Adrenal glands

Question 1

What are the 3 groups of steroid hormones of the adrenal medulla and cortex in this response, what are the zones associated with the production of each group and outline the synthetic pathways involved?

Answer 1

• Zone glomerulosa – mineralocorticoids
  ○ Mineralocorticoids will effected Na+ and K+
  ○ e.g. aldosterone
  ○ Controlled by the plasma K+ concertation and angiotensin (RAAS)
  ○ Synthesised in zona glomerulosa - aldosterone synthase is present in this region
  § CYP11B2
  ○ Main mineralocorticoids are aldosterone and deoxycorticosterone (DOC)
  ○ DOC has 3% mineralocorticoids activity of aldosterone
  § Precursor of aldosterone can cause 3% of the effect of aldosterone - precursor can bind to receptor sometime
  ○ Helps retain 10-20g of sodium/day by increasing the Na+ reabsorbing from wine in exchange for potassium
  § Na+ retained so water follows Na+ by osmosis and maintains body fluid volume to maintain blood pressure
  □ If lots of Na+ lost then blood pressure would collapse
  ○ Critical to salt and water balance in:
  § Colon, kidney, pancreas, salivary glands and sweat glands
  ○
  ○ cell to make Na+ Chanel’s and more Na+/K+ pump
  ○ Put into cell wall
  ○ Na+ is pumped across into cell
  ○ Water will move in by osmosis
  ○ Hold onto Na+ and remove K+ from the cell
  ○ This will increase the Na+ level and decrease the K+ level in the blood
  ○
  
  • Z fasciculata – glucocorticoids
    ○ glucocorticoids will affect the glucose metabolism
    ○ e.g. cortisol
    ○ ACTH from anterior pituitary gland
    ○ Could be stimulated by drop in glucose level.
    ○ ACTH stimulates corticosteroid synthesis
    ○ Tells cells to release more cholesterol and process it pregnenolone/ cortisol by increasing the delivery to the enzyme P450scc
    ○
    ○ Many actions do not directly initiate but allow to occur in presence of other factors.
    § e.g. the effects of catecholamines on vascular tone “Permissive” actions only apparent with deficiency
    ○ Important in homeostasis e.g. conditioning the body’s response to stress
    ○ Essential for survival and resistance to stress (resistance/adaptation phase)
    ○ 80% bound to CBG. (increace binding protein - increace total conc. of
    plasma hormone e.g. pregnancy)
    ○
  • Z reticularis – produce androgen precursors the sex steroids (pre sex steroids)
    ○ Poorly understood how it is controlled- controlled somewhat by ACTH from the anterior pituitary
  • Cholesterol is take up by al the cells and is converted into the steroid hormone in each section of the adrenal gland
  • Lipid soluble so can diffuse though the cell into the blood
  • Needs a transport protein in the blood
  • Bind to specific intracellular receptors e.g. GR, MR
  • Steroid hormones can alter gene transcription directly or indirectly- the exact actions depends on the structure and ability to bind to the receptors

Question 2

Describe the actions of aldosterone and how its release is regulated.

Answer 2

• Main mineralocorticoids are aldosterone and deoxycorticosterone (DOC)
  
  • DOC has 3% mineralocorticoids activity of aldosterone
    ○ Precursor of aldosterone can cause 3% of the effect of aldosterone - precursor can bind to receptor sometime
  • Helps retain 10-20g of sodium/day by increasing the Na+ reabsorbing from wine in exchange for potassium
    ○ Na+ retained so water follows Na+ by osmosis and maintains body fluid volume to maintain blood pressure
    § If lots of Na+ lost then blood pressure would collapse
  • Critical to salt and water balance in:
    ○ Colon, kidney, pancreas, salivary glands and sweat glands
  • cell to make Na+ Chanel’s and more Na+/K+ pump
  • Put into cell wall
  • Na+ is pumped across into cell
  • Water will move in by osmosis
  • Hold onto Na+ and remove K+ from the cell
  • This will increase the Na+ level and decrease the K+ level in the blood
  • Regulated by
    ○ aldosterone secretion follows a diurnal rhythm, with higher levels typically being released during sleep.
    ○ increase in plasma concentration of angiotensin-II
    ○ Increase in plasma K+ concentration
    ○ Decrease in plasma pH (acidosis)
    ○ Decreased blood pressure, as detected by atrial stretch receptors
  • What does too much aldosterone cause?
    ○ Too much Na+ retention
    Primary aldosteronism (adenoma - Conn’s syndrome)
    § Prevalence ~5-10% of “essential” hypertension - rare
    § Hypertension and hypokalaemia (30% of cases only)
    § increases aldosterone supresses renin, causes hypertension, sodium retention, potassium secretion – hypokalaemia. CV damage.
    ○ Causes
    ○ Adrenal adenoma – autonomous aldosterone secretion
    ○ Bilateral adrenal hyperplasia – excessive aldosterone secretion for prevailing ang II
    ○ Treatment
    ○ Surgery for adenoma (laparoscopic adrenalectomy)
    ○ Medical therapy for rest (spironolactone – MR blocker)

Question 3

What are the main actions of cortisol and describe how its released and its control?

Answer 3

• Cortisol actions
  
  • Cortisol relace and control
    
    1. CRH from the hypothalamus stimulates ACTH release from the anterior pituitary glands
    2. ACTH acutely stimulates cortisol release
    3. ACTH stimulates corticosteroid synthesis (and capacity)
    4. Cortical will travel in the blood back and circle back the hypothalamus and anterior pituitary and cause the production and release of CRH and ATCH to stop
  • Diurnal variations of ACTH so also cortisol levels - peaks at 4-7am
    ○ Diurnal = there is a rhythm of normal secretions thought the day
    ○ High at day the Decreased and peaks at night.
    ○ As cortisol levels are high your immune system is damped so you feel better in the morning when you have a cold
  • Lots of people with rheumatoid arthritis are given cortisol to dampen immune system (immune suppressant)
  • Cortisone Causes negative feedback
  • This means that with synthetic cortisone the ACTH is not relaced and the adrenal glands shrink.
    ○ Too little ACTH causes adrenals to shrink. This is non recoverable and can cause vascular crisis and death. Can not tell patients to come off steroids . Must ween them off the steroids.
    *

Question 4

What are the roles played by hormones of the adrenal medulla and cortex in the response to stress?

Answer 4

• Sympathetic branch of the autonomic nervous system
  
  • Main hormone produced is adrenaline but also some noradrenaline and dopamine
    ○ Secretion is increased as part of the diffuse sympathetic discharge in emergencies. (‘flight or fight’)
    ○ response is rapid/short acting - ALARM PHASE
    ○ Not vital for survival but does contribute to stress response
  • Failure of the adrenal medulla is uncommon and cause hypotension and hypoglycaemia but the hormones of the adrenal cortex are more important in regulating this.
  • Catecholamines
    ○ 80% adrenaline, 20% noradrenaline, Dopamine in small amounts
    ○ Normal catecholamine synthesis dependent on high local cortisol levels (permissive effect)
    ○ Catecholamines released during “flight or fight”. Major effect on cardiovascular system
    ○ Tachycardia and increased cardiac contractility
    ○ Redistribution of circulating volume
    ○ increased gluconeogenesis in liver and muscle
    ○ increased lipolysis in adipose tissue
    ○ Tumour of adrenal medulla – pheochromocytoma (symptoms: Headache, sweating, palpitations, pallor, nausea, tremor, weakness. (5-20% asymptomatic)
    ○

Question 5

What is the physiological response to stress?

Answer 5

• Stress can be causes by: infection, trauma, haemorrhage, medical illness, psychological, exercise, exhaustion, low levels of glucose….
  
  • When you are stressed you will release glucocorticoids
    ○ Blood glucose level is maintained or increased by gluconeogenesis
    § create new glucose molecules
    ○ Create amino acids to maintain blood glucose levels
    ○ Increased break down of stored fats/lipids to use to create energy to maintain blood glucose levels
    ○ Maintain of vascular tone to allow you to keep moving and for the heart to keep pumping
    ○ Maintain salt and water balance to maintain circulation (blood pressure)
    ○ Dampens immune system

Question 6

Describe the clinical picture in adrenocortical disease.

Answer 6

• Crushing disease
  ○ Over-secretion of corticosteroid hormones
  § Can also be Conn’s syndrome rather than crushing’s
  ○ Can also be caused if patients are on steroid drugs for a long time. Causes adrenal glands to shrink and not produce hormone. Need to be weaned of the drug. Can not just stop giving them the steroid as they can’t make more.
  ○ Iatrogenic Cushing’s
  § synthetic corticosteroids
  § ~1% of UK population taking chronic corticosteroid therapy.
  § Steroid inhalers – oral candidiasis
  ○ Endogenous Cushing’s
  1. ACTH-dependent:
  § Pituitary-dependent Cushing’s syndrome (Cushing’s disease) (75%)
  § Ectopic ACTH syndrome (15%)
  § Small cell lung carcinoma
  § Carcinoids
  2. ACTH independent
  § Adrenal adenoma/carcinoma (10%)destroy some of the adrenal glands
  § Use cortisol synthesis blocking drugs
  § Remove tumour if due to that
  § Can not stop giving steroids
  ○ If not due to steroids you can use radiotherapy to
  ○
  • Addison’s disease
    ○ Under-secretion of corticosteroid hormones
    § Can also be Congenital adrenal hyperplasia rather than Addison’s
    ○ Primary
    § failure of adrenals to secrete sufficient glucocorticoid in response to stimulation
    § Often gradual autoimmune destruction of adrenal eg HIV,TB
    § HPA axis compensates until 90% loss or until stress – adrenal crisis / acute adrenal insufficiency.
    § Weakness, fatigue, hypotension, hyponatraemia, hyperkalaemia, dehydration, nausea, vomiting, anorexia, hyperpigmentation
    ○ Secondary adrenal insufficiency – more common
    § Loss of ACTH secretion due to hypopituitarism
    § No hyponatraemia because no activation of the gene
    § No hyperpigmentation no activation of the gene that leads to increased hyperpigmentation
  • Adrenal lumps and bumps
    ○ Adenomas, carcinomas
  • Oral manifestations
    ○ See diagram bellow
    ○
  • Adrenalectomy
    ○ FATAL within a few days as a result of circulatory collapse (lack of ALDOSTERONE)
    ○ FASTING results in fatal hypoglycaemia
    ○ STRESS results in collapse and death