LECTURE 9 - adrenal glands - cortex Flashcards
(42 cards)
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)
