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FHB - Endocrine & Reproductive > Lecture 5 (72): HPA Axis and Adrenal Gland > Flashcards

Lecture 5 (72): HPA Axis and Adrenal Gland Flashcards

1
Q

What parts of the adrenal gland are regulated by the HPA axis?

Which are not regulated by HPA axis?

A
  1. Adaptive response to stress
    a) Catecholamines, epinephrine, norepinephrine)
    b) Glucocorticoids – cortisol
  2. Immune function
    a) Anti-inflammatory – glucocorticoids

NOT REGULATED:

1.Maintenance of water, sodium, potassium balance and blood
pressure
2.Mineralocorticoids – aldosterone

  1. Site of “weak” androgen production
    - DHEA/DHEAS
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2
Q

What is the HPA axis for ACTH?

A
  1. Hypothalamus –> CRH/CRF
  2. Pituitary –> ACTH
  3. Adrenal
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3
Q

What is the short feedback of the Adrenal Gland?

Long?

A
  1. ACTh

2. Cortisol

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4
Q

_____ is Central regulator of ACTH HPA axis - 41 amino acids

Produced in parvocellular neurons of _____.

Stimulates _____

A
  1. CRH
  2. PVN
  3. anterior pituitary (POMC/ACTH)
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5
Q

CRH release is _____ (pulsatile/slow).

What is the result?

Half life?

A
  1. PULSATILE
  2. Episodic release of ACTH
  3. Half life - 5 min
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6
Q

CRH uses what type of receptors?

CRH R1/R2 binds with highest affinity to CRH?

What doe R2 bind?

A

G protein-coupled receptors

– CRH R1 and CRH R2. Binds with highest affinity to CRH R1 in anterior pituitary.

CRH R2 binds with higher affinity to Urocortin.

Evidence for multiple intracellular signaling pathways – CRH can activate at least 5 different G proteins

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7
Q

What is CRH synergistic with?

A

AVP

-ACTH release is amplified in the presence of AVP

  • AVP
  • IMPORTANT MODULATOR OF THE STRESS RESPONSE because of the synergistic affect
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8
Q

ACTH:

Produced in the _____pituitary

Regulated by _____ (2) from hypothalamus

What is the precursor?

A
  1. anterior ((corticotroph)
  2. CRH and AVP
  3. Precursor = POMC (pro-opiomelanocortin)
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9
Q

ACTH:

Binds with high affinity to what receptor?

Binds with low affinity what other receptor?

High levels of ACTH lead to ______

A
  1. melanocortin 2 receptor (MC2R)
  2. to MC1R (skin)
  3. hyperpigmentation
    - Melanocye t 1 in skin - can get binding with increased ACTH = HYPERPIGMENTATION
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10
Q

What are some important effects of MC2R (ACTH receptor)?

A

Immediate Effects  stimulate the 1st step of steroid/hormone biosynthesis/ STAR important to transport cholesterol from outer to inner mitochondrial membrane
Subsequent effects
Long – Term consequences of overproduction of ACTH

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11
Q

The 1st step of steroid hormone synthesis requires ACTH why?

A

increases cAMP to increase cholesterol esterase and increase STAR to transport cholesterol from outer to inner mitochondrial membrane

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12
Q

What are the 2 divisions of the Adrenal Gland?

A

FUNCTIONALLY 2 GLANDS

1 Cortex = steroid hormones

  1. Medulla = catecholaines

Cortex derives from mesoderm

Medulla derives from neural crest: modified “sympathetic postganglionic neurons”.

Sympathetic innervation synapses on medullary cells.
in ADRENAL Gland (acting like neural tissue)

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13
Q

What are the 3 layers of the adrenal gland?

A
  1. Zona glomerulosa (mineralcorticoids)
  2. Zona fasciculata (GLUCOCORTICOIDS)
  3. Zona Reticularis - weak androgens (DHEAS)
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14
Q

What hormones do the following layers of the Adrenal Gland make?

  1. Zona glomerulosa
  2. Zona fasciculata
  3. Zona Reticularis
A
  1. Zona glomerulosa (mineralcorticoids)
  2. Zona fasciculata (GLUCOCORTICOIDS)
  3. Zona Reticularis - weak androgens (DHEAS)
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15
Q

What cells make cholesterol within the Adrenal Gland?

A

SPONGIOCYTES

- giant lipid droplets containing cholesterol

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16
Q

What is the blood supply to the ADRENAL gland?

  1. Cortex
  2. Medulla
A

Cortex: Suprarenal arteries break into subcapsular plexus of capillaries (fenestrated).

Medulla: Dual blood supply

Bathes the medullary cells with blood carrying corticosteriods from the cortex – important for conversion of NE to E.

Arterioles break into fenestrated (with diaphragm) capillaries.

All blood drains into central vein

17
Q

Cortisol:

  1. Released in response to_____.
  2. Binds with high affinity to _____. (2 receptors)
  3. Cortisone (inactive) converted to Cortisol by what?
A
  1. acute/chronic stress (physical – starvation, illness; psychological)
  2. glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in cytoplasm
  3. by 11β-HSD1
18
Q

Corticosteroid Binding Globulin (CBG)/TRanscortin

  1. Made where?
  2. Most found bound to what?
  3. What increases CBG –> increases FREE cortisol?
  4. What decreases CBG?
A
  1. 383 AA glycoprotein made in the liver
  2. 90% circulating cortisol bound to CBG; 7% bound to albumin
    - 4% “free” cortisol
  • 30-fold higher affinity for cortisol than aldosterone
    3. Estrogen decreases CBG – results in increased free cortisol
  1. Shock/severe infection decreases CBG
    - want free cortisol for anti-inflammatory affects
19
Q

What hormone causes more free cortisol?

A

Estrogen

20
Q
  1. Glucorticoids are made where?
  2. Peaks where?
  3. Bound to what transport proteins in blood? (active/inactive?)
A
  1. Made in the Zona Fasciculata Cortisol
    - Accounts for more than 80% of cortical hormones
  2. Released in circadian manner – peaks around 8:00 AM
  3. Bound to transport proteins in blood (CBG) – must dissociate in order to be active (~ 5% free)
21
Q

Why is cortisol a pleiotropic hormone?

A

CORTISOL:
decrease bone formation OSTEOPOROSIS risk
mood
state of arrousal
maturation of fetus
increase surfactant in blood ( Cortisol given to premature babies to increase surfactant production)
MOBILIZES GLUCOSE - gluconeogenesis

22
Q

What are the metabolic action of cortisol?

What does it counter?

A

Metabolic Actions – potent counter-regulatory hormone to insulin.

Mobilizes energy stores – increase plasma glucose = “glucocorticoid”.

  1. Increase gluconeogenesis and plasma glucose levels
  2. Increase lipolysis
  3. Breaks down muscle protein - proteolysis
  4. Redistributes fat – abdominal obesity, depletion of subcutaneous fat
  5. Antagonizes insulin action
  6. Inhibits intestinal calcium absorption** (will discuss more in Ca2+ regulation lecture)
    = BONE BREAKDOWN (one of the reasons)
23
Q

What are the main functions of cortisol?

WHat 3 enzymes does it need for this?

A
  1. Increase gluconeogenesis an plasma glucose levels
  2. Glucose - 6- Phosphotase
  3. PEPCK
  4. Tyrosin Aminotransferase
24
Q

How does cortisol affect muscle?

A
  1. Inhibit GLUT 4 insertion on membrane
  2. Decrease glucose uptake in muscle cells
  3. Maintains PLASMA GLUCOSE!
  4. PROTEOLYSIS
    - cortisol stimulates protein degradation and decreases protein synthesis

how? stimulate the phosphorylation of FOXO- P

= stimulate E3 ubiquitin ligase to increase protein degradation

25
Q

How does Cortisol affect fat stores?

A

Increases lipolysis

STIMULATE GENE TRANSCRIPTION: (2lipases)
Mag Lipase
HSTL (lipase)

26
Q

Glucocorticoid Receptor:

  1. What do local inflammatory responses cause?
  2. GR increases _____
  3. Glucocorticoids prevent ____ translocation to the nucleus.
A

Local inflammatory responses decreased by GR action on NF-κB (pro-inflammatory cytokines)

GR increases IκB transcription

Glucocorticoids prevent NF-κB nuclear translocation

27
Q

What are cortisol functions on the immune system?

A

Immune –

  1. Decreases inflammation
  2. stimulates anti-inflammatory cytokines
  3. inhibits prostaglandins
  4. Suppresses antibody production
  5. Increases neutrophils, platelets, and RBCs.

(Anti-inflammatory effects are primary reason for glucocorticoid therapy)

28
Q

What are the 3 affects of Cortisol on bone?

What receptors does it decrease?

A

Inhibits intestinal calcium absorption – transcellular transport

Inhibits bone formation – decrease IGF-I receptors

Increases bone resorption – activation of osteoclasts

29
Q

What are the affects of Cortisol on CARDIOVASCULAR?

A
  1. Cardiovascular – during “physical stress” want blood to flow to brain/heart – away from periphery
  2. Stimulates red blood cell production
  3. Maintains responsiveness to catecholamine pressor effects
  4. constrict peripheral vessels via alpha-adrenergic receptors
  5. Dilate coronary arteries in heart via beta-adrenergic receptors
  6. Glucocorticoid excess = increased blood pressure/hypertension
    Maintains vascular integrity and reactivity
30
Q

What does cortisol have negative feedback on?

A
  1. CRH and ACTH release
31
Q

What are the actions of cortisol on the CNS?

A 
Central Nervous System – 
Emotional response 
	depression 
	anxiety 
	nervousness 
	panic 
	rage/aggression
32
Q

What is cushing disease?

Why does it occur?

What are the symptoms?

A

Excessive cortisol secretion due to PITUITARY adenoma

Change in body fat distribution – moon face, buffalo hump, abdominal obesity, thin skin, bruising

Inhibition of intestinal calcium absorption – osteoporosis

Hypertension – excess glucocorticoids activate MR

Glucose intolerant – antagonism of insulin action

Purple Striae – Fragile thin skin stretches over increased abdominal fat, vessels hemorrhage into striae

**Also occurs with long-term glucocorticoid therapy

33
Q

When is glucocorticoid therapy administered?

A

Medical Emergencies
High acute dose to treat septic shock, severe asthma, severe autoimmune disease flare

Usually no long-term side effects

Chronic

Anti-inflammatory
Immunosuppressive

Adrenal insufficiency

Pre-term infants – improved lung function

34
Q

What are the analogs of glucocorticoid?

A
  1. Cortisol
  2. Prednisone
  3. Methylprednisone
  4. Dexamethasone
  5. Fludrocortisone
35
Q

What is adrenal insufficiency?

Describe:
1. Primary AI

  1. Secondary AI

Which one is Addison’s disease?

Which is associated with failure to secrete CRH or ACTH?

Which is failure at the adrenal level?

A
  1. Failure of adrenal to secrete glucocorticoids, mineralocorticoids, or both.

Primary – failure at adrenal level

Addison’s Disease = autoimmune destruction of adrenals
70% of primary AI cases

Secondary – failure to secrete CRH or ACTH

Most common cause = sudden cessation of glucocorticoid therapy

Anticipated if patient takes greater than 30 mg hydrocortisone, 7.5 mg prednisone, 0.75 mg dexamethasone for longer than 3 weeks

FHB - Endocrine & Reproductive (17 decks)

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