Steroids of the Adrenal Cortex Flashcards
What is functional zonation?
Blood flows from outer cortex to inner medulla
Steroid synthesis in 1 layer can inhibit diff enzymes in subsequent layers
This results in functional zonation of cortex w different hormones made in each layer:
Aldosterone is synthesised in the zona glomerulosa
Cortisol is synthesised in the zona fasiculata
Adrenal androgens is synthesised in the zona reticulates
Describe steroid synthesis in the adrenal cortex
Steroid synthesis begins w cholesterol
Genes for specific enzymes in the sER and mitochondria act on the different stages of the metabolic pathway to form different products. Products vary according to the layer of the adrenal cortex they are in.
Note- you don’t need to memorise these pathways below
What is CYP21A?
CYP21A: gene for steroid 21 hydroxylase enzyme. Mutations here result in most common form of congenital adrenal hyperplasia.
What are the adrenal steroids?
- *Glucocorticoids**: principally cortisol in mammals, involved in metabolism and immune function
- *Mineralocorticoids**: aldosterone, involved in salt and water balance
- *Androgens**
Cortisol and aldosterone have similar affinity for the aldosterone receptor
Circulating concentrations of cortisol is much higher than aldosterone so why doesn’t cortisol stimulate salt and water retention?
Cortisol is rapidly metabolized to inactive cortisone in the kidney
Requires enzyme 11beta-HSD2
Rare inactivating mutation of 11B-HSD2 leads to syndrome of apparent mineralocorticoid excess (AME)
Liquorice contains a compound that blocks this enzyme
What is the cardiovascular effect of cortisol?
Cortisol maintains vascular integrity and BP. We know this bc:
hypocortisolism: inappropriate vasodilation, hypotension
hypercortisolism: hypertension
What is glucocorticoid therapy?
GC therapy can involve cortisol itself (aka hydrocortisone) or GC drugs.
In all cases it activates the GC receptor, which involves a trade-off between the desired healing effect (eg preventing inflammatory reactions in asthma treatment) and the undesired metabolic effects (hyperglycaemia, hypertension).
Describe the cortisol receptor
Aka the glucocorticoid receptor
Member of the nuclear receptor super-family
Characteristic 3-domain structure
What is the mode of action of the cortisol receptor?
Free cortisol binds to its receptor, causing dimerisation and translocation into the nucleus
Transactivation: glucocorticoid receptor (GR) enhances transcription of target gene
Transrepression: GR represses transcription of target gene
Many anti-inflammatory effects of GCs maybe due to transrepression
Eg the JAK-STAT signalling pathway is activated by cytokine receptors but transrepression of this by GR= anti inflammatory effects
How does the hypothalamus control cortisol?
The hypothalamus controls the levels of cortisol and the adrenal androgens:
It releases CRH and VP which acts on the anterior pituitary to release ACTH. This acts on the adrenal cortex to release cortisol androgens
High levels of cortisol= Lower CRH and ACTH and vice versa
Describe ACTH
ACTH acts on a G protein coupled receptor to stimulate cortisol secretion from the adrenal cortex
It is a peptide hormone, which means it originates as a gene product, POMC. This prohormone is spliced differently in different tissues for diff biologically active hormones.
These inc ACTH and MSH which stimulates melanocytes to synthesize melanin
High levels of ACTH can activate the MSH receptor and thus cause skin pigmentation as a clinical sign.
