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Phase 2 3. Endocrinology > Corticosteroid production and regulation > Flashcards

Corticosteroid production and regulation Flashcards

1
Q

How are steroid hormones derived?

A

enzymatic modifcation of cholesterol

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2
Q

Where are enzymes involved in steroid production found?

A

in the mitochondria and smooth ER

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3
Q

What do all steroids share?

A

a typical (not identical) ring structure

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4
Q

What are the properties of steroid hormones?

A
  • lipid soluble
  • freely permeable to membranes
  • not stored
  • synthesised and immediately released
  • not water soluble
  • carried in blood complexed to specific binding globulins
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5
Q

What carries cortisol in the blood?

A

corticosteroid binding globulin

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6
Q

Where is the adrenal gland?

A
  • abdomen, above kidneys
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7
Q

What are the adrenal glands?

A

endocrine glands

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8
Q

What gives adrenal glands their colour?

A
  • yellow

- due to high cholesterol

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9
Q

Which area of the adrenal gland has a rich nerve and blood supply?

A

`medulla

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10
Q

Describe the adrenal glands

A
  • outer cortex composed of zones with characteristic histology
  • inner medulla - embryologically and histologically distinct
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11
Q

What arteries supply the adrenal glands?

A

Each gland is supplied by the superior, middle and inferior suprarenal arteries

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12
Q

Describe the blood flow in the adrenal glands

A

The blood reaches the outer surface of the gland before entering and supplying each layer (centrepetal blood flow).

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13
Q

Which vein in the adrenal gland does blood flow into

A

medullary vein

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14
Q

Describe the course of the medullary veins

A

emerge from the hilum of each gland before forming

the suprarenal veins, which join the inferior vena cava on the right side and the left renal vein on the left

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15
Q

Describe the nerve supply of the adrenal glands

A

derived from
the coeliac plexus and the thoracic splanchnic nerves. The nerves supply
the chromaffin cells of the adrenal medulla.

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16
Q

Describe the histology of the adrenal gland

A
  • fibrous capsule
  • cortex:
    - zona glomerulosa
    - zona fasciculata
    - zona reticularis
  • medulla
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17
Q

Describe the zona glomerulosa

A

clusters of small cells. Fewer lipids than other layers

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18
Q

Describe the zona fasciculata

A

large cells arranged in cords

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19
Q

Describe the zona reticularis

A

smaller cells - haphazard arrangement

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20
Q

Describe the medulla

A

Contains:

  • chromaffin cells
  • medullary veins
  • numerous capillaries
  • splanchnic nerves
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21
Q

Where are adrenal androgens produced?

A

zona reticularis

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22
Q

What regulates the production of adrenal androgens?

A

ACTH

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23
Q

Name adrenal androgens

A

DHEA

Androstenedione

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24
Q

Name glucocorticoids

A
  • cortisol

- corticosterone

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25
Q

Where are ghlucocorticoids produced?

A

zona fasciculata

26
Q

What regulates the production of glucocorticoids?

A

ACTH

27
Q

What is the importance of glucocorticoids?

A

Carbohydrate regulation

28
Q

What is the importance of adrenal androgens?

A
  • important source of androgens in women
29
Q

How is cholesterol taken up for steroid synthesis?

A

from circulation or synthesised de novo from acetyl CoA

also taken up by the cell in the form of low density
lipoprotein (LDL).

30
Q

What is the rate limiting enzyme in cholesterol biosynthesis?

A

HMG-CoA reductase

31
Q

What is LDL?

A 
complex composed of cholesterol, phospholipids, triglycerides,
and proteins (proteins and phospholipids make LDL soluble in blood).
32
Q

How is LDL taken into cells?

A

via LDL receptors, and broken down into

esterified cholesterol, and then free cholesterol

33
Q

What is the first enzymatic step in steroid hormone synthesis?

A

the conversion of cholesterol to pregnenolone.

34
Q

Which enzyme catalyses the conversion of cholesterol to

pregnenolone.

A

Cytochrome P450 which requires co-factor.

35
Q

Where is cytochrome P450 found?

A

in the inner mitochondria

36
Q

What is the rate-limiting step in transport of free cholesterol

A

the transport of free cholesterol from cytoplasm into mitochondria carried out by Steroidogenic Acute Regulatory Protein (StAR)

37
Q

Describe the mechanism of action of steroids

A
  • steroid diffuses through plasma membrane
  • binds to intracellular receptor
  • receptor-hormone complex enters nucles
  • binds to glucocorticoid response element (DNA sequence)
  • binding initiates gene transcription to produce mRNA
  • mRNA translated into a protein, which mediates the effects-target cell response
38
Q

Where are glucocorticoid receptors found?

A

widespread

39
Q

Where are mineralcorticoid receptors found?

A
  • Distal Nephron
  • Salivary glands
  • Sweat glands
  • Large intestine
  • Brain
  • Vascular tissue
  • Heart
40
Q

Describe the mineralcorticoid receptor affinity

A

Aldo>DOC>corticosterone>

cortisol>Dexamethasone

41
Q

Describe the glucocorticoid receptor affinity

A

Dexamethasone>corticosterone>

cortisol=aldosterone

42
Q

How is the mineralcorticoid receptor protected from glucocorticoid binding?

A

11b-HSDII catalyses the conversion of Cortisol (active) to Cortisone (inactive) in selective tissues (e.g kidney) allowing aldosterone to function normally.

43
Q

What are the effects of cortisol?

A
  • Stimulates gluconeogenesis in liver
  • Permissive effect on glucagon
  • stimulation of lipolysis in adipose tissue
  • insulin antagonist
  • breakdown skeletal muscle protein
  • memory, learning, mood
  • immune suppression
44
Q

What is the result of cortisols effect on lipolysis?

A

fatty acids released are used for production of energy
in tissues like muscle and the released glycerol
provides another substrate for gluconeogenesis.

45
Q

What are the actions of Aldosterone?

A

sodium reabsorption and concomitant K+ and H+ secretion

46
Q

How does aldosetrone effect sodium levels?

A

Acts on mineralocorticoid receptors (MR) in the principal
cells of the distal tubule and the collecting duct
of the nephron-upregulates/activates basolateral Na/K pumps.

Aldosterone upregulates epithelial sodium channel (ENaC)
increasing apical membrane permeability for Na+

Aldosterone stimulates Na+ and water reabsorption
from the gut, salivary and sweat glands in exchange for K+

47
Q

How does aldosetrone effect K+/H+ levels?

A

Aldosterone stimulates the secretion of K+

into the lumen.

Aldosterone stimulates secretion of H+ via the H+/ATPase
in the intercalated cells of the cortical collecting tubules

Aldosterone stimulates Na+ and water reabsorption
from the gut, salivary and sweat glands in exchange for K+

48
Q

Describe the action of aldosterone in the kidney

A 
Aldosterone binds to
mineralocorticoid receptor (MR)

Translocated into the nucleus,

Acts as transcription factor-
Binds to HREs

Repression or induction of
aldosterone responsive genes

mRNA transcripts (SGK-1,
ENaC, NaK-ATPase)

Aldosterone Action in Kidney.

= Sodium Reabsorption
= Potassium Excretion

49
Q

What process regulates cortisol and androgen production?

A 
hormones produced by hypothalamus and anterior
pituitary gland (HPA Axis)
50
Q

What process regulates aldosterone production?

A

renin-angiotensin system

(RAS) and plasma potassium

51
Q

How is ACTH formed?

A
  • cleavage of proopiomelanocortin (POMC)
52
Q

What other peptides are formed along with ACTH?

A
  • lipotropin
  • beta-endorphin
  • met-enkephalin
  • melanocyte-stimulating hormone (MSH)
53
Q

What is the action of ACTH?

A

ACTH has rapid and long-term actions:

Stimulation of cholesterol delivery to the
mitochondria (rapid).

Increased transcription of genes coding for steroidogenic
enzymes e.g. 11B-hydroxylase (long-term).

= increased cortisol (androgen production)

54
Q

Describe ACTH binding

A

ACTH binds to 7TMD G-protein receptors

Conformation changes in receptor stimulate adenyl cyclase , causing an increase in cAMP, activation of PKA and calcium influx

55
Q

When is RAS activated?

A

in response to low
blood pressure, plasma
sodium

56
Q

What is the result of RAS activation?

A

Leads to production of Ang II
which causes direct
(vasoconstriction) and indirect (aldosterone, thirst) methods
of BP elevation,

57
Q

Describe angiotensin II binding

A

AngII binds to 7TMD G-protein coupled receptor

Activates phospholipase C

58
Q

What is the function of phospholipase C (as a consequence of angiontensin II)

A

Hydrolyses phosphatidylinositol bisphosphate (PIP2) to form 2nd messengers inositol triphosphate (IP3) and diacyl glycerol (DAG).

59
Q

What is the function of IP3 (as a consequence of angiontensin II)?

A

causes stored Ca2+ to be released

60
Q

What is the result of a rise in intracellular calcium (as a consequence of angiontensin II)?

A

activates Ca2+-calmodulin
dependent protein kinases (CaMKs) which stimulate the
transcription of StAR and cholesterol uptake into mitochondria

61
Q

How does potassium regulate aldosterone?

A

Extracellular potassium tightly controlled

Increases in potassium = increases aldosterone

> Sodium reabsorption
Potassium excretion

= Normalises potassium concentration

Phase 2 3. Endocrinology (25 decks)

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