Hypothalamus Pituitary Axis.ppt

Hypothalamus and the Pituitary
Gland
Dr K. Nyatanga

Objectives
• Describe the physiologic and anatomic
relationships between the
hypothalamus and pituitary.
• Identify the hypothalamic releasing
and inhibitory factors controlling the
secretion of each of the anterior
pituitary hormones.
• Know the posterior & anterior pituitary
hormones, their functions and
conditions that result from deficiency
and oversecretion

Hypothalamus and pituitary
 This consortium forms the most
complex and dominant portion of the
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
◦ Limbic system
◦ reticular formation
◦ Eyes
◦ Neocortex

Embryological development of the pituitary
1. The hypophysis is an amalgam of two tissues.
2. Early in gestation a finger of ectoderm grows upward from the
roof of the mouth.
3. This protrusion is called Rathke's pouch and will develop into the
anterior pituitary or adenohypophysis.
4. Another finger of ectodermal tissue envaginates ventrally from the
developing brain.
5. This extension of the ventral brain will become the posterior
pituitary or neurohypophysis.
6. The two tissues grow into one another and become tightly
apposed

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/Adenohypophysis
 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
Histology

Neuroendocrine roles
 The neurohypophysis is an extension
of the hypothalamus.
◦ neurohypophysis (posterior or neural
pituitary).
◦ It composed of bundles of axons from
hypothalamic neurosecretory neurons
intermixed with glial cells.
 2 hormones ADH and oxytocin are
synthesised in the hypothalamus, stored
and secreted by posterior pituitary

Hypothalamus Pituitary Axis.ppt

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

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 V1 (V1a, V1b), V2
and (V3)
 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 (stress)
 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

secretion of vasopressin include
 Nausea and vomiting
 Standing,
 Adrenergic stimuli
 Nicotine,
 Morphine,
 Carbamazepine
 Exercise

secretion of vasopressin include

Factors 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 or 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

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

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 circulating 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

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 penetrance
 It is due to a mutation that codes for
fibroblast growth factor receptor 3
(FGFR3)

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

Hypothalamus Pituitary Axis.ppt

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