Where are the adrenal glands situated?
Adrenal glands are situated on the superior pole of the kidney in the retroperitoneal space
How much do the adrenal glands weigh?
~4g each
How does the anatomy of the left and right adrenal glands differ?
Left adrenal vein drains into left renal vein, while R adrenal drains directly into the inferior vena cava. Implications for surgery.
What are the 2 endocrine glands that make up the adrenals?
- Adrenal medulla
- Adrenal cortex
What is the adrenal medulla?
A modified sympathetic ganglion derived from neural crest tissue.
What does the adrenal medulla secrete?
Secretes catecholamines, mainly epinephrine (adrenaline), also norepinephrine and dopamine
What is the adrenal cortex?
A true endocrine gland derived from mesoderm
What does the adrenal cortex secrete?
- Mineralocorticoids e.g. aldosterone: involved in the regulation of Na+ and K+
- Glucocorticoids e.g. cortisol: involved in maintaining plasma glucose
- Sex steroids e.g. testosterone
What 2 hormones are essential for life?
- Cortisol
- Aldosterone
Describe the structure of the adrenal glands.
Cortex surrounds the medulla and is arranged in 3 concentric zones:
- Zona glomerulosa
- Zona fasciculate
- Zona reticularis
What does the zona glomerulosa secrete?
Aldosterone
What does the zona fasciculate secrete?
Glucocorticoids
What does the zona reticularis secrete?
Sex hormones
How are different products produced in the different adrenal zones?
All steroid hormones are derived from cholesterol, but different enzymes are found in different adrenal zones, resulting in different end products
What are the main products of the adrenal cortex?
- Cortisol
- Aldosterone
What is the prehormone of testosterone and oestrogen?
DHEA
What happens to DHEA with age?
Marked decline
What is a common cause of congenital adrenal hyperplasia?
Defects in 21-hydroxylase
What does congenital adrenal hyperplasia result in?
Deficiency of aldosterone and cortisol and associated disruption of salt and glucose balance.
Why is there excessive adrenal androgen production in congenital adrenal hyperplasia?
Androgen biosynthesis is unaffected so accumulating steroid precursors are channelled into excessive adrenal androgen production
What effect does an increase in cortisol have on CRH?
Negative feedback effect> decrease
Why does a deficit in 21-hydroxylase cause adrenal hyperplasia?
- Lack of 21-hydroxylase inhibits synthesis of cortisol.
- This removes the negative feedback on ACTH and CRH release.
- Increased ACTH secretion is responsible for enlargement of adrenal glands.
- Negative feedback of ACTH on CRH synthesis remains.
What type of hormone is cortisol?
Glucocorticoid hormone
What do glucocorticoid hormones influence?
Glucose metabolism
What do ALL nucleated cells have?
Cytoplasmic glucocorticoid receptors
What is ~95% of cortisol bound to?
A carrier protein, cortisol binding globulin (CBG)
Briefly describe how cortisol binding to its receptor leads to translation
The hormone receptor complex migrates to the nucleus, binding to DNA via a hormone-response element to alter gene expression, transcription and translation
Describe the characteristic pattern shown by plasma levels of cortisol.
There is a marked circadian rhythm, preceded by a similar pattern of release of ACTH. Cortisol “burst” persists longer than ACTH burst because half-life is much longer.
When do cortisol plasma levels peak?
~6-9am
When is the nadir of cortisol plasma levels?
~midnight
Why are there fluctuations of cortisol plasma levels during the day?
Due to effects of other stimuli which are related to stress
Why does removal of the adrenal glands result in death?
- Loss of cortisol means animals cannot deal with stress, particularly in terms of maintaining blood glucose levels. Cortisol as a glucocorticoid is crucial in helping to protect the brain from hypoglycaemia.
- Removal of adrenal glands also renders animals incapable of maintaining their extracellular fluid volume, an effect mediated by aldosterone
Why is the permissive action of cortisol on glucagon vital?
It has a permissive action on glucagon, which is vitals as glucagon alone is inadequate in responding to a hypoglycaemic challenge
What are the 4 actions of cortisol on glucose metabolism (glucocorticoid actions)?
- Gluconeogenesis
- Proteolysis
- Lipolysis
- Decreases insulin sensitivity of muscles and adipose tissue
How is cortisol involved in gluconeogenesis?
Cortisol stimulates formation of gluconeogenic enzymes in the liver thus enhancing gluconeogenesis and glucose production. This is aided by cortisol’s action on muscle
How is cortisol involved in proteolysis?
Cortisol stimulates the breakdown of muscle protein to provide gluconeogenic substrates for the liver
How is cortisol involved in lipolysis?
Cortisol stimulates lipolysis in adipose tissue which increases [FFA] plasma creating an alternative fuel supply that allows [BG] to be protected while also creating a substrate (glycerol) for gluconeogenesis
Why is cortisol said to be diabetogenic?
Cortisol acts to oppose insulin
What are the 4 non-glucocorticoid actions of cortisol?
- Negative feedback on Ca balance
- Impairment of mood and cognition
- Permissive effects on norepinephrine
- Suppression of the immune system
How does cortisol have a negative effect on Ca balance?
Decrease absorption from gut, increases excretion at kidney resulting in net Ca2+ loss. Also increase bone resorption leads to osteoporosis
What changes in mood are associated with excess cortisol?
Depression and impaired cognitive function
Describe the permissive effects that cortisol has on norepinephrine.
- Particularly in vascular smooth muscle (a-receptor effect = vasoconstrictive).
- Cushings Disease (hypercortisolaemia) is strongly associated with hypertension. Likewise, low levels of cortisol are associated with hypotension.
Describe the part cortisol plays in suppression of the immune system
Cortisol reduces the circulating lymphocyte count, reduces antibody formation and inhibits the inflammatory response. Latter effect can be useful clinically e.g. asthma/ulcerative colitis/organ transplant.
What action does cortisol have on adipose tissue?
Lipolysis
What action does cortisol have on muscle?
Protein catabolism
What action does cortisol have on liver?
Gluconeogenesis
What action does cortisol have on the immune system?
Function suppressed
Why does excess cortisol lead to thinning of the skin?
Loss of percutaneous fat stored and protein muscle wastage gives fragile appearance
What type of hormone is aldosterone?
Mineralcorticoid
What is the function of aldosterone?
- Acts on the distal tubule of the kidney to determine the levels of minerals reabsorbed/excreted.
- Aldosterone increases the reabsorption of Na+ ions and promotes the excretion of K+ ions.
How is the secretion of aldosterone from the adrenal cortex controlled?
The secretion of aldosterone by the adrenal cortex is primarily controlled by a complex reflex pathway originating in the kidney, the renin-angiotensin-aldosterone system (RAAS).
How does increased aldosterone increase BP?
Increased aldosterone release stimulates Na+ (and H2O) retention and K+ depletion, resulting increased blood volume and increased blood pressure
How does decreased aldosterone decrease BP?
Decreased aldosterone leads to Na+ (and H2O) loss and increase in [K+]plasma, resulting in diminished blood volume and decreased blood pressure
What condition is associated with hypersecretion of cortisol?
Cushing’s syndrome/Disease
What is hypersecretion of cortisol most commonly due to?
Due to a tumour in either adrenal cortex or pituitary
What causes primary hypercortisolism?
Tumour in adrenal cortex causing Cushing’s syndrome
What causes secondary hypercortisolism?
Tumour in pituitary gland causing excess ACTH leading to Cushing’s disease.
What is the main cause of iatrogenic hypercortisolism?
Too much cortisol being administered therapeutically
What condition is associated with hyposecretion of cortisol?
Addison’s disease
What is Addison’s disease?
Hyposecretion of all adrenal steroid hormones due to autoimmune destruction of adrenal cortex
What is Cushing’s disease characterised by?
Cushing’s Disease is characterised by wasting of the extremities (due to catabolic action of cortisol) but for unknown reasons fat is redistributed to the face (“moon face”) and trunk
What is CRH and ACTH release promoted by?
Stress
What can disinhibit the hypothalam-pituitary-adrenal axis?
- Alcohol
- Caffeine
- Lack of sleep
What effect does alcohol have on the hypothalamo-pituitary-adrenal axis?
Alcohol depresses the neurons involved in negative feedback further enhancing stress effect and increasing levels of CRH and ACTH.
How does elevation of cortisol increase vulnerability to infection?
Turns down the immune system
Describe how the adrenal medulla secretes hormones.
Preganglionic sympathetic fibres terminate on specialised postganglionic cells in the adrenal medulla. These postganglionic fibres do not have axons – instead they release their neurohormones (adrenaline) directly into the blood.
What rare neuroendocrine tumour is associated with the adrenal medulla?
Pheochromocytoma
What does a pheochromocytoma result in?
Excess catecholamines which:
- Increase Hr
- Increase CO
- Increase BP
What do pheochromocytomas respond well to?
Surgery
Describe CRH, ACTH and Cortisol levels in: secondary hypersecretion due to hypothalamic problem
- CRH: high
- ACTH: high
- Cortisol: high
Describe CRH, ACTH and Cortisol levels in: Secondary hypersecretion due to pituitary problem
- CRH: low
- ACTH: high
- Cortisol: high
Describe CRH, ACTH and Cortisol levels in: Primary hypersecretion due to problem with adrenal cortex
- CRH: low
- ACTH: low
- Cortisol: high
Why is care required when withdrawing glucocorticoid treatment?
Enhanced negative feedback effects of exogenous cortisol
Why is there risk of adrenal insufficiency if glucocorticoid treatment is withdrawn too fast?
- Additional, therapeutic cortisol enhances the negative feedback on hypothalamus and pituitary reducing release of CRH and ACTH.
- Loss of trophic action of ACTH on adrenal gland cause atrophy of gland. Risk of adrenal insufficiency if withdrawal is too fast.