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The hypothalamo-pituitary
axis
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Aim

• To explain the role of the hypothalamus and

pituitary gland in the co-ordination of the
hypothalamo-pituitary- dependent endocrine axis
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Objectives
• By the end of this lecture you will be able to:
• Describe and illustrate the anatomical & functional relationships
between hypothalamus & pituitary
• List the major cell types present in the anterior pituitary gland and the
protein hormones they produce
• Correlate the synthesis and secretion of anterior pituitary hormones to
specific hypothalamic releasing hormones and inhibitory factors
• Outline the negative feedback loops within the hypothalamo-pituitary
axes
• Analyze the effect of pituitary dysfunction
• List the hormonal products secreted from the posterior pituitary gland
• Describe the role of neural reflexes in the control of oxytocin secretion
• Understand the oxytocin positive feedback
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Contents

 Anatomical and functional relationships

between hypothalamus and pituitary
 Anterior pituitary hormones
 Control of anterior pituitary function
 Negative feedback loops
 Pituitary dysfunction
 Oxytocin and positive feedback
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The pituitary gland is protected
at the base of brain in the sphenoid bone
and connected by a pituitary stalk

Optic Chiasm

Hypothalamus

Pituitary
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The pituitary gland

Third
Ventricle Hypothalamus

Pituitary stalk
Portal
Vessels

Anterior
lobe
Posterior
lobe
Sheep pituitary gland
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Pituitary gland development

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Anterior pituitary
and Anterior pituitary hormones
 Lecture 2

Anterior Pituitary
Anterior Pituitary
Hypothalamic
neurons synthesize
GHRH, GHIH, TRH,
CRH, GnRH, PIH
hypophyseal
artery
When appropriately stimulated,
hypothalamic neurons secrete
releasing or inhibiting hormones
into the primary capillary plexus
Hypophyseal
the anterior pituitary
• Primary capillary capillary
plexus plexuses
• Hypophyseal (beds)
connected
by veins
capillary plexus

GH,TSH, ACTH,
FSH, LH,PRL

ESR02-9
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Histology of the Adenohypophysis

• The bulk of the anterior pituitary (adenohypophysis) is

pars distalis
• That tissue is composed of winding cords of epithelial
cells flanked by vascular sinusoids. In sections stained
with dyes such as hematoxylin and eosin, three distinct
cell types are seen among epithelial cells:

• Acidophils have cytoplasm that stains red or orange

• Basophils have cytoplasm that stains a bluish color
• Chromophobes have cytoplasm that stains very poorly
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The differential staining pattern with H&E is a

reflection of the hormonal content of the cells

Acidophils have
cytoplasm that stains
red or orange

Basophils have
cytoplasm that stains
a bluish color

Chromophobes have
cytoplasm that stains
very poorly
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Anterior pituitary cell types
Cells that contain the polypeptide hormones:
Acidophils  Somatotropes which produce growth hormone
 Lactotropes which produce prolactin

Cells that contain the glycoprotein hormones:

 Thyrotropes which produce thyroid stimulating hormone
 Gonadotropes which produce luteinizing hormone or
follicle-stimulating hormone
Basophils  Corticotropes which produce adrenocorticotrophic
hormone

Due the high carbohydrate content of the hormones within

basophils, they also stain bright purple with PAS stains
These are cells that have minimal or no hormonal content. Many
of the chromophobes may be acidophils or basophils that have
Chromophobes degranulated and thereby are depleted of hormone. Some
chromophobes may also represent stem cells that have not yet
differentiated into hormone-producing cells ESR02-
12
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Hormones secreted by the anterior pituitary cells

Brooks Cole, 2001

Anterior pituitary cell types NEWGIZA UNIVERSITY

Cell population Secreted hormone Endocrine action

Thyrotrophs TSH Stimulates synthesis and
(thyroid-stimulating secretion of thyroid
hormone) hormones
Gonadotrophs Gonadotrophins (released Stimulate steroid
in a pulsatile form): biosynthesis and germ cell
LH(luteinizing hormone) maturation in the gonads
FSH (follicle-stimulating
hormone)

Corticotrophs ACTH Stimulates steroid

(adrenocorticotrophic biosynthesis in adrenal
hormone) cortex
Somatotrophs Somatotrophin = GH Stimulates growth (via
(growth hormone) insulin-like growth factor
[IGF]-1)
Lactotrophs Prolactin Stimulates lactation
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Anterior pituitary hormones
TSH, LH & FSH :
 Heterodimeric glycoproteins
 Common  -subunit
 Specific -subunits (TSH, LH& FSH)

ACTH :
 39 a.a. fragment of POMC

GH & PRL :
 190 a.a. peptides - internal di-S bonds
 Homologous receptors (are capable of stimulating
each other’s receptors to limited degree)
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Pars Intermedia / Intermediate Lobe

The pars intermedia is closely associated with pars nervosa and separated from
the pars distalis by the hypophyseal cleft. This lobe of the pituitary shows
considerable variation in size among species. It is small in man, but much larger
in species such as amphibians. Melanocyte-stimulating hormone is the
predominant hormone secreted
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Control of Anterior pituitary

functions
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Hypothalamic Factors

Synthesis and secretion of anterior pituitary hormones can be

under dual control of:
 A.Hypothalamic releasing hormones
 B. Hypothalamic inhibitory factors

Synthetized in parvicellular neurones - secreted at median

eminence of third ventricle and delivered to the anterior
pituitary lobe through the hypophyseal portal circulation
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Hypothalamic-Releasing Hormones

 TRH (3aa) - stimulates thyrotrophin ( TSH ) also

stimulates prolactin secretion from lactotrophs

 GnRH (10aa) - stimulates gonadotrophins (LH & FSH )

 CRH (41aa) - stimulates corticotrophin ( ACTH )

 GHRH (44aa) - stimulates GH

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Hypothalamic-Releasing Hormones

 Increase synthesis and secretion via

AC-cAMP-PKA-CREB pathway
(e.g. CRH & GHRH)

 Increase intracellular Ca2+ via

PLC pathway
(e.g. GnRH & TRH)

N.B. CREB= cAMP responsive element

binding protein
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Dual Control of GH Secretion

Stress
(-)

Hypothalamus GHRH Somatostatin

(+) (-)
(-)
Anterior
pituitary GH
(+)
Negative ( - )
feedback
IGF-1
Pancreatic somatostatin
Liver
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Every rule has an exception

 Rule: anterior pituitary is stimulated by the

hypothalamic releasing hormones & may be suppressed by
hypothalamic inhibitory factors
• Prolactin appears to be under dominant negative control
by dopamine from hypothalamic arcuate nucleus
∴ stimulus = less inhibition to prolactin
synthesis and secretion
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Negative feedback loops

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Levels of negative feedback

Short-loop (between pituitary and hypothalamus):

 Effects of LH/FSH on GnRH
 Effects of growth hormone on GHRH

Long-loop (from peripheral endocrine glands to

pituitary or hypothalamus):
 Effects of gonadal steroids on GnRH
 Effects of corticosteroids on CRH
Hypothalamo-pituitary-target axis NEWGIZA UNIVERSITY

(+) ( +)
TRH TSH Thyroid hormones (T4 + T3)

Short loop
Long loop

GnRH LH (+ FSH) Progesterone / Testosterone /

Oestradiol
( -)

Hypothalamo-pituitary-adrenal: (HPA) axis

(+) (+)
CRH ACTH Cortisol

( -)
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Over-riding the negative Feedback

Higher centres of brain can over-ride hypothalamo- pituitary

drive to endocrine axis

Chronic stress :
 Over-rides negative feedback on CRH and
ACTH ➢ hyperactivity in adrenal axis
 Loss of GnRH and GHRH
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Pituitary dysfunction
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A. Functional disconnection of the pituitary gland

 Cranial trauma
 Pressure on pituitary stalk (?pituitarytumour)
 Inflammation / infection(?cytokines)
 Mid-line defects (e.g. septo-optic dysplasia:
underdevelopment of optic nerve, pituitary
and septum pellucidum➢ panhypopituitrism
with blindness)
 Defects in migration of hypothalamic
neurones (e.g. Kallman’s syndrome➢delayed
or absent puberty)
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B. Hyposecretion of anterior pituitary hormones

 Adenohypophyseal cells sensitive to irradiation

particularly somatotrophs

 Hyposecretion of individual anterior pituitary

hormones - rare
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C. Hypersecretion of selected anterior

pituitary hormones
 Functional pituitary tumours - rare

 Most common functional pituitary tumours

= prolactinomas
- galactorrhea
- infertility (suppression of HPG axis)
-can be shrunk (to operative size) by
administration of a dopamine agonist – e.g.
bromocriptine
 ACTH-hypersecretion
- From pituitary corticotrophs = Cushing’s disease
- Ectopic - From small cell lung tumours
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Why is ectopic ACTH not suppressed by

cortisol?
Hypothalamo-pituitary-adrenal: (HPA) axis
(+) (+)
CRH ACTH Cortisol

( -)

 In HPA axis, cortisol suppresses CRH -

suppress stimulus to ACTH synthesis
and secretion

 Ectopic ACTH secretion not dependent

on CRH
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C. Hypersecretion of selected anterior

pituitary hormones (cont.)
 GH hypersecretion
- Gigantism (in infancy)
- Acromegaly (in adulthood)

 TSH hypersecretion
- Very rare
- High TSH usually reflects hypothyroidism
- (or assay error ! )
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Posterior pituitary
Oxytocin and the positive
feedback
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Posterior Pituitary Paraventricular nucleus

1. Hypothalamic neurons
synthesize oxytocin or
antidiuretic hormone (ADH)
Posterior lobe

Supraoptic
Infundibulum
nucleus
(connecting stalk) 2. Oxytocin and ADH are
transported down the axons of
Inferior the hypothalamic- hypophyseal
Hypothalamic- hypophyseal tract to the posterior pituitary
hypophyseal artery
tract
Axon terminals
3.Oxytocin and ADH are
stored in axon terminals in
Posterior lobe the posterior pituitary

Oxytocin 4.When hypothalamic neurons

fire, action potentials arriving
ADH” at the axon terminals cause
oxytocin or ADH to be released
into the blood
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Posterior pituitary hormones

Posterior pituitary “Neurohypophyseal" hormones:

A. Oxytocin (OT)

B. Vasopressin (AVP) = anti-diurectic hormone (ADH)

 Synthetized in cell bodies of magnocellular neurones

(PVN & SON)
 Axonal transported from hypothalamus to posterior
pituitary through the supraoptic hypothalamic tract
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Oxytocin

• Oxytocin is a nine amino acid peptide that

is synthesized in hypothalamic neurons
• Oxytocin is also secreted from a few
other tissues, including the ovaries and
testes
• Oxytocin differs from antidiuretic hormone
in two of the nine amino acids
• Both hormones are packaged into
granules and secreted along with carrier
proteins called neurophysins
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Cellular Actions of Oxytocin
A. Stimulation of milk ejection
• Milk is initially secreted (under effect of
prolactin) into small sacs within the
mammary gland called alveoli, from which it
must be ejected for consumption or storage
• Mammary alveoli are surrounded by smooth
muscle (myoepithelial) cells which are a
target cell for oxytocin
• Oxytocin stimulates contraction of myoepithelial cells,
causing milk to be ejected into the ducts and cisterns
Role of Neural reflex in oxytocin NEWGIZA UNIVERSITY

secretion

Milk let down reflex

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Cellular actions of oxytocin
(cont.)
• B. Stimulates uterine smooth muscle contractions at birth
• During the later stages of gestation, oxytocin
receptors increase on uterine smooth muscle cells,
which is associated with increased "irritability" of the
uterus
• Oxytocin is released during labor when the fetus
stimulates the cervix and vagina, and it enhances
contraction of uterine smooth muscle to facilitate
parturition (Fergusson reflex)
• In cases where uterine contractions are not sufficient to
complete delivery, oxytocin analogues e.g. syntocin
can be given
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Oxytocin stimulates uterine contractions

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Cellular actions of oxytocin
(cont.)
• C. Establishment of maternal behavior:
• Successful reproduction in mammals demands that
mothers become attached to and nourish their offspring
immediately after birth
• Non-lactating females do not manifest such nurturing
behavior
• The same events that affect the uterus and mammary
gland at the time of birth also affect the brain
• During parturition, there is increase concentration of
oxytocin in CSF
• Oxytocin acting within the brain plays a major role in
establishing maternal behavior
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Oxytocin establishes maternal
behavior

J. Frontiers, 2012
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Positive feedback spirals and oxytocin

secretion
 Oxytocin secretion is stimulated by a positive feed-back
mediated by neural reflexes
Suckling reflex
The act of nursing or suckling is relayed within a few
milliseconds to the brain via a spinal reflex arc
These signals impinge on oxytocin-secreting neurons,
leading to release of oxytocin
 Fergusson reflex
It is a neuroendocrine reflex where pressure of the head of
the fetus over the cervix stimulates oxytocin release and
subsequent uterine contractions
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Now Can you outline:

 Anatomical & functional relationships

Between hypothalamus & Pituitary
 Anterior pituitary Hormones
 Control Of anterior Pituitary Function
 Negative feedback Loops
 Pituitary dysfunction
 Oxytocin and positive Feedback

ESR02-46
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Test yourself!

• 1. Which of the these hormones is an anterior pituitary hormone and

has only an inhibitory hypothalamic factor?
• A. Growth hormone
• B. Prolactin
• C. Oxytocin
• D. Luteinizing hormone
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Test yourself

• 2. Which of the followings can be a clinical manifestation of pituitary

hypofunction?
• A. Gigantism
• B. Galactorrhea
• C. Delayed puberty
• D. Acromegaly
• 3. All of the followings are general functions of the pituitary except:
• A. Growth
• B. Hair growth
• C. Thyroid function
• D. Breast milk production
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Further readings

• C.D.G.Brooke & N.J.Marshall (2001)

Essential Endocrinology (Fourth Edition) (Blackwell Science) –
Chapter 3 or R.I.G. Holt & N.A. Hanley (2006) Essential
Endocrinology and Diabetes (Fifth Edition) (Blackwell
Science)- Chapter 5
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THANK YOU