PBL 1: Natalie Kovic

1. Anatomy of the pituitary gland, hypothalamus and related structures

The pituitary gland is also known as the hypophysis, an is a component of the endocrine
system with two major parts: an anterior pituitary (adenohypophysis) and a posterior
pituitary (neurohypophysis). Each part secretes particular hormones, the anterior pituitary is
an outpouching from Rathke’s pouch and forms a cluster of secretory cells, non-neural in
origin. The posterior pituitary is a direct extension of neural cell bodies in hypothalamus,
and are involved in the secretion of AVP and Oxytocin.

The Pituitary Gland:

 Pea-sized oval structure, suspended from the brain by the pituitary stalk (also
referred to as the infundibulum)
 The pituitary gland sits in the sella turcica (a saddle shaped depression in the
sphenoid bone)
 Superiorly, the pituitary gland is covered by a reflection of the dura mater known as
the diaphragma sellae – this membrane has an opening centrally for the
transmission of the infundibulum
 Anatomical Relations of the Pituitary Gland
Anteriorly  Sphenoid sinus
 Surgically the pituitary gland is accessed via the
sphenoid sinus (this is known as a trans-sphenoidal
approach)
Posteriorly  Posterior intercavernous sinus
 Dorsum sellae (posterior wall of the sella turcica)
 Basilar artery
 Pons
Superiorly  Diaphragma Sellae
 Optic chiasm
Inferiorly  Sphenoid sinus
Laterally  Cavernous sinus

Anterior Pituitary Gland: The Adenohypophysis

 Embryologically derived as an outpouching of Rathke’s pouch (from the roof of the
pharynx)
 This means it does not have a blood brain barrier
 The lobe can be further divided into three main parts
 Pars anterior: the largest part, which is involved in hormone secretion
 Pars intermedia: a thin epithelial layer separating pars anterior from the
posterior pituitary
 Pars tuberalis: an upwards extension of pars anterior surrounding the
anterolateral aspect of the infundibulum
 The release of hormones from the anterior pituitary is under control of the
hypothalamus, which communicates with the anterior pituitary using
neurotransmitters transmitted via the hypophyseal portal vessels
Posterior Pituitary Gland: The Neurohypophysis
 Nervous tissue, embryologically derived from the forebrain (an extension of the
hypothalamus)
 Secretes ADH/AVP and oxytocin, both of which are produced by supraoptic and
paraventricular nuclei of the hypothalamus

Vasculature:
 The adenohypophysis receives arterial supply via the superior hypophyseal artery (a
branch of the ICA)
 This vessel first forms a capillary network around the hypothalamus, which then
drains into a secondary capillary plexus around the anterior pituitary
 This is known as the hypothalamo-hypophysial portal system
 Posterior pituitary and the infundibulum receive rich blood supply from many
arteries
 The superior hypophyseal artery
 Infundibular artery
 Inferior hypophyseal artery
 2. Physiology of the pituitary gland and the role of the hypothalamus in pituitary
control
Anterior Pituitary
Hypothalamic Target Cell Hormone Released Target of Anterior Pituitary
Releasing factor Hormone
GHRH and Ghrelin Somatotroph GH Multiple somatic tissues
(stimulatory)
Somatostatin
(inhibitory)
TRH (negative Thyrotroph TSH Thyroid follicular cells,
feedback loop) stimulated to make thyroid
hormone
CRH (inhibited by Corticotroph ACTH Fasciculata and reticularis cells
glucocorticoids like of the adrenal cortex to make
cortisol) corticosteroids
GnRH (negative Gonadotroph FSH Ovarian follicular cells, to make
feedback loop) oestrogens and progestins and
Leydig cells to make
testosterone
GnRH Gonadotroph LH Ovarian follicular cells to makes
oestrogens and progestins, and
Leydig cells to make
testosterone
Dopamine (tonically Lactotroph PRL Mammary glands – initiates
inhibits lactotrophs) and maintains production of
TSH, GnRH and VIP milk
(stimulatory)

Posterior Pituitary
Hormone Synthesized in Hormone Released into Target of Posterior Pituitary
Hypothalamus Posterior Pituitary
AVP AVP Collecting duct of nephron
to increase water
permeability, increase urea
cycling (also has
vasoconstrictive effects)
Oxytocin Oxytocin Uterus and breast

Troph Cells of the Adenohypophysis

Somatotrophs  Produce growth hormone (GH)
 Make up 50% of the anterior pituitary cells
Lactotrophs  Produce prolactin which is essential for lactation
(Mammotrophs)
Corticotrophs  Produce adrenocorticotropic hormone (ACTH), pro-
opiomelanocortin (POMC), melanocyte-stimulating
hormone (MSH), endorphins and lipotropin
Thyrotrophs  Produce thyroid stimulating hormone (TSH)
Gonadotrophs  Produce follicle stimulating hormone (FSH) and
 luteinising hormone (LH)
 FSH stimulates formation of graafian follicles in the
ovary
 LH induces ovulation and formation of corpora
lutea in the ovary

Anterior Pituitary Hormones

Hormone Target Function
Adrenocorticotrophic Adrenal glands Stimulates adrenal gland to produce cortisol
Hormone (ACTH) (ACTH can also be called corticotrophin)
Thyroid-Stimulating Thyroid gland Stimulates the thyroid gland to secrete
Hormone (TSH) thyroxine (TSH can also be called thyrotrophin)
Luteinising Hormone Ovaries Controls reproductive functioning and sexual
(LH) and Follicle- (women) and characteristics. Stimulates ovaries to produce
stimulating Hormone Testes (men) oestrogen and progesterone and the tests to
(FSH) produce testosterone and sperm. Collectively
these are known as gonadotrophins. In males
LH is also called interstitial cell stimulating
hormone (ICSH)
Prolactin Breasts Stimulates breasts to produce milk. Secreted in
large amounts during pregnancy and breast
feeding. Present in both men and women
Growth Hormone All cells of the Stimulates growth and repair
(GH) body
Melanocyte- Unknown Unknown
Stimulating Hormone

Posterior Pituitary Hormones

Hormone Target Function
Anti-Diuretic Hormone Kidneys Controls fluid balance – stimulates kidneys to
(ADH)/ Arginine Vasopressin reabsorb water. May also have some
(AVP) vasoconstrictive effects.
Oxytocin Uterus Affects uterine contractions in pregnancy and
and birth and subsequent release of breast milk.
breasts
 3. Anatomy of the breast, physiology of lactation and what hormonal pathways and
factors influence it?

The breasts are paired structures on the anterior thoracic wall in the pectoral region in both
males and females. However, they are more prominent in females following puberty. In
females the breasts contain the mammary glands – an accessory gland of the female
reproductive system, which are involved in lactation.

Surface Anatomy:
 The breast is found on the anterior thoracic wall, extending horizontally from the
lateral border of the sternum to about the mid axillary line
 Vertically it spans between the second and sixth intercostal cartilages and lies
superficial to the pectoralis major and serratus anterior muscles
 The breast can be considered as two regions:
 Circular body: the largest and most prominent part of the breast
 Axillary tail: smaller part which runs along the inferior lateral edge of the
pectoralis major toward the axillary fossa
 At the centre of the breast is the nipple (smooth muscle fibres), and surrounding this
is skin termed the areolae
 The areolae contain numerous sebaceous glands which enlarge during pregnancy

Anatomical Structure:
 The breast is composed of mammary glands surrounded by a connective tissue
stroma
 The mammary glands are modified sweat glands
 Series of ducts and secretory lobules (15-20)
 Each lobule consists of many alveoli drained by a single lactiferous duct which
converge at the nipple
 The connective tissue stroma is a supporting structure, surrounding the mammary
glands with a fibrous and fatty component
 The fibrous stroma condenses to form suspensory ligaments (of Cooper) which
function to attach and secure the breast to the dermis and underlying pectoral
fascia, and separate the secretory lobules of the breast
 Pectoral fascia which forms the base of the breast is a connective tissue sheet
associated with the pectoralis major muscles and provides an attachment site for the
suspensory ligaments of Cooper
 There is a potential space between the pectoral fascia and the breast known as the
retromammary space
 This is used in reconstructive plastic surgery
Lactation:
Process by which milk is synthesised from the mammary glands of a post-partum female.
Milk is produced in response to a suckling infant. The breast milk provides nutrition and
passive immunity for the infant. It also encourages mild uterine contractions to return the
uterus to its pre-pregnancy size (involution) and induces substantial metabolic increase in
the mother, consuming fat reserves stored during pregnancy.
 Prolactin is released from the anterior pituitary and is instrumental in establishing
and maintain break milk supply. It is also needed to mobilise micronutrients for
breast milk
 Oestrogen, progesterone and other hormones inhibit prolactin-mediated milk
synthesis during pregnancy
 After expulsion of the placenta this inhibition is lifted, and milk production
commences
 Upon suckling by an infant, there are sensory nerve fibres in the areolae which
trigger a neuroendocrine reflex resulting in milk production
 The posterior pituitary releases oxytocin which stimulates myoepithelial cells to
squeeze milk from alveoli to drain into lactiferous ducts
 Growth hormone, cortisol, parathyroid hormone and insulin all contribute to
lactation by the transport of maternal amino acids, fatty acids, glucose and calcium
into breast milk
 The neuroendocrine reflex due to suckling down-regulates dopamine release from
the hypothalamus (which normally inhibits prolactin release) and upregulates
vasoactive intestinal peptide (VIP) release which normally promotes prolactin release

Mammary Gland:
Modified sweat glands, composed primarily of adipose and collagenous tissue. Expand and
branch extensively during pregnancy, composed of milk-transporting lactiferous ducts. They
expand in response to oestrogen, growth hormone, cortisol and prolactin. In response to
progesterone, clusters of breast alveoli bud from the ducts and expand outward toward the
chest wall – these buds are lined with milk-secreting cuboidal cells (lactocytes)
 Clusters of alveoli draining into a common duct are called a lobule
 Lactating females have 12-20 lobules radially organised around the nipple
 The milk drains from lactiferous ducts into lactiferous sinuses which then meet at
perforations in the nipple called pores
 The small bumps of the areolae are called Montgomery glands which secrete oil to
cleanse the nipple opening and prevent chapping and cracking of the nipple during
breastfeeding

4. Pathophysiological changes which can cause lactation in a non-pregnant state

Galactorrhea is lactation in men or women who are not breast feeding. There are two
primary mechanisms which can cause this:
 Increase in prolactin levels
 Reduction in dopamine inhibition of prolactin

Description:
 Galactorrhea is a milky nipple discharge not associated with gestation or present
more than 1 year after weaning. Galactorrhea does not include serous, purulent or
bloody nipple discharge

Epidemiology:
 Predominantly effects females between 15-50
 Can occur in MEN1 and prolactinomas

Aetiology and Pathophysiology:

 Lactation is stimulated by prolactin, which is secreted in pulses by the anterior
pituitary
 Prolactin release is under tonic inhibition of dopamine, which is produced by the
hypothalamus, which binds to D2 receptors on lactotrophs

Disorder Cause
Affected afferent  Chest wall trauma
neural stimulation  Chiari-Frommel, del Castillo and Forbes-Albright
syndromes
 Herpes zoster
 Nipple stimulation
 Spinal cord injury
Organic  Craniopharyngiomas
hyperprolactinemia  Irradiation
 Meningiomas or other tumours
 Multiple sclerosis
 Pituitary stalk compression or injury
 Post-breast augmentation surgery
 Prolactinoma
 Sarcoidosis
 Traumatic injury
 Vascular malformations (aneurysms)
Functional  Adrenal insufficiency (Addison’s disease)
hyperprolactinemia  CKD
 Cirrhosis
 Hypothyroidism (reduced release of thyroxine, leading
to increased release of TSH which stimulates prolactin)
 Lung cancer
 Renal cell cancer
Medications Cardiology
 Reserpine, verapamil
GI
 H2 blockers, PPIs
Herbal
 Anise, barley, thistle
Illicit
 Cocaine, marijuana, opioids
Other
 Anti-psychotic s, SSRI’s (not always), neuroleptics,
tricyclic antidepressants
 5. The effects of antidepressants and antipsychotics on the hypothalamus and
pituitary gland, and how they may cause galactorrhoea

Natalie Kovic was previously treated with Sertraline, an SSRI.

Anti-depressants:
 SSRI’s and SNRI’s are the major class of anti-depressants used in the clinical studying
nowadays and so will be the focus of this dot point.
 Tricyclic antidepressants have more obvious effects on dopamine inhibition
 SSRI’s mode of action involves selectively blocking the reuptake transporters of
serotonin at the presynaptic terminal, thereby increasing serotonin levels in the
synaptic cleft and potentiating it’s effects

Anti-Depressants and Dopamine:

 The link between anti-depressants and dopamine neurons in the brain is unclear
 One proposed mechanism suggests that the increased level of serotonin in the
synaptic cleft due to the blockage of the reuptake transporter of serotonin, causes
shunting of serotonin through the dopamine reuptake transporter
 This in turn adversely affect dopaminergic firing, ultimately reducing the effects
of dopamine firing
 The reduced dopaminergic firing can lead to a lack of inhibition of prolactin,
which can in turn increase in serum causing galactorrhoea
 Other mechanisms:
 5-HT may hyperpolarise and abolish phasic discharge in neuroendocrine
tuberoinfundibular dopamine (TIDA) neurons which are the major inhibitors of
prolactin secretion
 This process is underpinned by serotonin receptor 5-HT1A which is a GPCR which
activates inward K+ currents
 Fluoxetine and sertraline are believed to directly suppress TIDA neuron activity
through parallel effects independent of 5-HT transmission
 SSRI’s are believed to have regionally selective effects on dopaminergic
neurotransmission in particular areas of the brain, and is an accumulative dose-
dependent effect

Anti-Psychotics:
 Antipsychotics also known as neuroleptics are used particularly in the treatment of
schizophrenia and other disorders involving psychosis and delusions.
 There are typical and atypical anti-psychotics
 Their mode of action involves blocking dopaminergic neurotransmission
 Atypical anti-psychotics also have an effect on serotonin receptors
 Block dopamine D2 receptors, these are particularly important in the inhibition
of prolactin release from the anterior pituitary
 Anti-psychotics can therefore cause disinhibition of prolactin, causing increased
levels of prolactin (hyperprolactinemia)
 6. APDTM of pituitary tumours, including the hormonal and mass effects of a
pituitary tumour

Overview:
 Most pituitary tumours are adenomas
 Symptoms include headache and endocrinopathies (when the tumour either
produces or inhibits hormone production)
 Diagnosis is mostly by MRI
 Treatment is usually surgery and some medical treatment. Radiation and
dopaminergic agonists may also be used
 Most pituitary and suprasellar region masses are pituitary adenomas, which can
either be secretory or non-secretory
 Meningiomas, craniopharyngiomas, metastases and dermoid cysts are less
common masses formed in the sella turcica
 Secretory adenomas produce pituitary hormones
 Microadenoma’s are < 10mm
 Macroadenoma’s are > 10mm
 Secretory adenomas are classified according to their histologic staining
characteristics
 Acidophilic
 Basophilic
 Correlates with hormone produce
 Any pituitary tumour can compress the optic chiasm and/or the optic tract
 These tumours may also compress or destroy pituitary and/or hypothalamic tissue

Signs and Symptoms:

 Headache, even if there is no raised ICP
 Visual manifestations: bitemporal hemianopia, unilateral optic atrophy and
contralateral hemianopia may develop if the tumour compresses optic nerve tracts
 Endocrinopathies
 Diabetes insipidus if AVP secreting neurons are injured or compressed
 Amenorrhea and galactorrhea in women due to overproduction of prolactin
 Erectile dysfunction and gynaecomastia in men due to overproduction of
prolactin
 Gigantism (acromegaly) if pre-puberty due to overproduction of growth hormone
 Cushing syndrome if ACTH is overproduced
 Sometime pituitary tumours compress tissue throughout the anterior lobe, leading
to a reduction in production of multiple pituitary hormones  generalised
hypopituitarism
 Rarely, haemorrhage into a pituitary tumour causes pituitary apoplexy with a sudden
headache, ophthalmoplegia and visual loss

Diagnosis:
  Gold standard is using MRI to visualise a mass
 Clinical signs and symptoms such as unexplained headaches, visual abnormalities
(particularly bitemporal hemianopia)
 CT scan can be useful for macroadenomas but less useful for microadenomas
compared to MRI
 Serum testing for pituitary hormones can also be done

Non-Functional Adenomas:
 Account for up to half of all pituitary adenomas
 Do not cause increased levels of pituitary hormones in the body
 Can cause mass effects if they increase in size beyond 10mm
Functional Adenomas:
 Produce a particular type of pituitary hormone
 Cause effects associated with that hormone, and if large enough can cause mass
effects
Pituitary Carcinoma:
 Rare malignant growth which can be functional or non-functional
 Can destroy pituitary tissue causing a drop in hormone levels, and if left untreated it
can spread

Sella Mass
Overview  Pituitary adenoma (functioning or non-functioning), rarely a
carcinoma
 Metastasis to pituitary
 Other tumours include craniopharyngioma, germ cell
tumours, meningioma, glioma, pituicytoma, chordoma
 Cystic lesions – Rathke’s cleft cyst, dermoid/epidermoid
cysts
 Aneurysms, vascular lesions, apoplexy
 Hypophysitis – lymphocytic, granulomatous, xanthomatous,
ipilimumab-induced, IgG4
Sign and  Headache, mass effect
Symptoms  Bitemporal hemianopia
 Diplopia (CN III, CN IV, CN VI) (due to involvement of the
cavernous sinus)
 Facial pain/ numbness due to involvement of the ophthalmic
branch of CN V
 Seizures (temporal lobe)
 Hydrocephalus due to impingement of the 3rd ventricle
Treatment  Prompt surgical debulking to restore impaired vision
 May be difficult to operate if extensive cavernous sinus
involvement, encases of carotid arteries
 Radiotherapy used for residual disease
 Management of hormonal deficiencies if present
 Treat primary cause if due to infection, inflammation and/or
infiltration
Mass Effects:
 Microadenomas rarely cause mass effects
 Macroadenomas can cause mass effects
 Mass effects involves the compression of surrounding structures and their
subsequent impairment due to a mass in the sella turcica
 Common mass effects include:
 Headaches and pain, if compression of the diaphragma sella (a sheet of dura
mater high in pain afferent density), and/or if there is a rise in ICP
 Compression of the cavernous sinus can have a number of effects, depending on
the degree of compression:
o ICA involvement: syncope and dizziness, potential cerebral stroke
o CN III, CN IV, CN VI: innervators of extra-ocular muscles, compression can
lead to diplopia
o CN V1: can lead to upper facial numbness or paraesthesia
 If involvement of third ventricle  hydrocephalus
 Compression of temporal lobe  seizures
 Compression of optic chiasm  bitemporal hemianopsia (recall that only the
nasal retinal fibres from both eyes cross over at the optic chiasm, and these
respectively provide information of the temporal field of view)
 Compression of other parts of the pituitary gland  hypopituitarism
o Hypopituitarism can in turn have secondary effects such as adrenal
insufficiency or hypothyroidism due to a lack of pituitary hormones being
released

Management and Treatment:

 Management and treatment aims to fill the following criteria:
  Normalise hormone levels for a functional adenoma (remove effects of excess
hormone)
 Normalise levels for a functional or non-functional adenoma producing mass
effects such as hypopituitarism
 Remove or reduce the size of a sella mass to decrease symptoms of mass effect
 Treat a primary cause if it is reversible, such as an infection or inflammation
 Treatment options include medical (which is preferable if it available), which aims to
target the hormone changes involved with pituitary masses
 Bromocriptine and cabergoline can be used for prolactinoma’s. They reduce
prolactin secretion and may even shrink the tumour. These drugs are
dopaminergic agonists
 Somatostatin analogues such as Lanreotide and Octreotide. These are used for
adenomas producing excess growth hormone (which causes acromegaly). These
drugs reduce growth hormone production and may decrease the size of tumour.
These can also be used to treat pituitary adenomas producing excess thyroid.
 Pegvisomant can be used to block the effects of excess growth hormones in
acromegaly
 Ketoconazole is used for treating Cushing’s syndrome, which involves
overproduction of ACTH leading to excess cortisol. This drug decreases cortisol
secretion but does not stop ACTH production or tumour shrinkage.
 If surgery is possible, it is the preferable first line of treatment, which may or may
not involve radiation therapy to shrink the tumour first
 Utilises a transsphenoidal approach
 Can also be done through the cavernous sinus

7. Pathophysiology of headaches and red flags for headaches

A headache involves pain in any part of the head, and this includes the scalp, face (including
the orbitotemporal area). Simply put a head occurs because pain-sensitive structures in the
head or neck are stimulated to fire nociceptive signals or there is some form of stimulus
(medications, dysfunction of nerves carrying pain afferents).
The pain-sensitive structures of the head include:
 Blood vessels, especially the large vessels at the base of the skull
 The meninges, particularly the dura mater
 Bone itself
 CN V, VII, IX and X
 Scalp and the associated muscles
 Sinus mucosa
 Teeth
 Eyes and ears

Primary headaches:
 Migraine (You did this in depth in the neuro block)
 Trigeminal autonomic cephalgia’s
 Includes cluster headache, chronic paroxysmal hemicrania continua and short-
lasting unilateral neuralgiform headache with conjunctival injection and tearing
 Tension-type headache

Cluster Headache  Multiple unilateral orbitotemporal attacks

 Often at the same time of day
 Deep, severe, lasting 30-180 minutes
 Often with lacrimation, rhinorrhoea, facial
flushing or Horner syndrome, restlessness
Migraine  Unilateral or bilateral
 Pulsating, lasting 4-72 hours
 Occasionally with an aura
 Usually accompanied by nausea, photophobia,
sonophobia or osmophobia
 Worsens with activity, patient prefers to lie in a
dark room and sleep
Tension-type Headache  Frequent or continuous, mild, bilateral and
vicelike occipital or frontal pain which spreads to
entire head
 Tends to be worse at the end of the day

Secondary Headaches
Cause Example
Extracranial Disorders  Carotid or vertebral artery dissection (also causes
neck pain)
 Dental disorders (such as infection, TMJ
dysfunction)
 Glaucoma
 Sinusitis
Intracranial Disorders  Brain tumours or anything causing a positive mass
effect (oedema due to stroke etc.)
 Chiari type I malformation
 CSF leak with low-pressure headache
 Haemorrhage (intracerebral, subdural,
subarachnoid which presents as thunderclap
headache)
 Idiopathic intracranial hypertension
 Infections (abscess, encephalitis, meningitis,
subdural empyema)
 Meningitis and non-infectious
 Obstructive hydrocephalus
 Vascular disorders (stroke, malformation, vasculitis,
venous sinus thrombosis)
Systemic Disorders  Acute severe hypertension
 Bacteraemia
 Fever
 Giant cell arteritis
 Hypercapnia
 Hypoxia (includes altitude sickness)
 Viral infection
 Viremia
Drugs and Toxins  Analgesic overuse
 Caffeine withdrawal
 Carbon monoxide
 Hormones such as oestrogen
 Nitrates
 PPI’s