Pituitary

Question 1

Distinguish between primary, secondary and tertiary disease states relating to pituitary function

Answer 1

• Hypopituitarism 
Decreased production of ALL anterior pituitary hormones (PANhypopituitarism) or of specific hormones 


Anterior Pituitary Hormones:

1. FSH/LH Gonadotrophins -> signals from AP controlling genitals
2. Prolactin -> controls lactation post-partum
3. Growth hormone GH
4. TSH thyroid stimulating hormone
5. ACTH – makes adrenal cortex to make cortisol

Top at the chain of command – hypothalamus (makes releasing and inhibiting hormones) TRH
Next, anterior pituitary hormone TSH
Effector organ – eg. Thyroid releases T3, T4

Primary hypothyroidism – When gland is problematic (auto-immune thyroid disease)

Secondary hypothyroidism- When pituitary gland is problematic

Question 2

Define the term pan-hypopituitarism and explain the causes of pan- hypopituitarism 


Answer 2

Panhypopituitarism 


• Can be due to congenital defects (RARE) 

• Can be due to gene mutations (VERY RARE) - e.g. PROP1 mutation - this is a 
transcription factor that allows the development of the pituitary gland to take 
place (leads to problems with all the anterior pituitary hormones) 

• Deficient in GH and at least 1 more anterior pituitary hormone
• Usually, panhypopituitarism will develop in an ADULT with progressive loss of 
pituitary secretion 

• The loss of secretion usually happens in the following order: 
Gonadotrophins (LH and FSH) GH
Thyrotrophin
Corticotrophin 
Prolactin deficiency is uncommon/unrecognised 

• If someone has been given radiotherapy on their pituitary gland, their anterior 
pituitary hormones tend to fail in a certain order stated above

ACQUIRED PANHYPOPITUITARISM- causes

1. Tumours - hypothalamic - craniopharyngiomas/ pituitary – adenomas, metastases, cysts
2. Radiation

hypothalamic/pituitary damage

GH most vulnerable, TSH relatively resistant

1. Infection eg meningitis
2. Traumatic brain injury
3. Infiltrative disease – often involves pituitary stalk eg neurosarcoidosis
4. Inflammatory (hypophysitis) (auto-immune disease – anterior pituitary distruction)
5. Pituitary apoplexy (sad, unhappy pituitary from haemorrhage or infarction)
6. haemorrhage (or less commonly infarction)
7. Peri-partum infarction (Sheehan’s syndrome)

Question 3

Recall the more common signs and symptoms of pan-hypopituitarism. 


Answer 3

THREE main types of Panhypopituitarism 


1. Simmond’s Disease 

2. Sheehan’s Syndrome 

3. Pituitary Apoplexy 


Simmond’s Disease

• INSIDIOUS onset - develops very slowly 

• Symptoms due to deficient hormones (FSH/LH secondary hypogonadism) -> Reduced libido, Secondary amenorrhoea, Erectile dysfunction
• ACTH Secondary hypoadrenalism (cortisol deficiency) -> Fatigue
• TSH - Secondary hypothyroidism -> Fatigue
• Causes: various 
Infiltrative processes (e.g. lymphocytic) Pituitary adenomas Craniopharyngiomas
Cranial injury 
Following surgery 

• Symptoms are mainly due to decreased thyroidal, adrenal and gonadal 
function 

• Symptoms: 


1. Secondary Amenorrhoea OR Oligomenorrhoea Impotence

2. Loss of libido

3. Tiredness 

4. Waxy skin
5. 
Loss of body hair
6. Hypotension

Sheehan’s Syndrome 


• SPECIFIC IN WOMEN 

• Develops acutely following post-partum haemorrhage resulting in PITUITARY 
INFARCTION 

• Neurohypophysis – neural tissue like brain
• In pregnancy, pituitary increases in size because lactotrophs become very big because they are preparing for lactation (lactotroph hyperplasia)
• Large haemorrhage –-> pituitary infarction
• The blood loss results in vasoconstrictor spasm of hypophysial arteries and this leads to: decrease BP – not enough blood flows to pituitary ->
Ischaemia of the pitutiary (which is enlarged during pregnancy) 
Necrosis of the pituitary 

• This develops very FAST 


PRESENTATION OF SHEEHAN’S SYNDROME

• Lethargy, anorexia, weight loss – TSH/ACTH/(GH) deficiency
• Failure of lactation – PRL deficiency
• Failure to resume menses post-delivery
• Posterior pituitary usually not affected

Pituitary Apoplexy 


• This is similar to Sheehan’s but is not specific to women 

• It is due to an intra-pituitary infarction or haemorrhage 

• There is a rapid presentation in patients with pre-existing pituitary tumours 
which suddenly infarct 

• RAPID presentation 

• May be first presentation of a pituitary adenoma
• Can be precipitated by anti-coagulants (blood thins, BP falls)

Presentation

• SEVERE sudden onset headache (because it presses on the dura)
• Visual field defect – compressed optic chiasm, bitemporal hemianopia (loss of outer fields)
• Cavernous sinus involvement may lead to diplopia (IV, VI), ptosis (III)

Question 4

List the investigations for identifying pituitary hormone deficiencies and explain the use of stimulation tests

Answer 4

Diagnosis of Hypopituitarism 


1. We can’t measure the hypothalamic hormones so we measure the basal plasma values of the pituitary or target endocrine gland hormones 

   * NOTE: most things released from the hypothalamus are release in pulses so a single measurement will mean nothing 


(interpretation may be limited- undetectable cortisol – what time of day?/ - T4 – circulating t_1/2 6 days/ - FSH/LH – cyclical/ - GH/ACTH – pulsatile)

• To find out if someone is producing a hormone at a normal level you have to do a
  2. STIMULATION (or provocation) test 

• This can be done using a combined function test - this involves the administration of various releasing hormones 

• The releasing hormones are administered IV 

• You can do the same thing with just one releasing hormone if you’re testing for a specific hypothyroidism 

• There are other specific tests such as the insulin-induced hypoglycaemia test for GH 


Example:
ACTH & GH = ‘stress’ hormones

• Hypoglycaemia (<2.2mM) = ‘stress’
• Insulin-induced hypoglycaemia stimulates

1. GH release
2. ACTH release (cortisol measured)

• After insulin you give TRH which stimulates TSH release
• GnRH stimulates FSH & LH release
  3. RADIOLOGICAL DIAGNOSIS (cont.)

Pituitary MRI: May reveal specific pituitary pathology

eg haemorrhage (apoplexy), adenoma

Empty sella – thin rim of pituitary tissue (possible)

Question 5

Recall how the endocrine consequences of pan-hypopituitarism can be treated, 
using hormone replacement therapy. 


Answer 5

HORMONE REPLACEMENT THERAPY IN HYPOPITUITARISM

Hypopituitarism (specific) 


• It is possible to have a deficiency in a single adenohypophysial hormone, resulting in SECONDARY endocrine gland failure 

• Examples of secondary endocrine gland failure: 
Gonadotrophins - Hypogonadism Thyrotrophin - Hypothyroidism Corticotrophin – Hypoadrenocorticalism 


Question 6

List the principal endocrine causes of short stature, identifying those that are 
caused by lack or excess of specific hormones and those that are related to 
receptor and post-receptor defects. 


Recognise that short stature can also be related to non-endocrine causes such 
as malabsorption, malnutrition and psychological deprivation. 





Answer 6

Lack of Somatotrophin 


• Children - pituitary dwarfism (in children results in short stature (=2 SDs < mean height for children of that age and sex)
• Adults - loss of GH effects are uncertain 


Other causes of short stature (in children) 


1. Genetic (Down’s syndrome, Turner’s syndrome, Prader Willi syndrome)
2. Malnutrition / Malabsorption
3. Emotional deprivation (potentially due to the stress response having an effect 
on the growth axis) 

4. Endocrine disorders (the absence of certain hormones such as T3 and T4 can
lead to a short stature- hypothyroidism) 

5. Skeletal dysplasias
6. Systemic disease – cystic fibrosis, rheymatoid arthritis

GH deficiency in children Congenital (RARE) 


• Deficiency of hypothalamic GHRH 

• Mutations of the GH gene (VERY rare) 

• Developmental abnormalities (e.g. aplasia or hypoplasia of the pituitary gland) 


Acquired (more common) 


• Tumours of the hypothalamus or pituitary 

• Other intracranial tumours nearby (e.g. optic nerve glioma) 

• Irradiation can affect the somatotrophs and cause problems 

• Head injury 

• Infection or inflammation 

• Severe psychosocial deprivation 


Endocrine-related short stature

• GH is controlled at the hypothalamic level by GHRH and Somatostatin (mainly GHRH) 

• Most endocrine-related causes of short stature are due to decreased production of GHRH 

• GH is a hormone in its own right but it also stimulates the production of other hormones that have an endocrine function 

• GH stimulates the production of IGF I (Insulin-like Growth Factor I) in the LIVER 

• NOTE: IGF is produced by many tissues in the body but the liver is the main 
source of it 

• IGF I - mediates growth effects 

• There could be effects where the IGF I is the cause of the short stature because GH and IGF I are together in generating a lot of metabolic effects associated 
with growth 

• LARON DWARFISM - this is due to a GH receptor defect 
As a result the IGF I levels are low 
This is because somatotrophin isn’t having its effect 

• DWARFISM: ACHONDROPLASIA: Mutation in Fibroblast Growth Factor Receptor 3 (FGF3)
• Abnormality in growth plate chondrocytes - impaired / linear growth / Average size trunk/ Short arms and legs
• PITUITARY DWARFISM: Childhood GH deficiency
• Importance of IGF I is identified by considering the pygmies in africa 
They have a very short stature
They have IGF I but it doesn’t work normally
They lack the growth that we normally associate with IGF I and that’s because IGF I is unable to carry out its function 


Tertiary Hypopituitarism 


• Caused by SPECIFIC HYPOTHALAMIC HORMONE DEFECTS 

• Example: GnRH deficiency 
Kallmann’s Syndrome
  
  • Hypogonadism 

  • Associated with various degrees of anosmia

This is caused by a genetic defect where the neurones in the embryo that will go on to produce GnRH are unable to migrate to the hypothalamus
So they have a hypothalamus that lacks GnRH neurones
The defect also prevents the migration of the neurones that are going to develop a sense of smell resulting in anosmia

Prader-Willi Syndrome:
GH deficiency 2^o to hypothalamic dysfunction

• Hypogonadism is one of the aspects of this disorder 

• This is a problem at the level of the hypothalamus 





Question 7

Explain how the diagnosis of endocrine-related short stature can be made, 
including a description of the use of standard growth charts and stimulation tests. 


Answer 7

Pituitary Deficiency 


• To test for pituitary deficiency you do a PROVOCATION CHALLENGE (stimulation test)

GH Provocation Tests

• You used to use IV GHRH to stimulate GH production 

• Now it is difficult to get a hold of GHRH so other alternatives are being used
• The standard way of testing the ability of the pituitary to produce GH is to stimulate GH production by inducing HYPOGLYCAEMIA 

• REMEMBER: hypoglycaemia is a potent stimulus for GH release 

• GOLD STANDARD: Insulin-induced Hypoglycaemia (IV) 

• There are also other alternatives: 
Arginine (IV)- amino acid that stimulates GH release
Glucagon (IM) - this is odd because glucagon causes hyperglycaemia but it’s been found that giving glucagon in people who have a lack of GH can stimulate GH release
  
  • It could be part of the glucagon molecule that has a direct stimulatory effect on the somatotrophs 

  • Glucagon is good at giving provocation to the GH axis
Exercise - e.g. 10 mins step climbing - good way of stimulating the release of GH 

• Plasma GH must be measure before AND after the test Insulin-induced Growth Hormone Secretion 

• Normally, hypoglycaemia will trigger a massive release in GH 

• If you are deficient in GH then that response will be reduced 


Question 8

Describe the pharmacodynamic and pharmacokinetic properties of human growth hormone and explain the rationale governing its use in the treatment of growth hormone deficiency in (a) children

Answer 8

Treatment of Pituitary Deficiency

• Main aim is to restore homeostasis by replacing the missing hormone(s) 

• Accurate diagnosis is crucial 
Hormone Replacement Therapy in Hypopituitarism 


• To check if GH is working you keep track of IGF 1 levels or keep a growth chart (in children)

Growth Hormone Therapy in Children

• Acceleration of linear growth (GH stimulates protein synthesis) 

• Decreased body fat 

• Younger children respond better 

• Obese children respond better 

• Only problem is that resistance may develop (antibody formation) - so you need to consider this when deciding when to start treatment 

• Other hormones may also be affected in which case you have to give other hormone replacement as well as GH 
Growth Hormone Therapy Continued 

• Preparation 
Human recombinant GH 
NAME: Somatotrophin 

• Administration 
Subcutaneous or Intramuscular
Tend to give it DAILY or 4/5 times per week
Tend to give it in the afternoon because GH varies during the day and they tend to be high in the night anyway
Adjust dose to size 

• Absorption and Distribution 
Maximal plasma concentration in 2-6 hours 

• Metabolism 
Hepatic/Renal 

• Duration of Action 
It is going to be working on protein synthesis so it’s duration of action is quite long
IGF I levels peak after around 20 hours 

• Adverse Effects 
Lipoatrophy at the site of injection
Intracranial hypertension
Headaches (as a result of the intracranial hypertension)
GH is also a cell stimulation hormone so there is increased risk that you’ll stimulate tumours - increased incidence of leukaemia

Question 9

Outline the signs and symptoms of Growth Hormone deficiency in adults

Answer 9

• Reduced lean mass 

• Increased adiposity 

• Increased waist:hip ratio 

• Reduced muscle strength and bulk (reduced exercise performance) 

• Decreased HDL and Increased LDL 

• Impaired psychological wellbeing and reduced quality of life 
As you get older there is a natural decrease in GH secretion (particularly in people over 60)
People become less strong as they get older and their bulk is reduced so could GH help? 


Diagnosis of GH Deficiency in Adults 


• Lack of response to GH stimulation test (e.g. insulin-induced hypoglycaemia) 

• Low Plasma IGF I 

• Low Plasma IGF-BP3 


Potential Benefits of GH Therapy in Adults 


• Improved body composition 

• Improved muscle strength and exercise capacity 

• Normalisation of HDL-LDL balance - good for the CVS 

• Increased bone mineral content (particular relevance to middle aged women) 

• Improved psychological wellbeing and quality of life 


Potential Risks of GH Therapy in Adults 


• Increased risk of cardiovascular accidents 
-> Because of its growth promoting effects, an excess of GH can cause 
cardiomegaly 

• Increased soft tissue growth, leading to e.g. cardiomegaly 

• Increased susceptibility to cancer 


Question 10

List the individual pituitary hormone excess states that can develop, and identify the principal consequences of each hypersecretory state.

Answer 10

Hyperpituitarism 
Symptoms associated with excess production of adenohypophysial hormones 


• Usually due to isolated pituitary tumours 

• It can also be ectopic in origin e.g. vasopressin producing lung tumours 

• Associated with visual field defects 

• May also be accompanied by other defects e.g. cranial nerve defects - this 
could be due to the tumour having an effect on nearby structures aside from the pituitary 


image

Question 11

Discuss bitemporal (Heteronymous) hemianopia

Answer 11

Bitemporal (Heteronymous) Hemianopia

• Quite a lot of people with pituitary tumours are picked up by their optician due to visual field defects 

• At the optic chiasm, the fibres from the inner (nasal) part of both retinae cross 
(nasal vs temporal)
• Light from the left visual field will hit the right part of the retina and vice versa 

• Because of the crossing over, all the light from the left visual field is detected 
by the right side of the brain 

• A pituitary tumour could protrude out of the sella turcica and disrupt the fibres 
coming from the nasal parts of the retinae 

• This means that you lose the temporal part of the visual field 


Question 12

Define hyperprolactinemia and list principal signs and symptoms

Answer 12

Hyperprolactinaemia

Excess circulating prolactin when not due to a physiological cause such as pregnancy or breast-feeding

• HYPOprolactinaemia isn’t really a problem because the absence of prolactin doesn’t really have any serious physiological consequences 

• HYPERprolactinaemia is associated with pituitary tumours - prolactinoma 

• Most common type of prolactinoma are microadenomas (< 10 mm) 


Hyperprolactinaemia due to Prolactinoma : = most common functioning pituitary tumour

• High prolactin suppresses GnRH pulsatility

HYPERPROLACTINAEMIA DUE TO PITUITARY ADENOMA PRESENTATION

IN WOMEN

• galactorrhoea (milk production)
• secondary amenorrhoea (or oligomenorrhoea)
• loss of libido
• infertility

IN MEN

• galactorrhoea uncommon (since appropriate steroid background usually inadequate)
• loss of libido
• erectile dysfunction
• infertility

Question 13

Recall how hyperprolactinaemia is diagnosed. 


Answer 13

TREATMENT OF HYPERPROLACTINAEMIA

• Medical treatment is 1^st line
  
  • Dopamine receptor (D2) agonists
    
    • Decrease prolactin secretion
    • Reduce tumour size
• Examples:
  
  • BROMOCRIPTINE
  • CABERGOLINE
• Oral administration
• Dopamine from hypothalamic dopaminergic neurones – inhibits prolactin secretion
• Dopamine agonist – reduces prolactin secretion

SIDE EFFECTS OF DOPAMINE RECEPTOR AGONISTS

• Nausea and vomiting
• Postural hypotension
• Dyskinesias
• Depression
• Pathological gambling (see BNF!)

Question 14

Recall the principal signs and symptoms of growth hormone hypersecretion in the child and the adult. 


Answer 14

Excess Somatotrophin 


• In CHILDREN = GIGANTISM 

• In ADULTS = ACROMEGALY 
(fusion of growth plates so unable to get taller)
• In adults, the growth plates of the long bones have fused so there is no longer 
a possibility of an increase in height but you still get other effects 


Acromegaly 


• Insidious onset 

• Signs and symptoms progress very gradually over many years 

• If untreated, gigantism (excess GH) and acromegaly are associated with increased 
morbidity and mortality due to cardiovascular (majority 60%) and respiratory 
complications 
25% and cancer 15%
• It is not just increased growth but also an increase in organ size 

• This means that there is increased demand for oxygen and the blood supply 
must keep up with this extra demand - this places a big strain on the CVS 


Increased Growth in Acromegaly:

1. Periosteal bone

2. Cartilage
3. 
Fibrous tissue

4. Connective tissue

5. Internal organs (cardiomegaly, splenomegaly, hepatomegaly etc.)

CLINICAL FEATURES OF ACROMEGALY

1. excessive sweating (hyperhidrosis)
2. headache
3. enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features
4. enlarged tongue (macroglossia)
5. mandible grows causing protrusion of lower jaw (prognathism)
6. carpal tunnel syndrome (median nerve compression)
7. barrel chest, kyphosis
8. Joint pain 

9. Galactorrhoea (often in women and occasionally in men) - at very high levels, 
GH has some prolactin like effects 

10. Menstrual abnormalities, decreased libido and impotence 

11. Hypertension - there is a massive strain on the CVS and this is associated with 
an increase in blood pressure as the body tries to supply blood to the extra 
tissues 

12. Abnormal glucose tolerance; symptoms of diabetes mellitus 


Question 15

Discuss metabolic effects and complications in acromegaly

Answer 15

EXCESS GROWTH HORMONE -> increased endogenous glucose production, decreased muscle glucose uptake –> increased insulin production = increased insulin resistance –> impaired glucose tolerance –> diabetes mellitus

GH stimulates an increase in blood glucose and part of that is to do with an increase in tissue resistance to insulin

COMPLICATIONS OF ACROMEGALY

• Obstructive sleep apnoea
  
  • Bone and soft-tissue changes surrounding the upper airway lead to narrowing and subsequent collapse during sleep
• Hypertension
  
  • Direct effects of GH &/or IGF-1 on vascular tree
  • GH mediated renal sodium reabsorption
• Cardiomyopathy
  
  • Hypertension, DM, direct toxic effects of excess GH on myocardium
• Increased risk of cancer
  
  • Colonic polyps, regular screening with colonoscopy

Question 16

Recall how gigantism and acromegaly are diagnosed. 


Answer 16

Diagnosis and Treatment of Pituitary Hypersecretory States 


• With HYPOsecretion you do a stimulation/provocation test 

• So with HYPERsecretion you do a SUPPRESSION TEST​
orElevated serum IGF-1

Glucose-induced suppression of growth hormone secretion 


• Remember the insulin-induced hypoglycaemia is used to stimulate GH release to determine whether the pituitary is functioning properly 

• So if, instead, you give GLUCOSE you should inhibit growth hormone release and growth hormone levels will decrease and then you get an overswing at the end 

• If you give glucose to someone with acromegaly - you get the OPPOSITE – high onset of glucose and a paradoxical increase in GH after glucose consumption

​EFFECT

• There is a PARADOXICAL RISE IN GH following the administration of GH

Question 17

List the principal treatments available for the treatment of gigantism and 
acromegaly

Answer 17

Treatment of Acromegaly

1. Surgery is the main treatment - transphenoidal hypophysectomy 

2. Radiotherapy: 
Problem with radiotherapy is that you do it over a long period of time and 
you may end up becoming hypopituitary as a result 

3. Chemotherapy 

4. Somatostatin analogues e.g. OCTREOTIDE
Dopamine Agonists e.g. BROMOCRIPTINE and CABERGOLINE 
(GH secreting pituitary tumours frequently express D2 receptors)

SOMATOSTATIN ANALOGUES

• Endocrine cyanide’
• Injection: sc (short acting) or monthly depot
• GI side effects common eg nausea, diarrhoea, gallstones can occur
• Reduces GH secretion and tumour size
• Pre-treatment before surgery may make resection easier
• Use post-operatively if not cured or whilst waiting for radiotherapy to take effect (slow)

Question 18

Summarize the function of vasopressin

Answer 18

• Principal effect of vasopressin = ANTI-DIURETIC ie increases water reabsorption from renal cortical and medullary collecting ducts via V2 receptors
• Vasopressin also known as ADH – Anti Diuretic Hormone
• Diuresis = increase in urine production
• Acts on the renal cortical and medullary collecting ducts 

• Stimulates synthesis and assembly of aquaporin 2 

• Aquaporin is inserted to apical membrane
• Increased water transport 

• INCREASED WATER REABSORPTION 

• This has an ANTIDIURETIC effect 

• Acts on V2 receptors 

• Other actions: 


1. Vasoconstrictor Activity - V1a
2. Corticotrophin (ACTH) Release - V1b
3. Factor VIII and von Willebrand Factor - V2
4. Central Effects 


REGULATION OF VASOPRESSIN RELEASE:

ORGANUM VASCULOSUM IS DEVOID OF A BBB – SO COMMUNICATES WITH THE SYSTEMIC CIRCULATION

Senses changes in plasma osmolality

1. Osmoreceptor - sensitive to changes in EC osmolality
2. Increase in extracellular Na+
3. Water comes out to the EC space
4. Receptor shrinks
5. INCREASED OSMORECEPTOR FIRING
6. VP RELEASE FROM HYPOTHALAMIC PVN & SON NEURONES

Question 19

Diabetes insipidus: recall the pathophysiology of diabetes insipidus (cranial vs nephrogenic), list the principle causes

Answer 19

DIABETES INSIPIDUS (DI):

1. Cranial or central: Absence or lack of circulating vasopressin
2. Nephrogenic: End-organ (kidneys) resistance to vasopressin

Diabetes Insipidus - Aetiology

Central (Cranial) 


• Damage to the neurohypophysial system 


1. Injury to neurohypophysis

2. Surgery
Cerebral thrombosis

3. Tumours (intrasellar and suprasellar)
4. Granulomatous infiltration of median eminence 


• Idiopathic 

• Familial (Congenital) (RARE) - usually receptor gene mutations

Nephrogenic 


1. Congenital – rare (e.g. mutation on gene encoding V2 receptor, aquaporin 2 type water channel)
2. Acquired / Drugs 
E.g. lithium- used in manic-depression, dimethyl chlortetracycline(DMCT)

SIGNS AND SYMPTOMS

• Large volumes of urine (polyuria)
• Urine very dilute (hypo-osmolar)
• Thirst and increased drinking (polydipsia)
• Dehydration (and consequences) if fluid intake not maintained - can lead to DEATH
• Possible disruption to sleep with associated problems
• Possible electrolyte imbalance

Question 20

Diabetes insipidus vs psychogenic polydipsia

recall and explain the clinical features, explain how diagnosis may be made,

Answer 20

DI cycle

1. INADEQUATE PRODUCTION OF/RESPONSE TO VP
2. LARGE VOLUMES OF DILUTE (HYPOTONIC) URINE
3. INCREASE IN PLASMA OSMOLALITY (AND SODIUM)
4. REDUCTION IN EC FLUID VOLUME
5. THIRST - POLYDIPSIA
6. EC FLUID VOLUME EXPANSION

• If they’re lacking vasopressin then you can’t reabsorb water so that leads to an increase in watery urine excretion and a reduction in extracellular fluid volume 

• This leads to an increase in plasma osmolarity so that will lead to osmoreceptors triggering vasopressin release and it will trigger thirst 

• This will result in an increase in drinking, decrease in plasma osmolarity and an expansion of extracellular fluid volume 

• Normal range for plasma osmolarity: 
When the patient presents they may have a normal plasma osmolarity if they are well hydrated


Another condition that presents in a similar way is polydipsia - large volumes of urine and increased drinking 


PSYCHOGENIC POLYDIPSIA

• Most frequently seen in psychiatric patients – aetiology unclear, may reflect anti-cholinergic effects of medication – ‘dry mouth’
• Can be in patients told to ‘drink plenty’ by healthcare professionals
• Excess fluid intake (polydipsia) and excess urine output (polyuria) – BUT unlike DI, ability to secrete vasopressin in response to osmotic stimuli is preserved

Cycle

1. INCREASED DRINKING (POLYDIPSIA)
2. EXPANSION OF EC FLUID VOLUME, REDUCTION IN PLASMA OSMOLALITY
3. LESS VP SECRETED BY POSTERIOR PITUITARY
4. LARGE VOLUMES OF DILUTE (HYPOTONIC) URINE
5. EC FLUID VOLUME RETURNS TO NORMAL

• There is a central disturbance and this increases the drive to drink 

• This leads to a fall in plasma osmolarity which means that vasopressin is 
inhibited and so you produce large volumes of urine 

• The increase in urine excretion reduces the ECFV and increases plasma 
osmolarity

1. FLUID DEPRIVATION TEST - this should stimulate the vasopressin system 


• Measures urine osmolality while deprived from fluids

Diabetes insipidus plasma osmolality: 290mmol / Psychogenic 270 mmol

• Plasma osmolarity in diabetes insipidus approximately normal (hydrated)
• Psychogenic polydipsia – Vasopressin system works so osmolarity more diluted so lower

2. Stimulation with Hypertonic Saline IV 


• Some places can measure plasma vasopressin 

• This gives you another way of stimulating the osmoreceptors without waiting for the patient to get dehydrated 

• You can give the patient hypertonic saline I.V. and this quickly increases plasma osmolarity and should stimulate AVP release 

• Normals, polydipsics and patients with nephrogenic diabetes insipidus will show a rapid increase in plasma vasopressin 

• Patients with Central Diabetes Insipidus will show NO change in plasma vasopressin

Question 21

Diabetes insipidus - Psychogenic polydipsia biochemical features

Answer 21

DIABETES INSIPIDUS: BIOCHEMICAL FEATURES

1. Hypernatraemia
2. Raised urea
3. Increased plasma osmolality
4. Dilute (hypo-osmolar) urine - ie low urine osmolality

PSYCHOGENIC POLYDIPSIA: BIOCHEMICAL FEATURES

1. Mild hyponatraemia – excess water intake
2. Low plasma osmolality
3. Dilute (hypo-osmolar) urine - ie low urine osmolality

• A normal person will release AVP (arginine vasopressin) and concentrate the urine so the urine osmolarity increases and plasma osmolarity will remain normal 

• In psychogenic polydipsia, the vasopressin system is working fine 

• When they are dehydrated they will release vasopressin and they will also concentrate their urine

• The urine osmolarity is slightly lower than a normal person because over a long period of time you will start to wash out the osmotic gradient that is necessary for AVP to exert its antidiuretic effect 

• With central and nephrogenic diabetes insidus they have no/little change 


Change in Urine Osmolarity with Plasma Osmolarity 


• As someone gets more and more dehydrated, their plasma osmolarity goes up and, in a normal person, their urine osmolarity should go up considerably as well 

• In a DI patient, urine osmolarity barely increases at all 


Question 22

Recall treatment modalities of diabetes insipidus

Answer 22

TREATMENT OF CRANIAL DIABETES INSIPIDUS

1. Exogenous Vasopressin
2. Desmopressin – V2 receptor agonist that mimics the effects of vasopressin
   Administration
   
   1. Nasally
   2. Orally
   3. SC

• Reduction in urine volume and concentration in cranial DI
• CARE – to tell patient starting this NOT to continue drinking large amounts of fluid – risk of hyponatraemia

Desmopressin (DDAVP) 

You are giving extra vasopressin so this will concentrate the urine of a normal person and the person with polydipsia


• The NEPHROGENIC diabetes insipidus patient will not respond because they have vasopressin anyway it just doesn’t have any effect 


TREATMENT OF NEPHROGENIC DIABETES INSIPIDUS

Thiazides, e.g bendroflumethiazide

•Possible mechanism

–Inhibits Na+/Cl- transport in distal convoluted tubule (→ diuretic effect)

–Volume depletion

–Compensatory increase in Na+ reabsorption from the proximal tubule (plus small decrease in GFR, etc.)

–Increased proximal water reabsorption

–Decreased fluid reaches collecting duct

–Reduced urine volume

Stimulation with Hypertonic Saline IV 


• Some places can measure plasma vasopressin 

• This gives you another way of stimulating the osmoreceptors without waiting for the patient to get dehydrated 


You can give the patient hypertonic saline I.V. and this quickly increases plasma osmolarity and should stimulate AVP release

• Normals, polydipsics and patients with nephrogenic diabetes insipidus will show a rapid increase in plasma vasopressin 

• Patients with Central Diabetes Insipidus will show NO change in plasma vasopressin

Question 23

SIADH: recall the pathophysiology of syndrome of inappropriate antidiuretic hormone (SIADH), list the principle causes, recall the clinical features

Answer 23

The Syndrome of Inappropriate ADH (SIADH) 


The plasma vasopressin concentration is INAPPROPRIATELY HIGH for the existing plasma osmolarity. 


1. INCREASED VASOPRESSIN
2. INCREASED H20 REABSORPTION FROM RENAL COLLECTING DUCTS
3. EXPANSION OF ECF VOLUME
4. HYPONATRAEMIA -ATRIAL NATRIURETIC PEPTIDE (ANP) FROM RIGHT ATRIUM
5. NATRIURESIS

• Also a decrease in urine volume 

• When AVP levels are really high you get a slight natriuresis - you get more 
sodium excreted in the urine 

• This may be a physiological mechanism to try and get more fluid to be excreted 


Signs of SIADH: 


1. Raised urine osmolarity

2. Decreased urine volume (initially)

3. HYPONATRAEMIA - decrease in plasma sodium concentration due to increased water reabsorption 


Symptoms of SIADH: 
Can be asymptomatic


When Na+ concentration falls < 120 mM you get:

• Generalised weakness 

• Poor mental function 

• Nausea 


When Na+ concentration falls <110 mM you get: 


• CONFUSION 

• COMA 

• DEATH 


Causes of SIADH: 


1. CNS – SAH, stroke, tumour, TBI
2. Pulmonary disease –Pneumonia, bronchiectasis
3. Malignancy –Lung (small cell) ectopic secretion)

4. Drug-related –Carbamazepine, SSRI
5. Idiopathic
6. Neurohypophysial malfunction (e.g. meningitis, cerebrovascular disease)

Question 24

Discuss treatment options for SIADH

Answer 24

Treatment of SIADH:

• Appropriate treatment (e.g. surgery for tumour)
• To reduce immediate concern, i.e. hyponatraemia

1. Immediate: fluid restriction
2. Longer-term: use drugs which prevent vasopressin action in kidneys
3. e.g. induce nephrogenic DI ie reduce renal water reabsorption - demeclocyline
4. inhibit action of ADH - V2 receptor antagonists

VAPTANS

–Non-competitive V2 receptor antagonists

–Inhibit aquaporin2 synthesis and transport to collecting duct apical membrane, preventing renal water reabsorption

–Aquaresis – solute-sparing renal excretion of water, contrast with diuretics (diuresis) which produce simultaneous electrolyte loss

–Licensed in the UK for treatment of hyponatraemia associated with SIADH

–Very expensive – limits their current use