Hyposecretion of Anterior Pituitary Hormones Flashcards
What is the term given to decreased secretion of ALL anterior pituitary hormones?
Panhypopituitarism
What is Sheehan’s syndrome? Explain its pathophysiology.
This is specific to WOMEN
Specifically describes post-partum hypopituitarism secondary to hypotension (caused by post partum haemorrhage - PPH)
During pregnancy, there is an increase in lactotroph cell number (lactotroph hyperplasia) for breastfeeding - the increase in size of the pituitary gland means it is more metabolically active
Lack of blood flow to the pituitary gland (ischaemia) due to hypotension leads to pituitary infarction (tissue death) as the increased metabolic demands are not being met
What is pituitary apoplexy?
Intra-pituitary haemorrhage or (less commonly) infarction (i.e. tissue death)
Why is a single measurement of most hypothalamic hormones not useful?
Most hypothalamic hormones tend to be released in pulses
What type of test do you do to test if someone is producing a hormone?
Stimulation/provocation test
How are the releasing hormones administered in these tests?
Intravenous
What is the name given to the secondary endocrine gland failure that results from a lack of corticotrophin release from the pituitary?
Hypoadrenocorticalism
What are the effects of a lack of GH (somatotrophin) in children and in adults?
Children – short stature (=2 SDs < mean height for children of that age and sex)
Adults – loss of GH effects are uncertain
State some genetic and acquired causes of GH deficiency in children.
Genetic:
Deficiency of hypothalamic GHRH
Mutations of GH gene
Developmental abnormalities (e.g. aplasia or hypoplasia of the pituitary gland)
Acquired:
Tumours of the hypothalamus and pituitary
Other intracranial tumours nearby (e.g. optic nerve glioma)
Irradiation
Head injury
Infection or inflammation
Severe psychosocial deprivation
What are most endocrine-related causes of short statue due to (with reference to the HP axis)?
Decreased production of GHRH
As well as being its own hormone, GH stimulates the production of other hormones. State one important hormone that is stimulated by GH, its side of production and its effects.
IGF I = insulin-like growth factor I
It is produced in the LIVER
It mediates growth effects
What type of dwarfism is caused by a GH receptor defect?
Laron Dwarfism
Describe the IGF I levels in people with this type of dwarfism.
LOW IGF I
Because functioning GH receptors are necessary for GH to stimulate the production of IGF I
Why are the Pygmies in Africa naturally short?
Their IGF I doesn’t function properly
Using GnRH as an example. State and describe two examples of tertiary hypopituitarism.
Kallmann’s Syndrome
Hypogonadism + Anosmia
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 affects the migration of neurones involved in olfaction (which causes anosmia)
Prader-Willi Syndrome
Hypogonadism is one of the aspects of this disorder and the problem is at the level of the hypothalamus
What is the gold standard method of testing the ability of the pituitary to release growth hormone?
Insulin-induced hypoglycaemia
Hypoglycaemia is a potent stimulus for growth hormone release
State three other triggers for an increase in GH release.
Arginine
Glucagon (seems odd as this increases blood glucose but it turns out that in people who have GH deficiency, glucagon is good at stimulating growth hormone release)
Exercise
Describe how the insulin-induced hypoglycaemia test is used to test GH secretion.
In a normal subject, the insulin-induced hypoglycaemia will give a massive rise in GH secretion
If you have a partial deficiency of GH then your response will be reduced
For each of the following anterior pituitary hormone deficiencies, state the replacement used and the parameter that is monitored during treatment: ACTH TSH Women - LH/FSH Men - LH/FSH GH
ACTH: Give hydrocortisone (cortisol drug) Monitor serum cortisol TSH: Give thyroxine Monitor serum T4 Women – LH/FSH: Give oestradiol (E2 - an oestrogen) and progestogen (a substance which binds to and activates the progesterone receptor) Monitor libido and oestrogen deficiency Men – LH/FSH: Give testosterone Monitor libido and serum testosterone GH: Give GH Monitor IGF I (because GH stimulates IGF I production by the liver)
State some of the effects of growth hormone therapy in children.
Increased linear growth
Decease in body fat
Younger children respond better
Obese children respond better
What is a problem with growth hormone therapy in children?
Tolerance may develop so you need to think about when to start GH therapy
How is the human recombinant GH used in GH therapy administered and how frequently must it be given?
Subcutaneous or Intramuscular
It is given daily or 4/5 times a week
Describe the absorption, metabolism and duration of action of the drug.
It has a maximal plasma concentration after 4-6 hours
Metabolism – renal and hepatic with a short half-life (20 mins)
Duration of action – it works on protein synthesis so it’s duration of action is going to be quite long.
IGF I levels peak after around 20 hours
State some adverse effects of GH therapy.
Lipoatrophy at the site of administration Intracranial hypertension
Headaches (due to intracranial hypertension)
GH is also a cell stimulation hormone so there is an increased risk of tumours
State some signs and symptoms of GH deficiency in adults.
Decreased muscle mass Increased adiposity Increased waist: hip ratio Decrease HDL and increased LDL Reduced muscle strength and bulk Impaired psychological wellbeing and quality of life
How can you diagnose GH deficiency in adults?
Lack of response to GH stimulation test (e.g. insulin-induced hypoglycaemia)
Low plasma IGF I
Low plasma IGF-BP3
What are the potential benefits of GH therapy in adults?
Improved body composition
Improved muscle strength and exercise capacity Normalisation of HDL-LDL
Increased bone mineral content
Improved psychological and mental wellbeing and quality of life
What are the potential risks of GH therapy in adults?
Increased risk of cardiovascular accidents
Increased growth of soft tissue e.g. cardiomegaly
Increased susceptibility to cancer
What are the hormones secreted by the anterior pituitary?
FSH/LH (gonadotrophins) Prolactin GH TSH (thyrotrophin) ACTH (corticotrophin)
What is a primary endocrine gland disease?
There is a problem with the peripheral endocrine gland so the required hormone is not being released
EXAMPLE: thyroid gland dysfunction so T3 and T4 not released
What is a secondary endocrine gland disease?
There is a problem with the pituitary gland so there is no signal to the peripheral endocrine gland to release the required hormone
EXAMPLE: anterior pituitary problem results in no TSH being released so there is no signal to the thyroid gland to relase T3 and T4
What is a tertiary endocrine gland disease?
There is a problem with the hypothalamus (releases hormones which have an inhibitory/stimulatory effect on anterior pituitary hormones)
EXAMPLE: TRH not released to signal to anterior pituitary to release TSH
Define hypopituitarism.
Decreased production of anterior pituitary hormones
Can be of all or specific hormones
It can be congenital (rare) or acquired
What can congenital panhypopituitarism be caused by?
Usually due to mutations of transcription factor genes needed for normal anterior pituitary development
EXAMPLE: PROP1 mutation - transcription factor which helps in the differentiation of the anterior pituitary cells (e.g. gonadotrophs, lactotrophs etc.)
Which hormones are patients with congenital hypopituitarism most commonly deficient in?
Growth hormone and at least one more anterior pituitary hormone
What do patients with congenital panhypopituitarism present with?
Short stature (due to GH deficiency) Hypoplastic anterior pituitary gland on MRI NOTE: hypoplastic = when an organ/tissue has not completely developed (below-normal number of cells)
What can acquired panhypopituitarism be caused by?
COME BACK TO THIS
Tumours:
hypothalamic - craniopharyngiomas (benign - grow just above the pituitary gland, near the base of the brain)
pituitary – adenomas (benign), metastases (cancerous), cysts (fluid filled lump)
Radiation:
hypothalamic/pituitary damage - radiation causes cell DNA damage, so can cause mutations or if the damage is excessive
GH most vulnerable, TSH relatively resistant
Infection eg meningitis
Traumatic brain injury
Infiltrative disease – often involves pituitary stalk
eg neurosarcoidosis
Inflammatory (hypophysitis)
Pituitary apoplexy
haemorrhage (or less commonly infarction)
Peri-partum infarction (Sheehan’s syndrome)
EXPLANATION:
All of these factors
What is panhypopituitarism occasionally called?
Simmond’s disease
How does panhypopituitarism present?
Symptoms due to deficient hormones and their individual functions
FSH/LH:
Secondary hypogonadism (oestrogen/testosterone deficiency)
Reduced libido (sexual drive/desire)
Secondary amenorrhoea (not primary because not a problem with the ovaries)
Erectile dysfunction
ACTH:
Secondary hypoadrenalism (cortisol deficiency)
Fatigue - brain lacks glucose and hence energy (cortisol is part of the normal stress response and stimulates and increase in blood glucose concentration)
TSH:
Secondary hypothyroidism (T3 and T4 deficiency)
Fatigue (reduced BMR)
How does Sheehan’s syndrome present?
Lethargy (lack of energy/enthusiasm) - TSH/ACTH/GH deficiency (all have metabolic effects; TSH increases BMR & ACTH/GH increases blood glucose levels)
Anorexia and weight loss - ACTH deficiency (cortisol increases appetite and
Failure of lactation – Prolactin deficiency
Failure to resume menses post-delivery - FSH/LH deficiency
Posterior pituitary usually not affected
Why is the posterior pituitary usually not affected in Sheehan’s syndrome?
Because it has a direct arterial supply, whereas the anterior pituitary has a low pressure portal venous system supply so is more susceptible to ischaemia due to hypotension
What condition is pituitary apoplexy connected to?
PITUITARY ADENOMAS
It often presents dramatically (i.e. suddenly) in patients with pre-existing pituitary tumours (adenomas)
It may be the first indication that a pituitary adenoma is present
Pituitary tumours could compress the blood supply to the pituitary gland causing infarction
Pituitary tumours can also increase the risk of haemorrhage - maybe due to tumour cells having a different higher pressure blood supply or the blood vessels supplying them have structural abnormalities making them more prone to damage
What can pituitary apoplexy be precipitated by?
Anticoagulants - blood thinners so increases the risk of haemorrhage (blood escapes more quickly out of BVs)
What are the symptoms of pituitary apoplexy?
SEVERE sudden onset headache due to increased pressure (around pituitary gland) Visual field defect – compressed optic chasm (just above pituitary gland) leading to bitemporal hemianopia Cavernous sinus (surrounding pituitary gland) involvement may lead to diplopia (IV, VI), ptosis (III) NOTE: intra-pituitary haemorrhage means bleeding into the pituitary gland but as bleeding continues some of this blood may leak out and compress surrounding structures
What is bilateral hemianopia?
Loss of vision in the outer/peripheral half of both the right and left eye
What is diplopia? Explain involvement of cranial nerves.
Double vision - due to compression of trochlear nerve (IV) and abducens nerve (VI) both innervate extrinsic eye muscles so are responsible for eye movement
What is ptosis? Explain involvement of cranial nerves.
Drooping eyelid - due to compression of the oculomotor nerve (III) which innervates extrinsic eye muscles including the one that raises the eyelid
What are the two forms of hypopituitarism diagnosis?
Biochemical
Radiological
What are the two types of biochemical diagnosis for hypopituitarism?
Determining basal (minimal) plasma concentrations of pituitary or target endocrine gland hormones Stimulated (‘Dynamic’) Pituitary Function Tests
What is the problem with trying to determine plasma hormone concentrations?
The hormones that we are measuring for are not released at a constant rate so results can be difficult to interpret
Cortisol is released in different amounts during the day - peaks in the morning when you wake up and then falls throughout the day (circadian rhythm)
GH and ACTH are released in a pulsatile fashion
FSH and LH are released in a cyclical fashion (i.e. according to the menstrual cycle)
It is important to bear in mind circulating half life when interpreting hormone levels (e.g. T4 - 6 days)
How do stimulated pituitary function tests work?
IN GENERAL: we provide the patient with certain stimuli which should stimulate the release of anterior pituitary hormones to determine if a normal or sub-normal amount is being released
ACTH & GH = ‘stress’ hormones
We use this to induce ‘stress’ in patients by insulin-induced hypoglycaemia (as excessive insulin means excessive reduction of blood glucose levels)
This stimulates GH ad ACTH release (but cortisol measured as an indication of ACTH secretion as it is easier to measure)
NOTE: Hypoglycaemia (<2.2mM) = ‘stress’
TRH can be administered to stimulate TSH release
GnRH can be administered to stimulate FSH & LH release
How does radiological diagnosis of hypopituitarism work?
Pituitary MRI scan
May reveal specific pituitary pathology (e.g. haemorrhage (apoplexy), adenoma)
Can also be used to see ‘empty sella’ - a condition where the pituitary gland appears shrunken or flattened within the sella turcica on the scan
State some possible causes of short stature
Genetic Emotional Deprivation Systemic disease Malnutrition Malabsorption Endocrine Disorders Skeletal dysplasias Achondroplasia, osteogenesis imperfecta
Give examples of genetic disorders which would cause short stature.
Down’s syndrome
Turner’s syndrome
Prader Willi syndrome
Explain how emotional deprivation causes short stature.
It creates an environment of extreme stress so body focuses on that and diverts the body’s resources away from things which are not immediately important like growth so leads to GH deficiency
Explain how systemic disease causes short stature.
EXAMPLES:
Cystic Fibrosis - pancreatic insufficiency leads to malabsorption
Rheumatoid arthritis - autoimmune inflammation of tissues and organ systems including joints and ligament leads to stunted growth
Explain how malnutrition causes short stature.
Body doesn’t receive enough nutrients required to have energy for growth
Explain how malabsorption causes short stature.
Body cannot absorb enough nutrients
Can be caused by coeliac disease - autoimmune inflammation of the small intestine when you eat gluten)
Give examples of genetic disorders which would cause short stature.
Cushing’s syndrome - protein catabolism leads to reduction in muscle mass and osteoporosis
Hypothyroidism - BMR too low for efficient growth
GH deficiency
Poorly controlled T1DM - glucose cannot be used to provide fuel for metabolism so lack of energy for growth
Explain what skeletal dysplasia is and how it causes short stature.
Skeletal dysplasia = group of genetic disorders which result in abnormalities in cartilage and bone growth
EXAMPLES:
Achondroplasia - problem with conversion of cartilage to bone during early development
Osteogenesis imperfecta - abnormal collagen structure which leads to defects in the mineralisation process of bones causing brittle bones
Describe the growth axis (also known as the hypothalamic-pituitary-somatotrophic axis).
Hypothalamus secretes GHRH (stimulatory - dominant) OR somatostatin (inhibitory) into the anterior pituitary
GHRH stimulates anterior pituitary to release GH (somatotrophin)
GH can have a variety of metabolic actions on its own
GH can also act on the liver, stimulating production of somatomedins (mainly IGF I and also IGF II)
IGF I can also have metabolic actions on target tissues, similar to the actions of GH
IGF II also has metabolic effects but is more effective during foetal development
What is the problem in Prader Willi syndrome which leads to short stature?
Lack of GHRH released from hypothalamus due to hypothalamic dysfunction
What is the problem in pituitary dwarfism which leads to short stature?
Lack of GH released from somatotrophs in the anterior pituitary
What is the problem in Laron dwarfism which leads to short stature?
GH receptor defect so it cannot have its metabolic effects on target tissues
What is the problem with HRT?
Because anterior pituitary hormones are not generally secreted at a steady rate throughout the day unlike drugs, it is hard for drugs to match their secretion (i.e. hard to get for example pulsatile secretory effect with drugs)
Therefore, patients don’t always feel completely better with HRT
However, doses can be adapted - e.g. can give higher dose of cortisol in the morning when patient wakes up and lower dose in the evening to try and match natural secretion
