L4 Mineralocorticoids Flashcards
What is the main endogenous mineralocorticoid in the body?
Aldosterone
Where is aldosterone produced?
in the zona glomerulosa of the adrenal cortex
Effect of aldosterone
Aldosterone acts on mineralocorticoid receptors in kidneys to increase both sodium reabsorption and potassium excretion - helps to regulate plasma electrolyte composition and BP
How does aldosterone regulate extracellular volume and potassium homeostasis?
by binding to the renal cortical collecting duct principle epithelial cell mineralocorticoid receptor
What happens when the activated MR translocates to the nucleus?
it binds to the glucocorticoid response element and functions as a transcription factor
Aldosterone increases the expression of which gene? What is the effect of this?
Serum- and glucocorticoid-inducible kinase (Sgk1) - leads to phosphorylation & inactivation of neural-precursor-cell-expressed developmentally downregulated gene (Nedd) 4-2, a ubiquitin ligase which is responsible for degrading the ENaC. Therefore, aldosterone stimulates ENaC to increase Na+ reabsorption, as well as K+ secretion.
What drives the uptake of potassium and export of sodium?
Na+/K+-ATPase activation at the basolateral membrane
GC & MC bind equally to the MR but specificity of action is due to what?
the glucocorticoid-degrading enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which prevents glucocorticoids from interacting with the receptor
Example of a synthetic mineralocorticoid that acts as a diuretic and is also often prescribed for PCOS?
Spironolactone
Example of an aldosterone antagonist and potassium-sparing diuretic?
Eplerenone
What is the most common synthetic mineralocorticoid and what is it used for?
Fludrocortisone: used to replace endogenous aldosterone in adrenocortical insufficiency and salt-losing adrenogenital syndrome
Fludrocortisone may mask signs of __.
infection (by depressing the normal immune response)
How does fludrocortisone work?
- binds MR, alters translation of proteins, increases density of Na+ channels & Na+/K+-ATPase
- this increases plasma Na+ conc, increasing BP & decreasing plasma K+ conc
- also acts on GC receptors, but with a much lower affinity
What is thought to be one of the reasons behind fludrocortisone’s profound mineralocorticoid pathway?
the reduction in 11β-oxidation
Fludrocortisone is not recommended to be given with what drugs?
strong inhibitors/inducers of CYP3A
Examples of conditions with low renin and high aldosterone
primary aldosteronism e.g. aldosterone-producing adenoma, bilateral idiopathic hyperplasia, unilateral adrenal hyperplasia, familial hyperaldosteronism
What condition has both low renin and aldosterone?
Hyperdeoxycorticosteronism e.g. congenital adrenal hyperplasia, deoxycorticosterone-producing tumour, primary cortisol resistance
What is the most common cause of Cushing Syndrome?
exogenous glucocorticoid administration
Management of Addison’s disease
hydrocortisone, fludrocortisone acetate
What causes congenital adrenal hyperplasia?
enzymatic defects in adrenal steroidogenesis that result in deficient secretion of cortisol
What does the lack of inhibitory feedback by cortisol on the hypothalamus and pituitary produce?
an ACTH-driven build-up of cortisol precursors proximal to the enzymatic deficiency
What causes the hypertension and hypokalaemia in CAH?
hypersecretion of the mineralocorticoid DOC (11-deoxycorticosterone)
2 types of CAH
- 11β-hydroxylase (CYP11B) deficiency
- 17α-hydroxylase (CYP17) deficiency
The mineralocorticoid effect of increased circulating levels of DOC decreases…
PRA and aldosterone secretion
CAH is autosomal __.
recessive
Markedly increased levels of what confirm the diagnosis of 11β-hydroxylase deficiency?
high levels of DOC, 11-deoxycortisol and adrenal androgens (due to the impaired conversion of DOC to corticosterone)
How does 11β-hydroxylase deficiency presentation differ between males and females?
- Males present with pseudoprecocious puberty
- Females present in childhood with hypertension, hypokalaemia, acne, hirsutism and virilisation
What normalises the steroid abnormalities and hypertension in CAH?
glucocorticoid and mineralocorticoid replacement
What does 17α-hydroxylase deficiency cause?
decreased production of cortisol and gonadal (sex) hormones
How does 17α-hydroxylase deficiency presentation differ between males and females?
- XY males present with either pseudohermaphroditism or as phenotypic females
- XX females present with primary amenorrhea
Biochemical findings of 17α-hydroxylase deficiency?
- low concentrations of plasma adrenal androgens, plasma 17α-hydroxyprogesterone and cortisol
- aldosterone and PRA are suppressed
Deoxycorticosterone-producing tumours are usually __ and __.
large and malignant
Some DOC-producing tumours secrete __ and __ in addition to DOC. What is the effect of this?
androgens and oestrogens
(this may cause virilisation in women and feminisation in men)
What confirms the diagnosis of DOC-producing tumours?
a high level of plasma DOC or urinary tetrahydrodeoxycorticosterone and a large adrenal tumour seen on CT
Optimal treatment for DOC-producing tumours?
Complete surgical resection
What is found in patients with primary cortisol resistance?
increased cortisol secretion and plasma cortisol concentrations without evidence of Cushing Syndrome
What does cortisol resistance lead to?
increased ACTH secretion, and subsequent increased steroid production
What is primary cortisol resistance characterised by?
hypokalaemic alkalosis, hypertension, increased plasma concentrations of DOC & cortisol, and increased adrenal androgen secretion
High rates of cortisol production overwhelm __.
11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity
Treatment for mineralocorticoid-dependent hypertension
blockade of the MR with a mineralocorticoid receptor antagonist or suppression of ACTH secretion with dexamethasone
What can impair renin release?
NSAIDs, beta blockers, diabetes, elderly, cyclosporine, tacrolimus
What can impair aldosterone metabolism?
Adrenal disease, heparin, ketoconazole (anti-fungal)
