Lecture 25: Adrenocorticosteroids

Question 1

What are secretions of the medulla?

Answer 1

adrenaline

catecholamine/amino acid hormone

Question 2

What are secretions of the cortex?

Answer 2

zona glomerulosa
zona fasciculata
zona reticularis
steroid hormones

Question 3

What are mineralocorticoids?

Answer 3

salt balance
aldosterone
zona glomerulosa

Question 4

What are glucocorticoids?

Answer 4

metabolic and immune effects
cortisol
zona fasciculata

Question 5

What are androgens?

Answer 5

DHEA
Precursors for strong androgens (testosterone) and estrogens
zona reticularis

Question 6

What are the “HPA” axis and steroidogenesis?

Answer 6

“HPA” axis controls cortisol release from the zona fasciculata

ACTH (pituitary) stimulates steroid production: after meals, circadian rhythm (high just before waking)

ACTH is controlled by CRH from the hypothalamus

steroid hormones cannot be stored like peptides; ACTH stimulates cortisol synthesis

Question 7

What is negative feedback in the HPA xis?

Answer 7

cortisol exerts negative feedback on: CRH (hypothalamus)and ACTH (ant. pituitary)

cortisol suppresses stress signals like cytokines involved in the stress response (“other regulatory signals”)

cortisol acts on glucocorticoid target tissues – stress response, catabolism and immuno-suppression - “glucocorticoid response”

Question 8

What is the RAAS system in aldosterone release?

Answer 8

RAAS: renin - angiotensin - aldosterone system

renin: released by the juxtaglomerular apparatus (kidney; generates AT1 from angiotensin

ACE (angiotensin converting enzyme) converts AT1 to AT2

AT2 triggers aldosterone release

aldosterone: primary target is kidneys, promotes Na+/water reabsorption, K+ excretion “mineralocorticoid response”

the primary role of RAAS is control of blood pressure/volume

Question 9

What is the generalized mechanism of steroid hormone action?

Answer 9

cytoplasmic unliganded receptor in complex with Hsp90

binding of hormone causes dissociation from Hsp, transport into nucleus

dimerized receptors, interact with DNA and influence transcription of target genes

GRE - Glucocorticoid receptor / response element

Question 10

What are the receptors for corticosteroids?

Answer 10

glucocorticoid receptor (stimulates GC response)

mineralocorticoid receptor (stimulates a MC response)

“spectrum”: steroids have different affinities for either receptor

each receptor activates/represses transcription of different sets of genes (and unique target tissues)

Question 11

What are mechanisms for in vivo specificity?

Answer 11

many glucocorticoid target tissues (adipose, muscle, liver) express 11beta-hydroxysteroid dehydrogenase, type 1, “activates” cortisol

corticosteroid specificity arises from affinity of the compound/receptor, and metabolism in target tissues

Question 12

What is prednisone?

Answer 12

not very effective topically

widely used (oral intake, injection)

must be metabolized to prednisolone to become effective

Question 13

What is prednisolone?

Answer 13

strong topical effect

active form of prednisone

Question 14

Cortisol activates the GR and MR but was weak mineralocorticoid effects in vivo. Why?

Answer 14

kidney cells (mineralocorticoid targets), express an enzyme (11beta-hydroxysteroid dehydrogenase, type 2) that renders cortisol inactive

Question 15

What is pseudohyperaldosteronism?

Answer 15

licorice contains an inhibitor of 11beta-hydroxysteroid dehydrogenase, type 2

this allows glucocorticoids to have an inappropriate effect in aldosterone target tissues like the kidney

a “licorice overdose” can cause high blood pressure (due to aldosterone-like effects including Na+ and water reabsorption

genetic disease called Apparent Mineralocorticoid Excess, arising from mutations in the 11beta-hydroxysteroid dehydrogenase, type 2 gene

Question 16

What are the short term/acute metabolic effects of glucocorticoids?

Answer 16

carbohydrate metabolism –> increases circulating glucose

fat/lipid balance –> promotes fat breakdown

muscle –> promotes breakdown of muscle, overall “catabolic” effects, loss of muscle and bone mass in limbs

inhibit action of insulin (inhibits glucose uptake in muscle, adipose)

Question 17

What are the long term/prolonged effects of glucocorticoids?

Answer 17

features include enhanced fat deposition (especially in the trunk)

characteristic physical appearance of adipose accumulation in the trunk, but loss of mass in limbs

likely partly due to increased insulin levels in response to elevated glucose caused by corticosteroid

also potential tissue specific actions of cortisol

Question 18

What are the key glucocorticoid-mediated mechanisms in inflammation?

Answer 18

inhibit AA generation

inhibit prostanoid synthesis

these two effects have widespread downstream effects on inflammatory reactions

Question 19

What is cyclooxygenase-2?

Answer 19

COX-2 is an important inflammatory mediator, early in the process of inflammation

COX-2 plays an early step in the metabolism of Arachadonic Acid to various prostanoids (depending on the cell type)

glucocorticoid regulation of COX-2 does not involve direct receptor antagonism

Glucocorticoids influence (suppress) transcription of the COX-2 gene, leading to a long-term suppression of COX-2 expression (protein levels)

they do not directly inhibit cyclooxygenase activity

Question 20

What are lipocortins/annexins?

Answer 20

are a large family of proteins characterized by “annexin repeats”

Question 21

Annexin A-I plays an important anti-inflammatory role for what two important reasons?

Answer 21

1. direct effects on Leukocytes inhibits their tissue infiltration
2. suppression of phospholipase A2 activity; this prevents AA generation, and thereby suppresses downstream generation of prostanoids

these effects are very early in the inflammatory response, so they have broad powerful anti-inflammatory efefcts

Question 22

What is lipocortin?

Answer 22

lipocortin is a protein – expression is induced by GC receptor activation

mechanism of inhibition of PLA2 is debated - could be by sequestering lipid substrates, or direct inhibition of PLA2

Question 23

What is Addison’s disease?

Answer 23

chronic adrenocortical insufficiency (fatigue, salt balance, sugar balance problems, skin discoloration)

low production of glucocorticoids, and often mineralocorticoids

typically treated with GC/MC supplementation (hyrocortisone/cortisol)

Question 24

What are the causes of Cushing’s syndrome?

Answer 24

adrenal tumor (cortisol producing)

pituitary tumor (ACTH production, stimulation of adrenal cortex)

drug-induced (long course of GC treatment)

ectopic tumor (ACTH producing)

Question 25

What are the symptoms of Cushing’s syndrome?

Answer 25

adrenal overactivity leading to excessive cortisol

round face, fat deposition in trunk

muscle loss, osteoporosis - protein and bone catabolism

resection of adrenals or pituitary tumor, followed by gradual adjustment towards a maintenance dose of cortisol

understanding the features of Cushing’s disease is helpful to understand the side effects of GC treatment

symptoms resemble side effects of therapeutic doses of GCs

Question 26

What causes the dark complexion in Addison’s disease?

Answer 26

it is a consequence of GC feedback mechanism

ACTH is generated in POMC neurons of the pituitary; cleavage of the POMC gene product generates multiple hormones, including melanocyte stimulating hormone

absence of feedback from cortisol causes hyperproduction of POMC and downstream products

Question 27

What are the feedback loops involved in glucocorticoid overproduction?

Answer 27

in an individual with an adrenal tumor producing unregulated cortisol, there would be high cortisol, and low ACTH

in an individual with a pituitary tumor producing unregulated ACTH, there would be high cortisol, and high ACTH

Question 28

What are glucocorticoids used to treat?

Answer 28

powerful anti-inflammatory, immunosuppressive actions of cortisol and analogs

allergic reactions (bee stings, contact dermatitis)

eye inflammation (uveitis, conjunctivitis)

reduction of pain and scarring after injury/surgery, by reducing inflammation

gastrointestinal diseases (inflammatory bowel syndrome)

hematologic disorders (leukemia, myeloma)

asthma

organ transplants (immunosuppression to avoid rejection)

Question 29

What are Addison-like side effects of glucocorticoids?

Answer 29

Addison-like symptoms if stopped abruptly

negative feedback from glucocorticoid administration will suppress CRH and ACTH production

“Addisonian” crisis: Hypoglycemia, hyponatremia, hyperkalemia, low blood pressure

tapering is needed when stopping long-term course of glucocorticoids (i.e., you should not abruptly stop taking a glucocorticoid)

Question 30

What are the metabolic side effects of glucocorticoid treatment?

Answer 30

hyperglycemia

care must be taken with diabetic patients

Question 31

What are the immunosuppressive side effects of glucocorticoid treatment?

Answer 31

caution with patients carrying infections

latent infections can emerge (TB)

opportunistic infections can emerge

Question 32

What are the catabolic side effects of glucocorticoid treatment?

Answer 32

osteoporosis, muscle wasting

Question 33

What are the anti-inflammatory side effects of glucocorticoid treatment?

Answer 33

slow wound healing, ulcerations

Question 34

What are the other side effects of glucocorticoid treatment?

Answer 34

hypertension considerations (non-specific MR effects of some GCs)

psychosis