Pituitary and adrenal cortex disorders Flashcards
List the hormones produced by the anterior pituitary gland
TSH ACTH Growth hormone LH & FSH Prolactin
List the hormones produced by the hypothalamus but stored by the posterior pituitary gland
Oxytocin
ADH (vasopressin)
List the hormones produced by the adrenal cortex
Mineralocorticoids - e.g. aldosterone
Glucocorticoids (major)- e.g. cortiosol and corticosterone
Androgens - e.g. degydorpiandrosterone (small amounts)
Describe the structure of adrenaline
It is a water-solible catecholamines (amino acid derived hormone) that is synthesised by enzyme-catalysed steps which convert the amino acid -> tyrosine -> dopamine -> noradrenaline -> adrenaline
What is the function of adrenaline?
Released in response to stressful situations, it stimulates the sympathetic NS. It has effects on:
- CVS - increase cardiac output and blood supply
- CNS - increases mental alertness
- Carbohydrate metabolism - increases glycogenolysis in liver and muscle
- Lipid metabolism - increase lipolysis in adipose tissue
What is the general structure of steroid hormones?
All are lipophilic (hydrophobic) and synthesised from cholesterol via progesterone in a series of enzyme catalysed reactions
How do steroid hormones affect their target tissues?
Steroid hormones (like cortisol) can cross the plasma membranes of target cells. Cortisol binds to cytoplasmic receptors and then the hormone/receptor complex enter the nucleus and interacts with specific regions of DNA. Other steroid hormones bind to pre-bound receptors on DNA. Steriod hormones change the rate of transcription of specific genes and may take some time to occur
What is the effect of ACTH and CRH on cortisol secretion?
CRH - corticotropin releasing hormone is produced in the hypothalamus and stimulates the secretion of ACTH
ACTH - is released from the anterior pituitary and is the main factor contolling secretion of cortisol
How can ACTH lead to increased pigmentation in certain areas of the body?
- The alpha-MSH sequence of 13 amino acids is contained within the ACTH sequence in POMC, giving ACTH some MSH-like activity when present in excess
What are the main actions of cortisol on target cells?
An important component of the stress response - it has a number of effects on metabolism. The major effects are in the starved and stressed states where it affects the availability of all major metabolic substrates by increasing proteolysis, lipolysis and gluconeogenesis.
How can cortisol have weak mineralocorticoid and androgen effects?
There is approximately 64% sequence homology between the glucocorticoid receptor and the mineralocorticoid receptor and approx. 62% with the androgen receptor. Therefore cortisol will bind these receptors with low affinity. This binding may become significant when high levels of the hormone are present.
Where is the pituitary gland located?
At the base of the brain suspended from the hypothalamus by a stalk. It lies in a deep recess of the sphenoid bone (pituitary fossa) surrounded by a small bony cavity (sella turcica)
What is unusual about the bloody supply to the pituitary gland?
It has a portal system - vessel connecting two capillary beds located in separate tissues, one in the hypothalamus and the other in the anterior pituitary
What is the arterial blood supply to the pituitary?
From the superior and inferior hypophyseal arteries arising from the internal carotid artery
From which cells are the anterior lobe of the pituitary derived?
Up-growth of ectodermal cells from the roof of the primitive phaarynx
From which cells are the posterior lobe of the pituitary derived?
Down-growth of neural tissue from the hypothalamus
List the hormones produced by the adrenal medulla
Adrenaline (epinephrine)
What is produced by thyrotropes in the anterior pituitary?
TSH - thyroid stimulating hormone
What is produced by corticotropes in the anterior pituitary?
ACTH - adrenocorticotropic hormone
What is produced by somatotropes in the anterior pituitary (represent the largest number of cells)?
Growth hormone
What is produced by gonadotropes in the anterior pituitary?
LH - luteinising hormone
FSH - follicle-stimulating hormone
What is produced by lactotropes in the anterior pituitary?
Prolactin
Underneath the connective tissue capsule with its plexus of blood vessels (capsular plexus) three zones can be recognised. List the three zones from the superficial to deep
Zona glomerulosa
Zona fasiculata
Zone reticularis
What do the cells in the Zona glomerulosa secrete and what are their functions?
Mineralocorticoids (e.g. aldosterone) that regulate body Na+ and K+ levels
What do the cells in the Zona fasiculata secrete and what are their functions?
Glucocorticoids (e.g. cortisol) that have a number of important functions including the regulation of carbohydrate metabolism
What do the cells in the Zona reticularis secrete and what are their functions?
Glucocorticoids and small amounts of androgens (e.g. dehydroepiandrosterone)
What stimulates the secretion of CRH?
Physical stress - pain, temperature
Chemical stress - hypoglycaemia
Emotional stressors
What creates negative feedback on the corticotropes of the anterior pituitary and the hypothalalmus release of CRH?
glucocorticoids
What type of hormone is ACTH and which receptors does it work on?
hydrophillic polypeptide hormone that targets G-protein coupled receptors (GPCR) on the plasma membrane of target cells. Specifically the GPCR melanocortin receptor type 2 (MC2), which uses cAMP as a second messenger
What is the name of the large protein that is a bio-synthetic precursor to ACTH and what other biologically active peptides does it create?
POMC - proopiomelanocortin
Other precursors:
Alpha-MSH - (melanocyte stimulating hormone)
Endorphins
Why does ACTH concentration need to measured at specific points of the day?
It has a short half-life in circulation (approx. 8 minutes) and is released in pulses that follow a circadian rhythm. Peak plasma levels occur in the early hours of the morning and lowest levels are seen in the late evening
What effect does binding of ACTH on the surface receptors of cells in the zona fasiculata and zona reticularis have?
Leads to activation of cholesterol esterase increasing the conversion of cholesterol esters to free cholesterol, as well as stimulating other steps in the synthesis of cortisol from cholesterol.
What clinical consequences does over-secretion of ACTH have?
- Effects on tissues - increased pigmentation due to partial MSH activity
- Effects on adrenal cortex - adrenal hyperplasia and over-production of cortisol
What clinical consequences does under-secretion of ACTH have?
Produces symptoms related to the lack of glucocorticoids but not mineralocorticoids as aldosterone release is not simulated by ACTH and therefore its secretion is normal
How does cortisol travel in plasma?
It is a steroid hormone and therefore is hydrophobic and must be transported bound to a plama protein. The major transport protein is transcortin (or corticosteroid-binding globulin, CBG) which carries approx. 90% of plasma cortisol - the remaining 10% being free and biologically active
List the metabolic actions of cortisol
Decrease amino acid uptake
Decrease protein synthesis, Increase proteolysis (not liver)
Increase hepatic gluconeogenesis and glycogenolysis
Increase lipolysis in adipose tissue (N.B. high levels of cortisol increase lipogenesis in adipose tissue - think Cushing’s)
Decrease peritheral uptake of glucose (anti-insulin)
What direct effects does cortisol have in addition to its general metabolic actions?
Direct effects on cardiac muscle, bone and immune system
What is synthesised in the adrenal medulla?
Adrenal medulla is in essence a modified sympathetic ganglion. It synthesises various catecholamines, which are stored in membrane-limited vesicle in medullary cells:
- Hormone - adrenaline (epinephrine)
- Neurotransmitters - noradrenaline (norepinephrine) and dopamine
What are the clinical consequences of over-secretion of adrenaline?
This is usually due to a tumour and may be associated with: Hypertension Anxiety Palpitations Pallor Sweating Glucose intolerance
What is Addison’s disease?
Decreased activity (hypoactivity) of the adrenal cortex
What can be the cause of hypoactivity of the adrenal cortex?
- Diseases of the adrenal cortex -> auto-immune destruction - reduces glucocorticoids and mineralcorticoids
- Disorders of the pituitary of hypothalamus -> decreased secretion of CRH of ACTH - only affects glucocortiocoids
What is Cushing’s syndrome?
Increased secretion (hyperactivity) of glucocorticoids
What may cause Cushing’s disease?
- Adenoma - adrenal cortex tumour increasing the cortex activity
- Disorders in the secretion of ACTH caused by pituitary adenoma (Cushing’s disease) or ectopic secretion of ACTH
What is the difference between Cushing’s syndrome and Cushing’s disease?
Cushing’s disease is a disease caused by over-secretion of ACTH by a pituitary adenoma. Cushing’s syndrome is a group of disorders which cause symptoms characteristic of Cushing’s and can be caused by adrenal adenoma and ectopic secretion of ACTH by tumours elsewhere in the body
What is congenital adrenal hyperplasia?
Refers to a number of clinical conditions caused by defects in enzymes that are required for the synthesis of corisol. The corresponding lack of negative feedback from cortisol results in over-secretion of ACTH and enlagement of the adrenal cortex (hyperplasia). The severity and consequences of these conditions depends on which enzyme(s) is affected
What are the characteristic signs of Cusing’s syndrome/ excess cortisol secretion?
Thin arms and legs Large amounts of abdominal fat Moon-shaped face Purple striae - lower abdomen, upper arms and thighs Easy bruising
Why can steroid diabetes occur from excess cortisol secretion?
It stimulates muscle proteolysis and hepatic gluconeogenesis that may lead to hyperglycaemia with associated polyuria and polydipsia.
Why are thin arms and legs a sign of excess cortisol secretion?
Increased muscle proteolysis leads to wasting of proximal muscles
Why is fat deposition in abdomen, neck and face producing a moon-shaped face and weight gain a sign of excess cortisol secretion?
Increased lipogenesis causes by high levels of cortisol (cortisol at lower levels causes increased lipolysis)
Why are purple striae on lower abdomen, upper arms and thighs, a sign of excess cortisol secretion?
Proteolysis in skin leads to easy bruising because of the thinning of skin and subcutaneous tissue
Why does excess cortisol secretion cause a susceptibility to bacterial infection and increased acne?
Cortisol causes immunosuppressive, anti-inflammatory and anti-allergic reactions
Why can excess cortisol secretion cause osteporosis and therefore back pain and collapse of ribs?
It can disturb calcium metabolism resulting in loss of bone matrix protein
What mineralocorticoid effects can excess cortisol produce?
Hypertension due to sodium and fluid retention
What can cause exogenous Cushing’s Syndrome?
prescribed glucocorticoids e.g. Prednisolone for treatment of inflammatory disorders:
- asthma
- IBD
- rheumatoid arthritis
- Other autoimmune conditions
What is the name of the acute emergency that can result from the auto-immune destruction of the adrenal gland?
Addisonian crisis
What is the name of the chronic debilitating disorder that can result from the auto-immune destruction of the adrenal gland?
Addison’s Disease
What can cause Addison’s disease to be exacerbated leading to an Addisonian crisis?
Exacerbation by stress such as trauma or severe infection
What are the signs and symptoms of an Addisonian crisis?
nausea vomiting severe dehydration hypotension confusion fever and even coma and death
Addisonian crisis is a clinical emergency that can lead to coma and death if not correctly diagnose and treated. How is it treated?
Intravenous cortisol Fluid replacement (dextrose in normal saline)
What are the signs and symptoms of Addison’s disease?
- Insiduous onset with non-specific symptoms of tiredness, extreme muscle weakness, anorexia, vague abdominal pain, weight loss and occasional dizziness
- Extreme muscular weakness and dehydration
- INCREASED PIGMENTATION on exposed areas of the body, points of friction, buccal mucosa, scars and plamar creases due to ACTH-mediated melanocyte stimulation
- Decreased blood pressure due to sodium and fluid depletion
- Postural hypotension due to fluid depletion
- Hypoglycaemic episodes on fasting
What is the function of the mineralocorticoid, aldosterone?
Aldosterone stimulates Na+ reabsorption in the kidney in exchange for K+ (or H+)
What is the effect of oversecretion of the mineralocortiocoid, aldosterone?
Oversecretion of aldosterone increases Na+ absorption and water reabsorption and loss of K+ - causing hypertension and muscle weakness (K+ is crucial in heart function and plays a key role in skeletal and cardiac muscle contraction)
What is the effect of oversecretion of the mineralocortiocoid aldosterone?
Undersecretion of aldosterone decreases Na+ reabsorption and water reabsorption and K+ is retained - causing hypotension
What is the function of androgens (male sex hormones)?
They stimulate the growth and development of the male genital tract and male secondary sexual characteristics including height, body shape, facial and body hair, lower pitch. They also have anabolic actions especially on muscle protein.
What is the effect of oversecretion of androgens?
Produces effects in females such as: hair growth, acne, menstrual problems, virilisation, increased muscle bulk, deepening voice
What is the effect of oestrogens?
Stimulate growth and development of the female genital tract, breasts and female secondary characteristics including broad hips, accumulation of fat in breasts and buttocks, body hair distribution. They are weakly anabolic and decrease circulating cholesterol levels.
What are the three endogenous causes of Cushing’s syndrome?
- Ectopic cause: tumour (e.g. lung tumour) that can secrete ACTH, but is not part of the negative feedback loop
- Adrenal cortex tumour: increased cortisol secretion
- Pituitary tumour: increased ACTH secretion
How do you test for the presence or absence of Cushing’s syndrome?
- Urine test for cortisol levels (and break-down products) - over 24hrs
Or - Low dose of Dexamethasone (potent synthetic steroid) at night - a normal response would be a greater that 50% increase in cortisol secretion - if this does not happen you have Cushing’s
How do you test where the malfunction that is causing Cushing’s is occuring?
Measure plasma ACTH levels:
- Low ACTH suggest adrenal problem
- High ACTH suggests ectopic or pituitary problem
How do you differentiate High ACTH levels in Cusing’s disease that are caused by a pituitary or ectopic problem?
Dexamethasone supression test. Give oral dose of Dexamethasone:
- Ectopic - expect no response as not part of negative feedback loop
- Pituitary - expect some sensitivity and response as Dex is a potent steroid and therefore would expect a drop in ACTH levels and consequently cortisol levels
What test can exclude Addinson’s disease?
Administration of Synacthen (synthetic analogue of ACTH) intramuscularly - would normally expect an increase in plasma cortisol by >200nmol/L. A normal response can exclude Addinson’s disease.
What are the signs and symptoms of Cushing’s disease?
Plethoric (flushed) Moon-shaped face Abdominal obesity Purple striae Acute weight gain Hyperglycaemia Hypertension
Why should prescribed corticosteroids not be stopped suddenly?
They inhibit the release of CRH from the hypothalamus and ACTH from the anterior pituitary by negative feedback. If they are stopped suddenly the body does not have time to immediately synthesis the concentration of CRH and ACTH that is needed to stimulate endogenous corticosteroid release, therefore results in an adrenal crisis (like that of an Addisonian crisis)
What are the net effects of increased cortisol secretion?
Increased glucose production (gluconeogenesis)
Breadown of protein
Redistribution of fat
In Cushing’s syndrome what specific areas show increased fat depostion?
Abdomen
Supraclavicular -> fat pads
Dorsocervical -> buffalo hump
On face -> moon-shaped face
Why does muscle wastage in the arms and legs occur?
- Cortisol inhibits insulin induced GLUT4 translocation in muscle which prevents glucose uptake and therefore glucose utilisation
- Increase proteolysis and decreased proteogenesis occur
What are the signs and symptoms of Addinson’s disease?
More common in woman than men Postural hypotension Lethargy Weight loss Anorexia Increased skin pigmentation Hypoglycaemia
How would you treat Addinson’s disease?
Sometimes underlying cause of AD can be treated e,g, TB with antibioics. Often cause is unknown and is treated with:
Corticosteroid replacement therapy (for cortisol and aldoesterone) - three doses when wake, noon and early eve to mimic natural cycle of corticosteroid release
What are causes of Addinson’s disease?
Most common: destructive atrophy from autoimmune response
fungal infection
adrenal cancer
adrenal haemorrhage (e.g. following trauma)
tuberculosis
What are the symptoms of an Addisonian crisis?
Nausea Vomiting Pyrexia Hypotension Vascular collapse
Addisonian crisis is a life threatening emergency due to adrenal insufficiency. What can it be precipitated by?
Severe stress Salt deprivation Infection Trauma Cold exposure Over exertion Abrupt steroid drug withdrawal
What can cause Cushing’s syndrome?
Increased activity of the adrenal cortex due to a tumour (adenoma)
What can cause Addinson’s disease?
Reduced glucocorticoid and mineralocorticoid secretion due to autoimmune destruction of the adrenal cortex
What type of hormone is aldosterone?
Steroid hormone
List some types of steroid hormone
Aldosterone, cortisol, testosterone, oestrogen - all derived from cholesterol
