unit 01: Adrenal axis Flashcards
describe the morphology of the adrenal cortex
- consists of inner medulla and outer cortex
- cortex aynthesizes and secretes steroid hormones essential for salt balance, intermediary metabolism and in females androgenic actions
what are the 3 classes of steroid hormones, what can they be collectively known as
mineralocorticoids, glucocorticoids and androgens
collectively they are known as adrenocorticocosteroids.
what are the 3 zones of the adrenal cortex
- from the capsule to the medulla the regions are zona glomerulosa, zona fasciculate and zona reticularis CTH).
- glomerulosa
- outermost region responsible for mineralocorticoid production
- syn aldosterone
- under the control of angiotensin II, blood potassium concentration and to a lesser extent, adrenocorticotropic hormone (ACTH)
Fasciculate
- syn glucocorticoids (cortisol)
- under control of ACTH which in turn is reg by CRH, vasopressin and cortisol
Reticularis
- syn androgens
- under control of ACTH which in turn is reg by CRH, vasopressin and cortisol
what does release of ACTH from the anterior pituitary stimulate
- stim production of both cortisol and adrenal androgens
- there is tissue specific expression of enzymes in each zone of the adrenal cortex
- aldosterone synthase which makes aldosterone in the glomerulosa
- steroid 11β-hydroxylase, and steroid 17α-hydroxylase in the fasciculata/reticularis
*determines the specificity of hormone production in that zone.
what is cortisol?
- an endogenous glucocorticoid synthesized from cholesterol
how is cortisol regulated?
- the hypothalmic pituitary unit coordinates the production of cortisol in respose to circadian rhythms and stress
- neurons in the paraventricular neucleus of the hypothalamus synthesize and secrete corticotropin releasing hormone CRH, a peptide hormone
- CRH then travels through the hypothalamic-pituitary potral system and bind to G protein coupled receptors on the surface of corticotroph cells in the ant pit gland
*inc the release of ACTH by ant pit gland
- ACTH regulates cortisol production by promoting synthesis of the hormone fromt he zona fasciculate and zona reticularis of the adrenal gland
describe the Hypothalamic pituitary target organ feedback loop
- stimulatory hypothalamic factors (CRH in this case) sitmualtes the release of pituitary hormones (ACTH in this case)
- in response to pituitary hormone signals, the target organ (adrenal gland in this case) produces a hormone (cortisol)
- cortisol negatively regulates the hypothalmic pituitary adrenal axid by inhibiting CRH and ACTH.
ACTH also negatively regualtes CRH, providing more sensitive control of the axis
how is aldosterone regulated?
- aldosterone = steroid hormone derived from cholesterol
- aldosterone synthesis is regulated by 3 systems: renin angiotensin system, blood potassium levels and ACTH
describe how the renin angiotensin system regualtes aldosterone
central regulator of extracellular fluid (ECF) volume
- decreases in ECF volume decreases perfusion pressure at the afferent arteriole of the renal glomerulus -> acts as a baroreceptor
- this stim the juxraglomerular cells to secrete renin, a protease that cleaves the prohormone angiotensinogen to angiotensinogen I
AT 1 is then converted to AT II by angiotensin converting enzyme ACE, expressed @ high conc by capillary endothelium of the lungs
- ATII has direct arteriolar pressure effects, stimulates aldosterone synthesis by binding and activating a G protein coupled receptor in zona glomerulus of adrenal cortexhttps://gryphlife.uoguelph.ca/organizations
summarize mineralcorticoids and the renin angiotensin system
dec BP detected by juxtaglomerular apparatus -> INC renin secretion into blood -> convertion of AT I to AT II by ACE -> INC aldosterone secretion -> INC renal sodium retention -> INC blood volume (pressure)
*ACE inhibitors used for treatment of CHF
describe the steroidogenesis of mineralocorticoids, glucocorticoids and androgens
- begins with pregnenolone synthesized from cholesterol
- this conversion is performed by the enzyme cytochrome P450 which involved hydroxylation and cleavage of one of th side chains
- pregnenolone which is referred to as a prohormone can undergo further steroid metabolism to generate glucocorticoids, androgens and aldosterone
describ hormone synthesis in the adrenal cortex
hormones of the adrenal cortex are steroids derived from cholesterol
- the rate limiting step is the modification of cholesterol to pregnenolone by side chian cleavage enzyme - then pregnenolone metabolism can be directed toward the formation of aldosterone, cortisol or androstenedione
* drugs act at various points in the synthesis pathway
where in the steroid hormone synthesis pathway does aminoglutethimide act?
inhibits cholesterol -> pregnenolone
where in the steroid hormone synthesis pathway does ketoconazole act
prevents cholesterol -> pregnenolone (1st step) and 17 hydrozypregnenolone -> dehydroepiandrosterone
where does trilostane act
inhibits conv of pregnenolone -> progesterone
what causes variation in adrenocorticosteroid transport
depends on the formone thats circualting through the body
- cortisol can be transported free in the blood (5%), bound to albumin (20%) or bound to transcortin - the major corticosteroid binding globulin for glucocorticoids
when is cortisol biologically active
when not bound to CBG, it is released when it reaches its target cell so it can diffuse thorugh the cell membrane and intot he cytoplasm
describe cortisol receptor
Glucocorticoid receptors (GR) are located in the cytoplasm and are complex to a chaperone protein
- binding of cortisol dissociates the chaperone from the GR allowing the cortisol-GR complex to translocate into the nucleus
- once inside, the complex will dimerize and associate with response elements which will upregulate or downregualte gene experession
*MOA of aldosterone is very similar to cortisol but its not transported bound to proteins - it circulares freely in blood, once insdie cytoplasm it binds to the mineralcorticoid receptor (MR)
what are teh actions of cortisol
- effects can be direct or permissive
- plays a role in carbohydrate, protein and lipid metabolism and overall inc blood-glucose levels and palys role in protecting brain and heart
- in liver, cortisol stimulates gluconeogenesis and glycogen storage while in the periphery it promotes decreased glucose use and increased protein and lipid metabolism
- also an anti-inflammatory and immunomodulatory effects by inhibiting production of proinflammatory medicatoes
- released in response to stress, plays role in mood and behaviour in CNS
- stim development of lung surfactant
what are the roles of aldosterone
- central role in the cardiovascular system through fluid and electrolyte balance, specifically sodium and potassium homeostasis
- acts on distal tubules and collecting ducts of the nephrone and promotes sodium ion reabsorption and hydrogen/potassium ion excretion
*overall essential role in BP reg
uses of different steroid hormone preparations prednisolone vs dexamethasone
relative to cortisol prednisolone is 5x more portent antiinflammatory with 0.3x salt retaining properties
- dexamethasons has 30x more anti-inflammatory properties and 0x salt retaining
what is fluticasone propionate
ka flonase
- topically active glucocorticoid (anti inflamm) thats used to treat asthma and allergic rhinitis
what is mifepristone
aka Ru486
- a synthetic steroid compound that is a progesterone receptor and glucocorticoid receptor antagonist that has been used to treat cushings syndrome
what is hyperadrenocorticism
- also called cushings syndrome
- marked by presence of eleated cortisol levels in body or hypercortisolism
- signs and symptoms associated include upper body obesity (moon face or buffalo hump), thinning of skin (easily bruised), muscle wasting of arms and legs, weakening of bones (osteopenia) and elevated liver enzymes
what are the causes of Cushing’s syndrome
- can be exogenous or endogenous
- most cases are caused by corticosteroid medications and are referred to as iatrogenic or exogenous
- includes individuals who are receiving steroid medications for asthma, arthritis or other inflammatory conditions
- Endogenous is result of bodys system releasing too much cortisol from pituitary gland or adrenal gland - can be due to the presence of a tumour that secretes ACTH
how is Cushings syndrome diagnosed
- clinical signs, blood tests and imaging
- 24 hours urine colelction can be performed to measure cortisol levels
- following confirmation of elevated cortisol, furhter tests can be performed to determine the source of the problem
- if tumour, then need surgery, radiation can be performed alone or as follow up to surgery
what is the therapy for cushings
- may include hormone synthesis inhibitors (ketoconazole, aminoglutethimide and trilostane)
or glucocorticoid receptor antagonists (mifepristone)
what is ketoconazole
most effective inhibitor of cortisol synthesis
- can be contraindicted due to damage it can cause in liver
what is aminoglutethimide
hinders the conversion of cholesterol to pregnenolone
what is trilostane
hinders the conversion of pregnenolone to progesterone
what is mitotane
aka lysodren, adrenocorticoteroid inhibitor
- antineoplastic medication
- can use to treat cushings
what is addisons disease
- hypoadrenocorticism
- result of adrenal insufficiency
- usully due to autoimmune or adrenal destruction
- other causes could include: abrupt steroid withdrawal or following surgery for adrenal or pituitary tumours
- can be acute or chronic
- acute adrenal crisis is often due to withdrawal of long lasting glucocorticoid therapy - it can also precipitate from exacerbation of chronic adrenal inufficiency
*acute adrenal insufficiency is often an emergency situation and requires intravenous fluid support or corticosteroids
- chronic adrenal insufficiency present with similar symptoms to acute adrenal insufficiency are often less severe.
treatment for chronic adrenal insufficiency
l ong term glucocorticoidd (such as hydrocortisone or prednisone) replacement therapy or mineralocorticoid (such as fudricortisone) therapy if primary Addison’s disease is present can be prescribed.
what types of non endocrine diseases are glucocorticoids prescribed for?
- anti-inflammatory and anti-allergy therapy
- goal is to reduce proinflammation mediators
- short term or emergency therapy during anaphylaxis, shock or heat stroke
- glucocorticoids administered rapidly thru intravenous prep and given at high dose
- Immunosuppressive therapy
- used to quiet an overzealous immune system that is detrimental such as during organ transplants or autoimmune disorders
- dexamethasone is currently being used to tret severe COVID 19 patients
- Neoplasias
- glucocorticoids have antilymphoproliferative effects and can e sueful for certain hematologic malignancies such as lymphoma or certain leukemias
* regardless of the disorder, appropriate hlucocorticoid therapy should be employed, they only mask symptoms of the condition being treated you still need to correct the underlying problem
how do you minimize the adverse effects of steroid therapy
apply the lowest dose possible, using low potency steroids like prednisone
*alternatign therapies and tapering the reduction of steroid therapy to allow the hypothalmic pituitary axid time to recover following treatment
