Where is the pituitary gland located?
Located at the base of the brain suspended from the hypothalamus by a stalk
What cell type in the pituitary produces TSH?
What cell type in the pituitary produces ACTH?
What cell type in the pituitary produces growth hormone?
Somatotropes - the largest number of cells in pituitary
What cell type in the pituitary produces LH FSH?
What cell type in the pituitary produces prolactin?
Where are the adrenal glands found?
Cap the upper poles of the kidneys and lie against the diaphragm
The adrenal gland consists of two regions, what are they?
- An outer cortex
- An inner medulla
What hormones do the outer cortex of the adrenal gland produce?
1) Mineralocorticoids; Eg Aldosterone
2) Glucocorticoids: Eg Cortisol and corticosterone
3) Androgens; Eg dehydroepiandrosterone (DHEA)
What hormone does the inner medulla produce?
The outermost adrenal cortex can be further subdivided into 3 layers. What are they and what do they produce?
1) Zona glomerulosa (outermost); mineralocorticoids (salts)
2) Zona Fasciculata; glucocorticoids (sugar steroids)
3) Zona Reticularis; Androgens (Sex)
Describe the structure of cortisol
- Member of the C21 steroid family that differ from other steroids in the number of C-atoms, presence of functional groups and distribution of C=C double bonds
Note: All steroids are lipophilic and are synthesised from cholesterol via progesterone in a series of enzyme catalysed reactions
How is cortisol secretion controlled?
- Adrenocorticotropic hormone secreted from the corticotropes of the anterior pituitary is the main factor controlling cortisol release
- ACTH release is subject to corticotrophin releasing factor (CRF) control
What stimulates corticotrophin releasing factor?
Response to physical (temperature, pain), chemical (hypoglycaemia) and emotional stressors
Describe the synthesis of ACTH
- Cleaved from POMC
- α-MSH found found contained within the ACTH sequence so it has some MSH-like activity when in excess
How long is the half life of ACTH and how is it released?
- 8 minutes
- Released in pulses that follow a circadian rhythm
What type of receptor dos ACTh bind to?
- G-protein coupled receptor
- Uses cAMP as a second messenger
- Not to be confused with mechanism of action of steroids
How is cortisol transported in the blood?
- Like all steroids, lipophilic
- Transported bound to plasma protein transcortin
- Carries 90% of plasma cortisol
- Free, unbound cortisol biologically active
Describe the mechanism of action of cortisol
- Can freely cross the plasma membrane
- The hormone-receptor complex enters the nucleus and interacts with a specific area of DNA
- This interaction changes the rate of transcription of specific genes and may take time to occur
Cortisol is an important component of the ______ response and it has a number of important effects on metabolism
What metabolic changes does cortisol elicit?
- Decreased amino acid uptake
- Decrease protein synthesis
- Increased proteolysis (except liver)
- Increased hepatic gluconeogenesis and glycogenolysis
- Increased lipolysis in adipose tissue
- Decreased peripheral uptake of glucose (anti-insulin)
Why can the adrenal medulla be considered a modified sympathetic ganglion?
- Synthesises various catecholamines
- Include the hormone adrenaline
- Include the neurotransmitters noradrenaline and dopamine
How are catecholamines synthesised in the adrenal medulla?
- Synthesised in a series of enzyme-catalysed steps that convert amino acid tyrosine into dopamine
- Dopamine is then converted into noradrenaline
- Noradrenaline is then converted to adrenaline
Where are catecholamines produced in the adrenal medulla stored?
- Stored in the medullary cells in membrane-limited vesicles
What response is adrenaline produced in?
- Fright, flight or fight response Sympathetic nervous system
What are the affects of adrenaline on the body?
- Increased cardiac output and increased blood supply to muscle
- Increased mental alertness
- Increased glycogenolysis in liver and muscles
- Increased lipolysis in adipose tissue
What is a pheochromocytoma?
- A catecholamine secreting tumour of the adrenal medulla
What is associated with a pheochromocytoma? (catecholamines)
- Glucose intolerance
What is a tumour of the adrenal medulla (catecholamines) called?
Define Addison's disease
Hypoactivity of the adrenal cortex
Define Cushing's syndrome
Hyperactivity of the adrenal cortex with increased secretion of GLUCOCORTICOIDS
What is the possible pathology of Addison's disease?
1) Diseases of the adrenal cortex (auto-immune destruction) - reduces glucocorticoids and mineralocorticoids
2) Disorders in pituitary or hypothalamus that lead to decreased secretion of ACTH or corticotrophin-releasing hormone (CRF) - only affect glucocorticoids IMPORTANT
What is the possible pathology of Cushing's syndrome?
1) Increased activity of the adrenal cortex due to tumour (adenoma)
2) Disorders in the secretion of ACTH caused by pituitary adenoma (Cushing's disease) or ectopic secretion of ACTH
Outline the clinical effects of excess cortisol secretion
- Increased muscle proteolysis and hepatic gluconeogenesis may lead to hyperglycaemia with associated polyuria and polydipsia (steroid diabetes)
- Increased muscle proteolysis leading to wasting of proximal muscles producing thin arms and legs and muscle weakness
- Increased lipogenesis in adipose tissue leading to deposition of fat in abdomen, neck and face and producing characteristic body shape, moon face and weight gain
- Purple striae on lower abdomen, upper arms and thighs reflecting the catabolic effects on protein structures in the skin; leads to easy bruising because of thinning skin and subcutaneous tissue
- Immunosuppressive, anti-inflammatory and anti-allergenic reactions of cortisol leading to increased susceptibility to bacterial infections and producing acne
- Back pain and collapse of ribs due to osteoporosis caused by disturbances in calcium metabolism and loss of bone matrix proteins -
Outline the clinical effects of under secretion of cortisol
- Insidious onset with initial non-specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss and occasional dizziness
- Extreme muscular weakness and dehydration
- Increased pigmentation, particularly on the exposed areas of the body, points of friction, buccal mucosa, scars and palmer 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 These effects may be exacerbated by stress such as trauma or severe infection leading to nausea, vomiting, extreme dehydration, hypotension, confusion, fever and even coma (ADDISONIAN CRISIS)
How is an Addisonian crisis treated?
A clinical emergency treated with:
- Intravenous cortisol
- Fluid replacement
- dextrose in normal saline
How can adrenal cortical function be tested?
- Dexamethasone suppression test
- ACTH stimulation test
- Measurement of plasma cortisol and ACTH levels, 24hrs urinary excretion of cortisol and its breakdown products (17-hydroxysteroids)
Explain the Dexamethasone suppression test
A potent synthetic steroid that when given orally would normally suppress, by feedback inhibition, the secretion of ACTH and thus cortisol
If cortisol overly suppressed = Cushing's syndrome; The diseased pituitary will be insensitive to cortisol but will be sensitive to to potent synthetic steroids
Explain the rationale behind synacthen intramuscular administration
- Synacthen is a synthetic analogue of ACTH
- Would normally increase plasma cortisol by 200nmol/L
- A normal response usually excludes Addison's disease
What family of proteins do steroid receptors belong to?
Nuclear DNA binding proteins
Family includes vitamin D and thyroid receptors
What three main regions does a steroid receptor process?
1) A hydrophobic-hormone binding region
2) A DNA-binding region rich in cysteine and basic amino acids
3) A variable region
What effect does aldosterone have on the body?
- Na+ reabsorption in the kidney in exchange for K+ (or H+) Over secretion of aldosterone increases Na+ and water retention and loss of K+ causing hypertension and muscle weakness Under secretion causes hypotension
What affect do androgens have on the body?
- Stimulate the growth and development of male genital tract and male secondary characteristics including height, body shape, facial and body hair, lower pitch voice
What effect does over secretion of androgens have? (especially in women)
Hair growth (hirsutism), acne, menstrual problems, virilisation, increase muscle bulk and deepening voice
What effect do oestrogen have on the body (female) ?
Development of female genital tract, breasts and female secondary characteristics including broad hips, accumulation of fat in breasts and buttocks, body hair distribution
They are weekly anabolic and decrease circulating cholesterol levels
How do you account for a patients abdominal obesity from steroid treatment?
Steroids redistribute muscle to fat
- Increased lipogenesis
- Increased proteolysis, particularly of peripheral muscle (arms and legs)
Outline the major structural differences between the various classes of steroid hormone
- Number of C-atoms
- Presence of functional groups
- Distribution of C=C double bonds
Describe the role of the hypothalamus in the control of pituitary function
- The hypothalamus releases releasing or inhibiting hormones (somatostatin) that act on the anterior pituitary cells
- These hormones travel to the pituitary via the hypophyseal portal vessel
- Releasing and inhibiting hormones allow the brain to control pituitary hormone secretion, and explains, for example how the secretion of hormones can change during stress
Explain why cortisol can have a androgen-like effect when present in high concentrations
- Cortisol acts by binding to cytoplasmic/nuclear receptors
- All steroid receptors have similar basic structure with hormone and DNA binding domains
- Hormone binding domain of glucocorticoid receptors share over 60% homology with mineralocorticoids and androgen receptors
- Therefore, cortisol, in high concentrations can bind to other steroid receptors with limited affinity
Explain why high levels of ACTH can lead to increased pigmentation?
- Pigment (melanin) is produced by melanocytes which are activated by MSH (melanocyte stimulating hormone)
- ACTH and MSH derived from cleavage off of POMC
- MSH sequence contained within ACTH -
ACTH has therefore some MSH-like activity when present in excess
- Therefore, ACTH increases pigmentation due to partial MSH activity
How does ACTH stimulate cortisol secretion?
- Hydrophilic hormone that binds to cell surface melanocyte 2 receptors in the zona fasciculata on cell surface membranes
- Initiates a secondary messenger within a cell which activates conversion of cholesterol ester to free cholesterol and cortisol synthesis