Download Hypothalamus and the Pituitary Gland

Hypothalamus and the Pituitary
Gland
EPK
Objectives
Describe the anatomic connections
between the hypothalamus and the
pituitary gland and the functional
significance of each connection.
 Name the hypophysiotropic hormones,
and outline the effects that each has an
anterior pituitary function.
 Describe the synthesis, processing,
storage, and secretion of the hormones of
the posterior pituitary.

Objectives
Discuss the effects of vasopressin, the
receptors on which it acts, and how its
secretion is regulated.
 Discuss the effects of oxytocin, the
receptors on which it acts, and how its
secretion is regulated.

Hypothalamus and pituitary
Pituitary gland
Anatomy
Anatomy
Pituitary lies in the sella turcica of
sphenoid bone below hypothalamus at
base of brain
 Blood supply is from the superior and
inferior hypophyseal arteries
 There is a portal system from the median
eminence
 Pituitary has two lobes the anterior and
the posterior

Anterior pituitary
Traditionally cells are divided into
chromophobes and chromophils
 Chromophobes contain and secrete IL6
 Chromophils are further divided into
basophils and acidophils
 Acidophils secrete GH and Prolactin
while basophils secrete ACTH, TSH, LH,
and FSH

Posterior pituitary-histology
Post lobe: endings of SON and PVN can
be observed in close relation to the blood
vessels
 Pituicytes (modified asrocytes) are also
present

Hypothalamus and pituitary
This consortium forms the most complex
and dominant portion of entire endocrine
system
 Output of this unit regulates the function
of the thyroid gland, adrenal gland and
also shares in control of somatic growth,
lactation, milk secretion and water
metabolism

Hypothalamic function
Plays a key role in the regulation of
pituitary function
 It receives afferents from

◦
◦
◦
◦
◦
Thalamus
reticular formation
Limbic system
Eyes
Neocortex
Neuroendocrine roles
2 hormones ADH and oxytocin are synthesised
in the hypothalamus,stored and secreted by
posterior pituitary
 A group of tropic hormones are synthesised,
stored and released by anterior pituitary
 A set of releasing and inhibiting hormones are
synthesised in the hypothalamus, travel to ant.
Pituitary to regulate the synthesis and secretion
of these tropic hormones

cntd
Close connections with the ANS allow
coordination btwn ANS and pituitary
function
 Therefore pituitary function can be
influenced by pain, sleep, emotion, light
and possibly thought
 HP axis is under the influence of blood
borne substances and neural input

Hypophysiotropic hormones
These are hormones secreted by the
hypothalamus which influence pituitary
function
 They are either releasing or inhibiting
factors
 The hormones include CRH, TRH, GHRH,
GnRH, Dopamine, serotonin

Anterior pituitary is exposed to higher
concentration of these hormones than
blood
 Most are peptides except dopamine
 It was once believed that each factor was
responsible for release of one pitiutary
hormone.
 However, this is not the case

TRH increases prolactin release and
somatostatin can inhibit release of TSH in
addition to GH
 Dopamine (PIF) inhibit prolactin secretion

Hypothalamic Pituitary Axis
Posterior Pituitary
Post Pituitary
It is responsible for secretion of
vasopressin and oxytocin
 These are nonapeptides or octapeptides
depending on whether cysteine or cystine
is considered
 The structures of the two hormones are
similar, with 2 different amino acid
residues
 They are synthesised in the hypothalamus

Post Pituitary
Vasopressin is synthesised mainly in the
SON and oxytocin is synthesised mainly
in the PVN, although both nuclei produce
each hormone
 Due to the similarity in structure
vasopressin has 20% of the activity of
oxytocin and oxytocin has 0.5% to 1% of
the activity of vasopressin

Arginine vasopressin and oxytocin
What would happen to the
secretion of posterior pituitary
hormones if there was transection
of the connection between the
hypothalamus and pituitary gland?
Arginine vasopressin(ADH)
Basically involved in the regulation of
water balance and blood pressure
 Acts on 3 receptors V1a, V1b(V3) and V2
 V2 is through the mediation of cAMP and
V1 (IP3 and DAG)

Physiological effects of ADH
Increases permeability of collecting ducts
to water
 Increases urea reabsorption in the inner
medullary collecting duct
 Increase sodium absorption in TAL by
activating the NaK-2 Cl transporter

Physiological effects of ADH
Vasoconstriction
 Increases glycogenolysis in the liver
 Depresses the cardiovascular centres
 Increases ACTH secretion from
corticotrophes
 Increases synthesis of factor VIII and vWF

Increasing permeability of collecting
ducts to water
Through V2 receptors(cAMP)
 Involves insertion of water channels in
the luminal membrane known as
aquaporins
 There are several types of aquaporins: 1,
2, 3, 6 and 7 are found in the kidney, 4 in
the brain and 5 in salivary glands
 Vasopressin acts to increase the
concentration of aquaporin 2 on
membranes

Stimuli which increase the secretion
of vasopressin
 Increased
osmotic pressure of
plasma
 Decreased ECF volume(at least 20
%), (via cardiopulmonary receptors)
 Angiotensin II,
 Pain, emotion,stress
Stimuli which increase the secretion
of vasopressin include
Nausea and vomiting
 Standing,
 Adrenergic stimuli
 Nicotine,
 Morphine,
 Carbamazepine
 Exercise

Factor decreasing secretion
Decreased effective osmotic pressure
 Increased ECF volume
 Alcohol
 Parasympathetic innervation
 Stretching of the atrial baroreceptors
 Atrial natriuretic peptide
 Clonidine
 Haloperidol

Clinical Correlates
Excess ADH leads to SIADH
 Insufficient ADH leads to Diabetes
Insipidus

Syndrome of Inappropriate ADH
secretion (SIADH)
Due to inappropriately elevated ADH that
cause water retention in excess of Na+
 Excess water causes dilutional
hyponatremia

Causes of SIADH
Malignancy eg lung , gastrointestinal,renal
 Trauma –head injury , post surgery
 Cerebrum diseases eg infections like
meningitis
 Stimulation of volume receptors like in
artificial ventilation
 Drug induced eg
thiazides,chlorpropamide
 Infections eg pneumonia

(SIADH)
Diseases in the lung also decrease tonic
inhibition of ADH secretion leading to an
increase in ADH secretion
 This will result in hyponatremia
 Excessive ECF volume will be lowered by
the ‘escape phenomenon’
 It is treated using demeclocycline

Features of the syndrome
Hyponatremia (Na+ < 135 mmol/L)
 Hypotonicity ( osmolality <280moSm/kg )
 Urine osmolality (>100moSm/kg)
 Increased urinary Na+
excretion(>40mmol/L)

Diabetes Insipidus
Is due to deficient secretion of ADH
 The symptoms are polyuria and polydipsia
 It can be neurogenic or nephrogenic

Nephrogenic DI
One interesting form of this condition is
inherited X – Linked receessive
 Gene for V2 is located on the X
chromosome
 It can also be due to lithium or
hypercalcemia oy hypokalemia
 It does not respond to desmopressin (a
vasopressin analogue)
 It can be treated using thiazide diuretics

Nephrogenic DI

It can be treated using thiazide
diuretics
How do thiazides act???
Oxytocin
Is derived from oxy- meaning rapid and
tocia meaning labour
 Acts on oxytocin receptors(PLC) which
uses Ca ++ as a second messenger

Actions of Oxytocin






On the mammary gland: it is important for the
milk let down reflex
Augmentation of labour by increasing uterine
contractions
Ejaculation in males
May be involved in luteolysis
May be responsible for propulsion of sperms in
the female during or after intercourse
In pharmacological doses can cause transient
vasodilation
Secretion can be increased by
Suckling
 Stimulation of female external genitalia
and cervix
 Thought of the baby, (tender thoughts)
 Cervical dilatation

Pregnancy
Progesterone decreases synthesis of
oxytocin receptors
 Towards labour estrogen increases the
synthesis of oxytocin receptors in the
myometrium

Side effects of oxytocin overdose
Water intoxication
 Neonatal jaundice
 Uterine overstimulation-uterine rupture
 Hypotension (transient)

Secretion decreased by
Pain or physical discomfort
 Breast feeding under embarrassing
circumstances
 Fear and anger

Clinical correlates

Deficiency of this hormone has no known
problems
Anterior Pituitary
Hormones secreted by the gland appear
to divide into 3 groups
 A) ACTH Related peptides
e.g. ACTH, B endorphin, B Lipotropin ,
B MSH
 B) Glycoproteins
eg FSH, TSH and LH
 C) Somatomammotropins

Glycoproteins
They have two subunits an alpha and beta
 Alpha subunits are identical or closely
similar and they do not have biological
activity
 Beta chains confer hormone specificity
 Beta chains alone have little biological
activity

c) Somatomammotropins
Prolactin
 GH

Growth Hormone
GH
Secreted by somatomammotrophs of
pituitary
 Wide range of metabolic activity which
may involve every type of cell
 Some of its effects are mediated by
somatomedins
 GH release is controlled by GHRH and
GHIH (somatostatin)

GH secretion rate reflects
Metabolic requirements (decreased
glucose, increased Aas)
 Neural factors (eg stress, circadian
rhythms)

Structure
Gene for GH is on chr 17
 hGH has intrinsic lactogenic activity
 GH is bound to a protein in plasma that is
a large fragment of EC domain of
receptors
 Concentration of fragment is an index of
number of GH receptor in the tissues
 About half of GH is protein bound and
the T1/2 is 6 – 20 mins

Effects of GH

In liver
◦
◦
◦
◦
◦
◦
◦
RNA synthesis is increased
Increased protein synthesis
Increased gluconeogenesis, glycogenolysis
Increased somatomedin
In Adipose tissue
Decreased glucose uptake
Increased lipolysis; hence decreased adiposity
In Muscle
Decreased glucose uptake
 Increased amino acid uptake
 Increased protein synthesis
 Anti insulin effect in muscle
 Increased lean body mass
 Increased calcium absorption in
Gastrointestinal tract and decreased
sodium and potassium excretion in kidney

Somatomedins
Polypeptide growth factors secreted by
liver and other tissues
 Principal circulation somatomedins are
 - IGF I (somatomedin C)
 - IGF II
 They are closely related to insulin but C
chains are not separated

Somatomedins (cont.)
There are 6 binding proteins
 IGF I is mainly bound to IGFBP 3 (95%).
 GH increases synthesis of this protein
 The protein directs IGF to their specific
receptors
 IGF receptor is similar to that of insulin
 IGFs are essential for embyronic
development

Effects of Somatomedins
Increase protein sythesis
 Increase RNA synthesis
 Increase DNA synthesis
 Increase cell size and number
 This leads to increased organ size and
function

Effects on chrondrocytes








Increased amino acid uptake
Increase protein synthesis
Increase RNA synthesis
Increase DNA synthesis
Increase collagen
Increase chrondoiton sulfate
Increase cell size and number
This increases linear growth
Other effects of Somatomedins
Stimulate neuronal survival
 Stimulate myelin synthesis

Control of GH release

Stimulation
◦
◦
◦
◦
◦
Glucose and free fatty acid decrease
Increase in amino acids
Fasting and prolonged caloric deprivation
Deep sleep
Exercise
Cntd
Estrogens and androgens
 Dopamine and serotonin
 Alpha adrenergic agonists
 Enkephalins
 Stress (due to pain, surgery, psychogenic)

Inhibition
Glucose increase
 Free fatty acid increase
 Cortisol
 Obesity
 Pregnancy
 Somatostatin
 hGH

Control of GH secretion
Physiology of growth
Growth is a complex process
 It is also affected by thyroid hormones,
insulin, glucocorticoids, nutrition and
genetic factors

Role of nutrition
Food supply is the most important
extrinsic factor affecting growth
 A diet should be adequate in proteins,
vitamins and calories
 Fasting and protein deprivation decreases
IGF secretion
 Age at which deficiency occurs is of
importance

Growth Periods





In humans there are two periods of rapid
growth which are
i) Infancy and
ii) Late puberty before growth stops
The 2nd growth spurt is due to GH, sex
hormones, and cessation of growth due to
closure of epiphyses
Sex hormones increase spikes of IGF I release
In infants there is episodic growth
 Thyroid hormones are critical during this
period
 Thyroid hormones potentiate the action
of IGF I and are permissive to the effects
of GH.
 They are necessary for normal GH
secretion

Insulin is also important for growth.
 When deficient, IGF I secretion is
decreased
 Adrenocortical hormones other than
androgens have a permissive effect on
growth
 However, Glucocorticoid treatment can
slow or stop growth in children

Catch Up Growth
In periods of severe stress like illnesses
children do not grow
 They will be below the expected averages
compared to peers of the same age
 They will, after they recover, experience a
period of growth which is greater than
average to catch up with their peers –
catch up growth

Short Stature
Short stature can be due to
 i) GHRH deficiency
 ii) GH deficiency
 iii) Deficient secretion of IGF I
 iv) Other causes
 Isolated GH deficiency is usually due to
deficient GHRH

Laron Dwarfs
Is due to GH insensitivity due to loss of
function mutation in the receptor
 The plasma IGF I and IGFBP 3 are
decreased, while the concentration of GH
is either normal or increased

African Pygmies
They have a normal GH level and a modest
decrease in plasma level of GHBP
 Plasma [IGF I] fails to increase at the time of
puberty
 However, they experience less growth than non
pygmy controls throughout the pre pubertal
period
 Explanation for short stature is still unsettled

Other Causes of short stature
Cretinism
 Precocious Puberty
 Gonadal dysgenesis (Turner’s Syndrome)
 Chronic abuse and neglect can cause
dwarfism (Psychosocial dwarfism –
Kasper Hauser Syndrome)
 Achondroplasia

Achondroplasia
It is the most common form of dwarfism
in humans
 It is characterised by short limbs and a
normal trunk
 It is inherited Autosomal Dominant with
complete penetranc
 It is due to a mutation that codes for
fibroblast growth factor receptor 3
(FGFR3)

Achondroplasia
Prolactin
Prolactin
Is a hormone principally concerned with
stimulating breast development and milk
production
 It is secreted by acidophils and it has
receptors which resemble those for GH
 It is unique in that it is under
predominant inhibition from the
hypothalamus by dopamine

Control of Secretion

Secretion is stimulated by
◦
◦
◦
◦
◦
◦
Sleep
Nursing
Breast stimulation in non lactating women
Stress
Hypoglycemia
Exercise
cntd
Pregnancy
 TRH (hypothyroidism)
 Estrogens
 Sexual intercourse in women
 Histamine antagonists (H2) eg cimetidine
 -Dopamine antagonists

Factors decreasing secretion
Dopamine
 L Dopa
 Apomorphine
 Bromocriptine and related ergot
derivatives
 Prolactin

Effects of Prolactin
Stimulating breast development (done in
concert with other hormones like
estrogens, progesterone, cortisol, GH)
 Causes milk production secretion from
breast after estrogen and progesterone
priming (increases synthesis of casein and
lactalbumin)
 Inhibits action of gonadotropins

Effects of prolactin dysfunction
In women prolactin deficiency produces
an inability to lactate
 Hypersecretion of prolactin causes
hyperprolactenemia

Hyperprolactinemia
Is caused by chromophobe adenoma, damage to
pituitary stalk and tumors secreting prolactin
 It is characterised by

◦
◦
◦
◦
Loss of menses, decreased libido
Anovulation
Infertility and less often
Galactorrhea (lactation unassociated with pregnancy).
Gynecomastia is uncommon
Excessive production of GH
Leads to either gigantism or acromegaly
 Gigantism occurs when there is an
excessive secretion before epiphyses
close and acromegaly occurs after
epiphyseal closure
 Is usually due to microadenomas of the
GH secreting cells in the pituitary

Acromegaly-features
Enlarged hands and feet (spade like hands)
 Prognathism,coarse facial features,
bulbous nose, prominent bony ridges
 Hirsutism
 -Gynecomastia and lactation
 Osteoarthritic vertebral changes

Visual field changes (bitemporal
hemianopia)
 Carpal tunnel syndrome
 Glucose intolerance
 Proximal myopathy
 Cardiac failure (and also ischemia)

B MSH, B Lipotropin
Function of B lipotrophin is unsettled but
it may be for mobilisation of fats
 MSH is important for skin pigmentation
 It increases synthesis of melanin
 It is under the control of hypothalamus
via MIF
 ACTH can also cause skin pigmentation

Pituitary Hyperfunction
Acromegaly
 Cushing’s Syndrome (Nelson’s syndrome
– tumors secreting ACTH)
 Hyperprolactenemia
 Tumors secreting other anterior pituitary
hormones are rare

Pituitary Insufficiency
It is usually caused by tumors of anterior
pituitary and suprasellar cysts
 Pituitary infarction can also lead to
pituitary insufficiency (Sheehan’s
syndrome, hemorrhagic fevers)

Clinical Features

It is characterised by
◦
◦
◦
◦
◦
Growth inhibition
Hypothyroidism
Hypogonadism
Inability to cope with stress
Pallor
Other Anterior Pituitary Hormones
Regulate the function of peripheral glands
 i) TSH – thyroid gland
 ii) ACTH – adrenal cortex
 iii) Gonadotropins – Gonads
 These will be covered in subsequent
lectures

Thank You