adrenal glands

what are the adrenal glands composed of

• capsule

• cortex

• medulla

what does the zona glomerulus produce?

mineralocorticoids → aldosterone

what does the zona fasciculata produce?

glucocorticoid → cortisol

what does the zona reticularis produce?

androgens

what is the rate limiting step in steroid biogenesis

conversion of cholesterol to pregnenolone

genomic action of cortisol

• cortisol is released into blood stream bound to globulins eg tramscortin or albumin

• glucocorticoid receptors w heat shock proteins throughout the body

• binding to receptor displaces the protein

• steroid receptor complex migrates to nucleus 

• binds to steroid response element on target gene

• disassociates very rapidly from gene after initial binding

• alters gene transcription / translation

non genomic activation of cortisol

• rapid responses to stress

• binds to receptors in plasma membrane

  • g protein coupled

  • activation of kinases

• results in dec excitability or secretion of ions

how does acth increase production of cortisol

• ACTH binds to G protein coupled receptor

• adenylyl cyclase produces cAMP

• stimulates protein kinase A

• induction of steroidogenic genes

• inc in production of cortisol

• happens within mitochondria of cells

endocrine actions of steroids

• dec insulins secretion

• inc proteolysis

• dec GLUT4 transport

• inc lipolysis 

• inc bone resorption

• inc sodium reabsorption

anti inflammatory effects of glucocorticoids

• Stabilises lysosomal membranes

  • Reduced release of proteolytic enzymes

• Decreases permeability of capillaries

  • Reduced oedema

• Decreases migration of white blood cells

  • Reduces prostaglandins, leukotrienes and other chemical mediators

• Suppression of the immune system

  • Reduction in T cells and antibodies

• Reduction of fever

  • Reduces production of IL-1

• Rate of healing increases

  • Amino acids, glucose, fatty acids available for repair of tissues

• Blocks inflammatory response in allergic reactions

  • Decreases white blood cells in blood

• Prevents rejection of transplanted tissues and organs

  • Suppression of immune system

metabolic effects of glucocorticoids

• Permissive action

  • Indicates to catecholamines to exert lipolytic effects

  • Indicates to glucagon to exert calorigenic effects

• Increased gluconeogenesis, particularly in the liver

  • Increases enzymes to convert amino acids into glucose

  • Mobilises amino acids from muscle

• Increased storage of glycogen in liver and in muscle

• Uptake and use of glucose in muscle and adipose tissue decreased

• Reduction in protein stores

  • Decreased protein synthesis

  • Increased catabolism

• Increases liver and plasma amino acids and proteins

• Increased mobilisation and oxidation of fatty acids

spironolactone

• competitive inhibitor of mineralocorticoid receptors 

• diuretic and antihypertensive effects

when does aldosterone release increase

• Increased K+ in kidney tubules

• Increased activity of renin-angiotensin system

• ACTH (necessary, but doesn’t affect rate of release

• increased Na+ in kidney tubules has small effect 

examples of synthetic steroids

• hydrocortisone

• prednisolone, prednisone

• dexamethasone, betamethasone, beclomethasone 

• fludrocortisone 

which synthetic steroid has equal GC/MC activity

hydrocortisone

which synthetic steroids have pure GC activity

Dexamethasone, betamethasone, beclomethasone

which synthetic steroids have mixed GC/MC activity

• prednisolone 

• prednisone 

which synthetic steroids have mainly MC activity

fludrocortisone

which synthetic steroids have a short half life

• hydrocortisone

• fludrocortisone

which synthetic steroids have an intermediate half life

prednisolone

which synthetic steroid has a long half life

dexamethasone

• requires less dosage

• less withdrawal symptoms 

how is cushings syndrome treated

• glucocorticoid receptor antagonists - mifepristone 

• counteract effects of cortisol 

• dose management is difficult

• progesterone receptor antagonists

  • relacorilant is still in clinical trials for no anti progesterone activity 

treatment for addisons disease

• Hydrocortisone, prednisone or methylprednisolone are used to replace cortisol

• mimic the normal 24-hour fluctuation of cortisol levels

• Fludrocortisone acetate to replace aldosterone

• Limited side effects as plasma levels mimic natural situation

what are the main areas of therapeutic use for corticosteroids

• replacement of physiological corticosteroids

• treatment of inflammation and immunosuppression

DHEAS

• androgen precursor

• regulates oestrogen synthesis and substrate for androgen synthesis in women

  • excessive amounts in women can cause ovarian dysfunction

which cells form the inner adrenal medulla and what is their potential 

• chromaffin cells

• have potential to develop into postganglionic sympathetic neurons

• innervated by preganglionic sympathetic cholinergic neurons

• release catecholamine adrenaline

effect of high cortisol on differentiation of chromaffin cells

• high cortisol inhibits differentiation

• stimulates expression of PNMT to produce adrenaline 

what maintains the high blood conc of cortisol

• rich arterial supply

• many cortisol sinusoids secreting steroid hormones

how is adrenaline synthesised

• tyrosine → DOPA

  • tyrosine hydroxylase

• DOPA → dopamine

  • amino acid decarboxylase

• within the chromaffin granule dopamine → noradrenaline

  • dopamine beta hydroyxlase

• noradrenaline diffuses out → adrenaline

  • PNMT

what transports adrenaline back into the chromaffin granules

vascular monoamine transporters VMATs

what do chromaffin granules complex with

ATP, Ca2+ and chromagranins

what can act as a marker for tumors?

chromogranins

chemical signalling via Ach

• binds to nicotinic receptor on chromaffin cells

• depolarisation

• calcium voltage gated sensitive channels open

• inc activity of tyrosine hydroxylase

alpha 1 adrenergic receptor

• inc IP3 and DAG

• found in vascular smooth muscle

alpha 2 adrenergic receptor

• decreases cAMP

• found in pancreatic beta cells

beta 1 adrenergic receptors

• inc cAMP

• found in the heart

• increases cardiac output

beta 2 adrenergic receptors effects and location

• inc cAMP

• found in the liver

• glycogenolysis, inc blood [glucose], lipolysis, ketogenesis

beta 3 adrenergic receptors

• inc cAMP

• found in adipose tissue

which metabolic enzymes is noradrenaline degraded by

monoamine oxidase

COMT 

pheochromocytoma

• neuroendocrine tumour

• excess adrenaline and noradrenaline

mechanism action of cortisol with GR

• cortisol binds to GR, translocated out of nucleus

• dimerisation and binding to glucocorticoid response elements GRE

• recruitment of coactivators

• change in transcription factors

• phosphorylation

• degradation of GR

how does cortisol inc blood [glucose] in terms of gene expression?

• inc gene expression of PEPCK and glucose 6 phosphatase

• stimulates gluconeogenesis

which receptor does ACTH bind to and where

• melanocortin-2-receptor MC2R

• located on zona fasiculata

3 phases of ACTH effects

• acute - cholesterol metabolism, StAR protein activation

• chronic - transcription of genes, inc expression of LDL receptor

• trophic - occurs on zona fasciculata and reticularis, repression of CRH and ACTH, atrophy of zona fasciculata

what does zona reticularis produce

adrenal androgens - DHEAS

what promotes production of adrenal androgens such as DHEAS

ACTH

which zone does not produce cortisol and why? whats made instead?

• zona glomerulosa

• no CYP17 expression

• aldosterone

how does aldosterone increase Na+ reabsorption?

• increases the expression and stability of the alpha subunit of the epithelial Na+ channel

• increases SGK1 gene expression - so less degradation of the epithelial Na+ channel, increased ROMK activity

Explain how catecholamines can cause vasoconstriction in some blood vessels, while causing vasodilation in others.

• vasoconstriction through alpha 1 receptors, increase in IP3 and DAG so increase in intracellular Ca2+ which stimulates contraction

• vasodilation through beta receptors by increasing cAMP, inactivating myosin light chain kinase, smooth muscle relaxation. found in heart and skeletal muscle

Why does the adrenal cortex undergo atrophy in response to prolonged administration of synthetic glucocorticoids?

• atrophy of the zona fasciculata

• from repression of CRH and ACTH production by negative feedback

Explain the interaction of ENaC and SGK1 in the actions of aldosterone.

• aldosterone increases the expression and stability of ENaC

• inc transcription and synthesis of SGK1

  • this further enhances ENaC actviation and also stimulates ROMK

• this promotes Na+ reabsorption which increases the salt conc and thus the volume of the blood

Explain the differences between the causes of orthostatic hypotension in patients with pheochromocytoma and those with Addison disease

• pheochromocytoma - there is neuroendocrine tumour - excess amount of adrenaline and noradrenaline released, hypersecretion decreases the postsynaptic response to noradrenaline as a result of downregulation of the receptors

• addison’s disease - autoimmune destruction of the adrenal cortex resulting in adrenal insufficiency - loss of cortisol decreases the vasopressive response to catecholamines, this leads to hypotension, lack of aldosterone so cannot maintain extracellular volume leading to hypotension