PH1124 - corticosteroids Flashcards
what are the two steroids synthesized within the adrenal cortex? (2)
- corticosteroids
- androgens
what are the two types of corticosteroids? (2)
- glucocorticoids (cortisol)
- mineralocorticoids (aldosterone)
what are synthesized in the adrenal medulla?
- catecholamines (noradrenaline and adrenaline)
what are the layers of the adrenal gland? (outside to inside) (3)
- zona glomerulosa
- zona fasiculata
- zona reticularis
(adrenal medulla)
what is the role of the zona reticularis?
- secretes glucocorticoids and some sex steroids
what is the role of the zona fasiculata?
- widest region that secretes glucocorticoids and some sex steroids
what is the role of the zona glomerulosa?
- secrete aldosterone (lacks 17-α-hydroxylase)
what are the two pathways of corticosteroid synthesis? (2)
- glucocorticoid pathway (17-hydroxylated corticosteroids)
- mineralocorticoid pathway (17-deoxycorticosteroids)
what is the structure of corticosteroids? (3)
- 21 carbon skeleton
- cyclohexane rings A, B and C in ‘chair’ conformation
- cyclopentane ring D
what is the synthesis of corticosteroids like in the adrenal cortex? (2)
- only produces steroids as required
- produces sufficient steroids for only a few minutes secretion
what stimulates the transport of cholesterol into cells?
- adrenocorticotrophin
what is cholesterol transported by in the blood?
- LDL (low density lipoprotein)
why is cholesterol important in the synthesis of corticosteroids?
- it is an important precursor when corticosteroid production is stimulated
where does cholesterol come from? (3)
- 60-80% comes from your blood
- stored in the adrenal cortex
- made in cells from acetate and acetylcoenzyme A
how is cortisol transported in the blood? (2)
- 90% corticosteroid-binding proteins by transcortin and albumin (majority is bound to transcortin)
- 10% free plasma glucocorticoids are biologically active
what are the differences in capacity and affinity for the corticosteroid-binding proteins? (2)
- transcortin has a low capacity but high affinity
- albumin has a high capacity but low affinity
how are cortisol, corticosterone and aldosterone metabolised and excreted? (4)
- metabolised in the liver
- reduction of 4,5 double bond and the C3 and C20 keto groups
- resultant derivatives conjugated with glucuronic acid or sulphate at C3 hydroxyl group
- excretion in urine
what is the regulation of corticosteroid biosynthesis?
- glucocorticoids (in ZF and ZR) cause negative feedback loop causing the anterior pituitary to stop producing ACTH
- the glucocorticoids stop the hypothalamus releasing CRH which also inhibits the production of the glucocorticoids
- the release of ACTH also causes a short negative feedback loop to the hypothalamus to stop the production of CRH
what does CRH stand for?
- corticotropin releasing hormone
what is CRH?
- causes the anterior pituitary gland to release more ACTH which causes the release of glucocorticoids
where is CRH released from and when?
- hypothalamus
- in response to emotional or traumatic stress and the sleep-wake cycle
- release potentiated by vasopressin, oxytocin, adrenaline and cytokines
what does CRH act on?
pituitary corticotroph cells
what is ACTH?
- adrenocorticotropic hormone
what is the release of ACTH regulated by? (2)
- CRH
- glucocorticoids
when is ACTH released?
- response to the sleep-wake cycle, stress, psychiatric disturbances, neurotransmitters and peptides
what is the secretion of ACTH stimulated by?
- vasopressin
what is diurnal variation? (3)
- natural rhythm for the release of CTH and glucocorticoids
- adapts of changes in sleep-wake patterns
- rhythm controlled by CRH
what are steroid receptors?
- located inside the cell (intracellular) and belong to a gene superfamily of nuclear recepotrs
- they interact with nuclear DNA to modulate transcription of specific genes
what are the steroid receptors found in the cytoplasm? (2)
- glucocorticoids
- mineralocorticoids
what are the steroid receptors found in the nucleus? (3)
- androgen
- oestrogen
- progesterone
what is the molecular mechanism of the action of steroids? (3)
- steroids enter the cytoplasm of the cell to bind to a receptor to make a substrate receptor complex
- two of the complexes form to make a dimer
- this enters the nucleus of the cell and can either up/down regulate the transcription of a gene by the zinc fingers it contains
what are the physiological actions of corticosteroids? (7)
- carbohydrate and protein metabolism
- fat metabolism
- central nervous system effects
- effects on bone
- mineralocorticoid effects
- permissive effects
- anti-inflammatory and immunosupressive effects
what is the role of corticosteroids in carbohydrate and protein metabolism? (2)
- they antagonise the action of insulin on glucose uptake increasing blood glucose
- increase protein breakdown and reduce protein synthesis
what would happen to an individual is there were no corticosteroids present?
- if subjected to a shortage of food or extensive exercise they may have hypoglycaemic episodes
what would prolonged high doses of corticosteroids cause to an individual?
- hyperglycaemia, wasting of muscle with thinning of capillary walls and loss of the bone matrix
how do corticosteroids control fat metabolism?
- they stimulate fat breakdown (lipolysis) and inhibit fat synthesis
what do high levels of corticosteroids do to body fat?
- causes redistribution of body fat to the neck shoulders and cheeks with loss of fat from the limbs
how do corticosteroids affect the central nervous system? (2)
- involved in the neuronal development in the foetal and neonatal brain
- development of the CRH-ACTH axis
how do corticosteroids effect bone? (2)
- leads to a net decrease in plasma calcium as it is regulated by calcium metabolism
- prolonged doses of glucocorticoid steroids leads to osteoporosis
what are the mineralocorticoid effects from corticosteroids?
- increased Na+ reabsorption in exchange for K+ excretion
- increased water retention
what are the permissive effects of corticosteroids? (2)
- allow other hormones to exert effects
- helps the body to maintain its temperature and respond to stress
what leads to increased cortisol?
- stress
how does stress protection work?
- prevents stress-induced defense reactions from getting out of control
what are the some of the anti-inflammatory effects caused by corticosteroids? (4)
- decreased vasodilation and fluid exudation by direct vasoconstriction on small blood vessels
- decreases fibroblast function so less chronic inflammation
- decrease generation of pro-inflammatory mediators and increases the production of anti-inflammatory mediator
- stabilises mast cells and lysosomal membranes
how does corticosteroids cause immunosuppressive effects? (5)
- decreases the action of T helper cells and reduce clonal proliferation of T cells due to the decreases interleukin production
- reduce the numbers of circulating T and B lymphocytes and antibody production
- impairs recognition responses in antigen presentation
- reduces numbers of toxic radicals produced by macrophages
- reduces phagocytic activity of macrophages
what happens at the cellular site of action of corticosteroids? (4)
- antigen recognition
- stimulation of IL-1
- expression of IL-2 and other cytokines
- proliferation and differentiation
what controls the secretion of aldosterone?
- controlled mainly by the renin-angiotensin system but hyperkalaemia and ACTH increase release
where are the aldosterone receptors found?
- distal and convoluted tubules and collecting duct in the kidney, bladder, colon, sweat and salivary glands
what is the main action of aldosterone?
- retain Na+ and lose K+ therefore water is retained because it follows Na+
what is the mechanism of action of aldosterone? (3)
- increased production of the Na+ transporter in luminal membrane
- pumps Na+ out of the luminal fluid into the tubular cells
- increases Na+/K+ ATPase pump to pump Na+ out of tubular cells into the plasma increasing the blood volume
what is cushings disease/syndrome?
- increased ACTH (adrenocorticotropic hormone) causes increased cortisol
what are the symptoms of cushings disease? (6)
- muscle weakness and wasting
- easily bruised
- redistribution of body fat
- prominent abdomen
- diabetes
- high levels of plasma and urine cortisol
