LECTURE 9 - adrenal glands - cortex Flashcards
What is the basic structure of the adrenal glands?
- sit on top of kidney
- split into the adrenal cortex and medulla
What are the adrenal cortex hormones?
- corticosteroids: glucocorticoids, mineralocorticoids
- -> synthesised with P450 cytochrome enzymes
- (weak) androgens
- -> derived from cholesterol (synthesised from acetate)
Describe the histological zonation of the adrenal glands
Cortex split into 3 zones:
1. Zona glomerulosa
2. Zona fasciculata
3. Zona reticularis
(All 3 responsible for corticosteroid synthesis)
Medulla responsible for catecholamine synthesis
How is cholesterol imported into mitochondria?
- by Steroidogenic acute regulatory (StAR) protein
- transported from mitochondrial membrane into inner mitochondrial membrane
- this is the RATE LIMITING STEP
Describe the structure and regulation of StAR protein
- contains a cholesterol transfer domain
- produced in response to stimulation usually through a cAMP secondary messenger system
- promoted by ACTH and LH
- suppressed by alcohol
How is pregnenolone formed?
cholesterol –> pregnenolone
- using cytochrome P450scc
(scc = side chain cleavage)
- occurs within inner membrane of mitochondria
- two hyrdoxylase reactions produce 20,22-dihydroxycholesterol
- final stage = cleavage of bond between carbon 20 and 22 to produce pregnenolone
How is P450scc regulated?
- requires electrons for function
- works in a complex with 2 other proteins: adrenodoxin reductive and adrenodoxin (these provide initial electrons)
- always active but dependent on supply of cholesterol
- ACTH induces expression of all the genes in the complex
What are glucocorticoids?
- C21 steroids
Examples: - cortisol (aka hydrocortisone)
- corticosterone
*cortisol binds, cortisone does not, cortisone is converted by the body to cortisol
Describe the biosynthesis of glucocorticoids
CYP11B1
- metabolises precursors to make cortisol
- requires different layers of enzymes
How is cortisol transported in the blood?
- 90%+ bound to plasma protein
- -> transcortin (CBG) - 80+%
- -> albumin - 10%
Why is cortisol transported bound to plasma protein?
- lipophilic = doesn’t like water therefore transporting cortisol in blood is difficult
- transcortin = carrier protein for cortisol
- in circulation, cortisol exists in 2 forms, bound and unbound
How does bound cortisol become unbound?
random equilibrium means carrier proteins randomly drop off molecules
What can impact cortisol levels in the body?
- emotion via limbic system
- biochemical stressors
- drive for diurnal rhythm
How is ACTH generated?
- produced from single gene = POMC
- ACTH produced when POMC gets cleaved by enzymes
- ACTH acts on adrenal but is also a prohormone
- can be cleaved into a-MSH (regulates melanocytes) and CLIP (no known function)
What are the effects of ACTH?
- interacts with cell surface receptor (melanocortin 2 receptor) and uses secondary messengers as peptide receptor
- cAMP activates secondary messenger
Immediate = increased cholesterol into mitochondria Subsequent = increased gene transcription of hydroxylases, increased LDL receptors Long-term = increased size and functional complexity of organelles, increase size and number of cells => HYPERPLASIA
What effect do glucocorticoids have on responsive cells?
- intracellular receptors (Glucocorticoid receptor)
- glucocorticoid response element
- protein synthesis (e.g. lipocortin)
What effects do glucocorticoids have on metabolism?
CARBOHYDRATES
- increased plasma glucose
- increased hepatic gluconeogenesis
- inhibits glucose entry into tissues
PROTEIN muscles - increase breakdown of protein --> amino acids --> wasting/ growth retardation liver - increase uptake of amino acids --> protein synthesis --> gluconeogenesis
FAT
- increased metabolism of fatty acids from adipose tissue –> gluconeogenesis
- redistribution to extremities
What are the effects of glucocorticoids on bones?
- decreased absorption of Ca2+
- increased excretion
- inhibition of osteoblasts –> osteoporosis
What are the effects of glucocorticoids on the CNS and the immune system?
CNS: affects mood and cognition
Immune system:
- decreased lymphocytes, eosinophils (disease fighting white blood cells)
- increased neutrophils, RBCs and platelets
What are the therapeutic actions of glucocorticoids?
- Anti-inflammatory: potentially decrease leukocyte action - rheumatoid arthritis: potential proteolysis at site of damage
- Anti-allergic: decreased histamine synthesis and release
- Immunosuppression
What diseases can arise from an excess of glucocorticoids?
Cushings syndrome - pituitary tumour = Cushing's disease - ectopic ACTH producing tumour - autonomous adrenal adenoma - trunkal obesity, thin arms/ legs, striae Treatment: - surgery/ radiotherapy - drugs: Metyrapone (11 hydroxylase inhibitor) - inhibiting this will reduce cortisol production
Iatrogenic = relating to illness caused by medical examination or treatment
- long term immunosuppression with synthetic cortisol analogues
What can result from decreased adrenal function?
1° - Addison's disease - 65+ % autoimmune attack on adrenal gland symptoms: - fatigue: hypoglyceamia - weight loss - skin pigmentation - ion imbalance treatment - cortisol replacement therapy - mineralocorticoid replacement
2°
- decrease of pituitary function (decreased ACTH)
- stopping long-term glucocorticoid therapy
What are mineralocorticoids?
- C21 steroids
- named due to effect on ion levels in plasma
- e.g. aldosterone
Describe the biosynthesis of aldosterone
Occurs in z. glomerulosa
Progresterone –> 11-deoxycorticosterone –> corticosterone –> 18-hydrocorticosterone –> aldosterone
Arrow 1 = 21-hydroxylase
Arrow 2 = 11-hydroxylase
Arrow 4 = aldosterone synthase (an 11-hydroxylase enzyme)
How is aldosterone transported in the blood?
- requires a binding proteins but not a specific kind
- albumin + transcotrin (50%)
- free in plasma
How is aldosterone secretion regulated?
- ACTH (minor role): large ↑ in ACTH can ↑ ald.
- Plasma K+: ↑ in plasma K+ of 10% will ↑ ald.
- Plasma Na+: ↓ in plasma Na+ of 10% will ↑ ald.
- Renin-angiotensin system
What is the renin-angiotensin system?
- drop in pressure sensed by the kidneys => renin production from juxtaglomerular cells
- renin causes liver to convert angiotensinogen into angiotensin I which turns into angiotensin II
- aldosterone comes from this step which causes renal Na+ retention which increases ECF again
Describe the mechanism of action of aldosterone
There are 2 types of intracellular receptors (differing affinities for aldosterone)
Low = glucocorticoid receptors
What issues arise with the mechanism of action of aldosterone?
2 types of intracellular receptors with differing affinities for aldosterone
Low = glucocorticoid receptors
- can also bind aldosterone as similar structure between ald. and cortisol
- affinity of GR for cortisol is much higher than ald. so no issue
High = mineralocorticoids - can bind both ald. and cortisol - ald. affinity = cortisol affinity BUT [cortisol] > [ald.] therefore every time we get stressed and release cortisol MR will be active not just when ald. binds Need mechanism to overcome this
What diseases can arise from an excess of mineralocorticoids?
Syndrome of apparent mineralocorticoid excess (AME)
- severe hypertension
- hypokalaemia (low levels K+)
- low renin, low (or normal) ald. levels
- there is no aldosterone excess (even though it looks like there is)
- problem is cortisol
Explain the pre-receptor regulation of kidney MR transactivation
- 11b-HSD2 enzyme converts cortisol –> cortisone (essentially inactivates cortisol)
- in normal physiology, kidney turns cortisol into cortisone so MR free for ald. so no issue
- in AME patients, they have a gene mutation in 11b-HSD2, so cortisol not inactivated so will bind to MR => consequences
What are 11-beta hydroxysteroid dehydrogenases?
- tissue specific glucocorticoid metabolism
- 11-BHSD2: allows MR to bind to aldosterone
- 11-BHSD1: role in obesity and related disorders?
What is the effect of mineralocorticoids on protein synthesis?
- increases protein synthesis
- proteins involved in Na+ handling
What is the effect of mineralocorticoids on Na and L reabsorption?
Increased Na+ reabsorption
- DCT and collecting duct
- sweat glands
- salivary glands
- GIT
Decreased K+ reabsorption
What are some other systemic actions of mineralocorticoids?
- ↑ hydrogen loss –> metabolic alkalosis
- ↑ H2O reabsorption ( ↑Na+ reabsorption)
–> regulation of BP
(only really increases ECF by ~15% - this is because people with CHF would die if BP increased too much as ald. increases BP)
What diseases can arise from abnormal mineralocorticoid levels?
- Hyperaldosteronism (1° and 2°)
- Addisons disease
What is 1° hyperaldosteronism?
- autonomous production of aldosterone
Conn’s syndrome
Cause: hyperplasia or adrenal adenoma in z.glomerulosa
(renin levels normal or low)
Symptoms:
- hypertension
- alkalosis
- hypokalaemia
- -> muscle weakness + cardiac arrhythmias
Treatment:
- surgery
- spironolactone (drug that targets receptor to which ald. will bind)
What is 2° hyperaldosteronism?
- increased ald. due to high renin levels
(problem to do with kidney unlike adrenal gland as 1°)
Cause:
- renal artery stenosis
- diuretic therapy
- XS liquorice ingestion
What can arise from an aldosterone deficiency?
Addisons disease
- ion imbalance
- -> hyperkalaemia
- -> hypotension
What is CAH?
Congenital Adrenal Hyperplasia
- Block in adrenal steroidogenesis affecting glucocorticoid synthesis
Symptoms:
- dehydration, salt loss, weakness
- females: male genitalia, hirsutism
- males: precocious puberty
Treatment:
- corticosteroid replacement
What is 21 hydroxylase CAH?
- Autosomal recessive; 1/10000 births
- decreased glucocorticoid and mineralocorticoid production
- 21-hydroyxlase deficiency
- stops production of cortisol (which should stop ACTH in a -ve feedback mechanism) therefore –> increased ACTH –> steroid production continues –> enlarged adrenal glands –> push everything towards androgen production
What are adrenal androgens?
- synthesised in small amounts in z.reticularis
- DHEA and Androstenedione
- redundant in males?
- in females may cause growth of pubic and axillary hair and could be responsible for female libido
