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NEUROSCIENCE 2 > LECTURE 9 - adrenal glands - cortex > Flashcards

LECTURE 9 - adrenal glands - cortex Flashcards

1
Q

What is the basic structure of the adrenal glands?

A
  • sit on top of kidney

- split into the adrenal cortex and medulla

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2
Q

What are the adrenal cortex hormones?

A
  • corticosteroids: glucocorticoids, mineralocorticoids
  • -> synthesised with P450 cytochrome enzymes
  • (weak) androgens
  • -> derived from cholesterol (synthesised from acetate)
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3
Q

Describe the histological zonation of the adrenal glands

A

Cortex split into 3 zones:
1. Zona glomerulosa
2. Zona fasciculata
3. Zona reticularis
(All 3 responsible for corticosteroid synthesis)
Medulla responsible for catecholamine synthesis

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4
Q

How is cholesterol imported into mitochondria?

A
  • by Steroidogenic acute regulatory (StAR) protein
  • transported from mitochondrial membrane into inner mitochondrial membrane
  • this is the RATE LIMITING STEP
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5
Q

Describe the structure and regulation of StAR protein

A
  • contains a cholesterol transfer domain
  • produced in response to stimulation usually through a cAMP secondary messenger system
  • promoted by ACTH and LH
  • suppressed by alcohol
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6
Q

How is pregnenolone formed?

A

cholesterol –> pregnenolone
- using cytochrome P450scc
(scc = side chain cleavage)
- occurs within inner membrane of mitochondria
- two hyrdoxylase reactions produce 20,22-dihydroxycholesterol
- final stage = cleavage of bond between carbon 20 and 22 to produce pregnenolone

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7
Q

How is P450scc regulated?

A
  • requires electrons for function
  • works in a complex with 2 other proteins: adrenodoxin reductive and adrenodoxin (these provide initial electrons)
  • always active but dependent on supply of cholesterol
  • ACTH induces expression of all the genes in the complex
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8
Q

What are glucocorticoids?

A
  • C21 steroids
    Examples:
  • cortisol (aka hydrocortisone)
  • corticosterone

*cortisol binds, cortisone does not, cortisone is converted by the body to cortisol

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9
Q

Describe the biosynthesis of glucocorticoids

A

CYP11B1

  • metabolises precursors to make cortisol
  • requires different layers of enzymes
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10
Q

How is cortisol transported in the blood?

A
  • 90%+ bound to plasma protein
  • -> transcortin (CBG) - 80+%
  • -> albumin - 10%
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11
Q

Why is cortisol transported bound to plasma protein?

A
  • lipophilic = doesn’t like water therefore transporting cortisol in blood is difficult
  • transcortin = carrier protein for cortisol
  • in circulation, cortisol exists in 2 forms, bound and unbound
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12
Q

How does bound cortisol become unbound?

A

random equilibrium means carrier proteins randomly drop off molecules

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13
Q

What can impact cortisol levels in the body?

A
  • emotion via limbic system
  • biochemical stressors
  • drive for diurnal rhythm
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14
Q

How is ACTH generated?

A
  • produced from single gene = POMC
  • ACTH produced when POMC gets cleaved by enzymes
  • ACTH acts on adrenal but is also a prohormone
  • can be cleaved into a-MSH (regulates melanocytes) and CLIP (no known function)
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15
Q

What are the effects of ACTH?

A
  • interacts with cell surface receptor (melanocortin 2 receptor) and uses secondary messengers as peptide receptor
  • cAMP activates secondary messenger
Immediate = increased cholesterol into mitochondria 
Subsequent = increased gene transcription of hydroxylases, increased LDL receptors 
Long-term = increased size and functional complexity of organelles, increase size and number of cells => HYPERPLASIA
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16
Q

What effect do glucocorticoids have on responsive cells?

A
  • intracellular receptors (Glucocorticoid receptor)
  • glucocorticoid response element
  • protein synthesis (e.g. lipocortin)
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17
Q

What effects do glucocorticoids have on metabolism?

A

CARBOHYDRATES

  • increased plasma glucose
  • increased hepatic gluconeogenesis
  • inhibits glucose entry into tissues
PROTEIN
muscles 
- increase breakdown of protein --> amino acids 
--> wasting/ growth retardation 
liver 
- increase uptake of amino acids 
--> protein synthesis 
--> gluconeogenesis

FAT

  • increased metabolism of fatty acids from adipose tissue –> gluconeogenesis
  • redistribution to extremities
18
Q

What are the effects of glucocorticoids on bones?

A
  • decreased absorption of Ca2+
  • increased excretion
  • inhibition of osteoblasts –> osteoporosis
19
Q

What are the effects of glucocorticoids on the CNS and the immune system?

A

CNS: affects mood and cognition

Immune system:

  • decreased lymphocytes, eosinophils (disease fighting white blood cells)
  • increased neutrophils, RBCs and platelets
20
Q

What are the therapeutic actions of glucocorticoids?

A
  • Anti-inflammatory: potentially decrease leukocyte action - rheumatoid arthritis: potential proteolysis at site of damage
  • Anti-allergic: decreased histamine synthesis and release
  • Immunosuppression
21
Q

What diseases can arise from an excess of glucocorticoids?

A 
Cushings syndrome 
- pituitary tumour = Cushing's disease 
- ectopic ACTH producing tumour 
- autonomous adrenal adenoma 
- trunkal obesity, thin arms/ legs, striae
Treatment:
- surgery/ radiotherapy
- drugs: Metyrapone (11 hydroxylase inhibitor) - inhibiting this will reduce cortisol production

Iatrogenic = relating to illness caused by medical examination or treatment
- long term immunosuppression with synthetic cortisol analogues

22
Q

What can result from decreased adrenal function?

A 
1° - Addison's disease 
- 65+ % autoimmune attack on adrenal gland 
symptoms:
- fatigue: hypoglyceamia 
- weight loss
- skin pigmentation 
- ion imbalance 
treatment 
- cortisol replacement therapy 
- mineralocorticoid replacement

2°

  • decrease of pituitary function (decreased ACTH)
  • stopping long-term glucocorticoid therapy
23
Q

What are mineralocorticoids?

A
  • C21 steroids
  • named due to effect on ion levels in plasma
  • e.g. aldosterone
24
Q

Describe the biosynthesis of aldosterone

A

Occurs in z. glomerulosa

Progresterone –> 11-deoxycorticosterone –> corticosterone –> 18-hydrocorticosterone –> aldosterone

Arrow 1 = 21-hydroxylase
Arrow 2 = 11-hydroxylase
Arrow 4 = aldosterone synthase (an 11-hydroxylase enzyme)

25
Q

How is aldosterone transported in the blood?

A
  • requires a binding proteins but not a specific kind
  • albumin + transcotrin (50%)
  • free in plasma
26
Q

How is aldosterone secretion regulated?

A
  • ACTH (minor role): large ↑ in ACTH can ↑ ald.
  • Plasma K+: ↑ in plasma K+ of 10% will ↑ ald.
  • Plasma Na+: ↓ in plasma Na+ of 10% will ↑ ald.
  • Renin-angiotensin system
27
Q

What is the renin-angiotensin system?

A
  • drop in pressure sensed by the kidneys => renin production from juxtaglomerular cells
  • renin causes liver to convert angiotensinogen into angiotensin I which turns into angiotensin II
  • aldosterone comes from this step which causes renal Na+ retention which increases ECF again
28
Q

Describe the mechanism of action of aldosterone

A

There are 2 types of intracellular receptors (differing affinities for aldosterone)

Low = glucocorticoid receptors

29
Q

What issues arise with the mechanism of action of aldosterone?

A

2 types of intracellular receptors with differing affinities for aldosterone

Low = glucocorticoid receptors

  • can also bind aldosterone as similar structure between ald. and cortisol
  • affinity of GR for cortisol is much higher than ald. so no issue
High = mineralocorticoids 
- can bind both ald. and cortisol 
- ald. affinity = cortisol affinity BUT 
[cortisol] > [ald.] therefore every time we get stressed and release cortisol MR will be active not just when ald. binds
Need mechanism to overcome this
30
Q

What diseases can arise from an excess of mineralocorticoids?

A

Syndrome of apparent mineralocorticoid excess (AME)

  • severe hypertension
  • hypokalaemia (low levels K+)
  • low renin, low (or normal) ald. levels
  • there is no aldosterone excess (even though it looks like there is)
  • problem is cortisol
31
Q

Explain the pre-receptor regulation of kidney MR transactivation

A
  • 11b-HSD2 enzyme converts cortisol –> cortisone (essentially inactivates cortisol)
  • in normal physiology, kidney turns cortisol into cortisone so MR free for ald. so no issue
  • in AME patients, they have a gene mutation in 11b-HSD2, so cortisol not inactivated so will bind to MR => consequences
32
Q

What are 11-beta hydroxysteroid dehydrogenases?

A
  • tissue specific glucocorticoid metabolism
  • 11-BHSD2: allows MR to bind to aldosterone
  • 11-BHSD1: role in obesity and related disorders?
33
Q

What is the effect of mineralocorticoids on protein synthesis?

A
  • increases protein synthesis

- proteins involved in Na+ handling

34
Q

What is the effect of mineralocorticoids on Na and L reabsorption?

A

Increased Na+ reabsorption

  • DCT and collecting duct
  • sweat glands
  • salivary glands
  • GIT

Decreased K+ reabsorption

35
Q

What are some other systemic actions of mineralocorticoids?

A
  • ↑ hydrogen loss –> metabolic alkalosis
  • ↑ H2O reabsorption ( ↑Na+ reabsorption)
    –> regulation of BP
    (only really increases ECF by ~15% - this is because people with CHF would die if BP increased too much as ald. increases BP)
36
Q

What diseases can arise from abnormal mineralocorticoid levels?

A
  • Hyperaldosteronism (1° and 2°)

- Addisons disease

37
Q

What is 1° hyperaldosteronism?

A
  • autonomous production of aldosterone
    Conn’s syndrome

Cause: hyperplasia or adrenal adenoma in z.glomerulosa
(renin levels normal or low)

Symptoms:

  • hypertension
  • alkalosis
  • hypokalaemia
  • -> muscle weakness + cardiac arrhythmias

Treatment:

  • surgery
  • spironolactone (drug that targets receptor to which ald. will bind)
38
Q

What is 2° hyperaldosteronism?

A
  • increased ald. due to high renin levels
    (problem to do with kidney unlike adrenal gland as 1°)

Cause:

  • renal artery stenosis
  • diuretic therapy
  • XS liquorice ingestion
39
Q

What can arise from an aldosterone deficiency?

A

Addisons disease

  • ion imbalance
  • -> hyperkalaemia
  • -> hypotension
40
Q

What is CAH?

A

Congenital Adrenal Hyperplasia
- Block in adrenal steroidogenesis affecting glucocorticoid synthesis

Symptoms:

  • dehydration, salt loss, weakness
  • females: male genitalia, hirsutism
  • males: precocious puberty

Treatment:
- corticosteroid replacement

41
Q

What is 21 hydroxylase CAH?

A
  • Autosomal recessive; 1/10000 births
  • decreased glucocorticoid and mineralocorticoid production
  • 21-hydroyxlase deficiency
  • stops production of cortisol (which should stop ACTH in a -ve feedback mechanism) therefore –> increased ACTH –> steroid production continues –> enlarged adrenal glands –> push everything towards androgen production
42
Q

What are adrenal androgens?

A
  • synthesised in small amounts in z.reticularis
  • DHEA and Androstenedione
  • redundant in males?
  • in females may cause growth of pubic and axillary hair and could be responsible for female libido

NEUROSCIENCE 2 (32 decks)

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