unit 01: Adrenal axis

Question 1

describe the morphology of the adrenal cortex

Answer 1

• consists of inner medulla and outer cortex
• cortex aynthesizes and secretes steroid hormones essential for salt balance, intermediary metabolism and in females androgenic actions

Question 2

what are the 3 classes of steroid hormones, what can they be collectively known as

Answer 2

mineralocorticoids, glucocorticoids and androgens

collectively they are known as adrenocorticocosteroids.

Question 3

what are the 3 zones of the adrenal cortex

Answer 3

• 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

Question 4

what does release of ACTH from the anterior pituitary stimulate

Answer 4

• 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.

Question 6

what is cortisol?

Answer 6

• an endogenous glucocorticoid synthesized from cholesterol

Question 7

how is cortisol regulated?

Answer 7

• 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

Question 8

describe the Hypothalamic pituitary target organ feedback loop

Answer 8

• 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

Question 9

how is aldosterone regulated?

Answer 9

• aldosterone = steroid hormone derived from cholesterol
• aldosterone synthesis is regulated by 3 systems: renin angiotensin system, blood potassium levels and ACTH

Question 10

describe how the renin angiotensin system regualtes aldosterone

Answer 10

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

Question 11

summarize mineralcorticoids and the renin angiotensin system

Answer 11

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

Question 12

describe the steroidogenesis of mineralocorticoids, glucocorticoids and androgens

Answer 12

• 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

Question 13

describ hormone synthesis in the adrenal cortex

Answer 13

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

Question 14

where in the steroid hormone synthesis pathway does aminoglutethimide act?

Answer 14

inhibits cholesterol -> pregnenolone

Question 15

where in the steroid hormone synthesis pathway does ketoconazole act

Answer 15

prevents cholesterol -> pregnenolone (1st step) and 17 hydrozypregnenolone -> dehydroepiandrosterone

Question 17

where does trilostane act

Answer 17

inhibits conv of pregnenolone -> progesterone

Question 18

what causes variation in adrenocorticosteroid transport

Answer 18

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

Question 19

when is cortisol biologically active

Answer 19

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

Question 20

describe cortisol receptor

Answer 20

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)

Question 21

what are teh actions of cortisol

Answer 21

• 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

Question 22

what are the roles of aldosterone

Answer 22

• 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

Question 24

uses of different steroid hormone preparations prednisolone vs dexamethasone

Answer 24

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

Question 25

what is fluticasone propionate

Answer 25

ka flonase

• topically active glucocorticoid (anti inflamm) thats used to treat asthma and allergic rhinitis

Question 26

what is mifepristone

Answer 26

aka Ru486

• a synthetic steroid compound that is a progesterone receptor and glucocorticoid receptor antagonist that has been used to treat cushings syndrome

Question 27

what is hyperadrenocorticism

Answer 27

• 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

Question 28

what are the causes of Cushing’s syndrome

Answer 28

• 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

Question 29

how is Cushings syndrome diagnosed

Answer 29

• 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

Question 30

what is the therapy for cushings

Answer 30

• may include hormone synthesis inhibitors (ketoconazole, aminoglutethimide and trilostane)

or glucocorticoid receptor antagonists (mifepristone)

Question 31

what is ketoconazole

Answer 31

most effective inhibitor of cortisol synthesis

• can be contraindicted due to damage it can cause in liver

Question 32

what is aminoglutethimide

Answer 32

hinders the conversion of cholesterol to pregnenolone

Question 33

what is trilostane

Answer 33

hinders the conversion of pregnenolone to progesterone

Question 34

what is mitotane

Answer 34

aka lysodren, adrenocorticoteroid inhibitor

• antineoplastic medication
• can use to treat cushings

Question 35

what is addisons disease

Answer 35

• 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.

Question 37

treatment for chronic adrenal insufficiency

Answer 37

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.

Question 38

what types of non endocrine diseases are glucocorticoids prescribed for?

Answer 38

• 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

Question 39

how do you minimize the adverse effects of steroid therapy

Answer 39

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