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MNE Exam 2 > Adrenal Steroids 2 > Flashcards

Adrenal Steroids 2 Flashcards

1
Q

What are the 3 steps from cholesterol in lipid droplets to the first step of steroid synthesis and where in the cell do they occur?

A

1) Cholesterol in lipid droplet (cytosol) cleaved by cAMP-dependent Esterase
2) Cholesterol brought by StAR protein into mitochondria (cAMP-dependent)
3) P450 cleaves side chain to make pregnenolone (cAMP-dependent)

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2
Q

What are the 3 regions of the adrenal cortex and which hormones do they make?

A

1) Zona glomerulosa: mineralocorticoids
2) Zona fasciculata: glucocorticoids
3) Zona reticularis: weak androgens

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3
Q

What is the control mechanism for each zona of the adrenal cortex? Which class of hormone is affected?

A 
1) Z. glomerulosa: renin-angiotensin
   (aldosterone - mineralocorticoid)
2) Z. fasciculata: ACTH
   (Cortisol - glucocorticoid)
3) Z. reticularis: ACTH
   (DHEA - weak androgen)
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4
Q

What are the 5 intermediates of mineralocorticoid synthesis?

A

1) Cholesterol
2) Pregnenolone
3) Progesterone
4) 11-deoxycorticosterone (DOC - active)
5) Corticosterone
6) Aldosterone

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5
Q

What are the 3 steroid conversion steps that occur in the Z. fasciculata?

A

1) Pregnenolone –> 17OH Pregnenolone
2) Progesterone –> 17OH Progesterone
3) Corticosterone –> Cortisol

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6
Q

Which 2 steroid conversions occur in the Zona reticularis?

A

17OH Pregnenolone & 17-OH Progesterone are converted to androgens.

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7
Q

What is the order of enzymatic reactions in mineralocorticoid synthesis?

A

1) P450 SCC
2) 3b-hydroxysteroid DH & d5-4 isomerase (SER)
3) 21-hydroxylase (SER)
4) 11b-hydroxylase (mito)
5) 18-hydroxylase, then 18-hydroxydehydrogenase (mito)

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8
Q

What are the 2 equilibrium forms of aldosterone? What is the significance of the 2 forms?

A

Aldehyde & Hemiacetal

The hemiacetal protects aldosterone from degradation by enzymes targeting glucocorticoids.

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9
Q

Which important enzyme is missing from the glomerulosa, creating specificity of this tissue for mineralocorticoid synthesis?

A

Glomerulosa lacks 17a-hydroxylase, so it does not produce hormones of cortisol, androgen, or estrogen pathways

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10
Q

What factor regulates mineralocorticoid synthesis?

A

Angiotensin II

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11
Q

What is the specificity of mineralocorticoid receptors for mineralocorticoids vs glucocorticoids? How is selectivity regulated?

A

Glucocorticoids bind tightly to MC receptors. Tissues with MC receptors protect from GC by enzymatically inactivating them.

  • 11b-HSD removes H from 11-OH on GCs –> inactive ketone
  • Aldosterone’s 11-OH protected by hemiacetal
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12
Q

How is aldosterone transported and excreted?

A

Binds weakly to albumin & cortisol binding globulin for transport
Half-life around 15 min, rapidly metabolized by liver
Excreted in urine as tetrahydro form

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13
Q

What are the 2 mechanisms that affect aldosterone synthesis?

A

1) Renin-Angiotensin system
2) Potassium levels

NOT usually regulated by ACTH or sodium levels

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14
Q

What is the controlling step of the renin-angiotensin cascade? Where does it occur?

A

Renin production in juxtoglomerular cells of renal afferent arteriole

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15
Q

What factors stimulate & inhibit renin production?

A

Stimulated by:

  • Decreased BP
  • Salt depletion

Inhibited by:

  • Increased BP
  • Salt loading
  • Negative feedback from angiotensin II
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16
Q

What is the function of renin?

A

Cleaves angiotensinogen into angiotensin I, which rapidly converts to angiotensin II via angiotensin-converting enzyme

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17
Q

What is the function of angiotensin II? What is another factor that has similar function?

A
  • Acts on adrenal glomerulosa cells
  • Activates aldosterone synthesis at 2 steps:
    1) cholesterol to pregnenolone
    2) corticosterone to aldosterone

Potassium regulates same steps

18
Q

What is the role of atrial natriuretic hormone? Where is it produced?

A
  • ANH, aka ANF, is a vasodilator
  • Decreases aldosterone synthesis by decreasing renin production as well as aldosterone itself
  • Produced in right atrium in response to stretch
19
Q

What is the function of 17a-hydroxylase and where does it work?

A

Converts pregnenolone (sometimes progesterone) to 17-hydroxy derivative

20
Q

In the zona fasciculata, is 17a-hydroxylase activity obligatory? Why?

A

17a-hydroxylation is not obligatory; cortisol & DOC pathways can both occur, but fasciculata lacks 18-hydroxylase so aldosterone can’t be produced. (18-hydroxylase present only in glomerulosa)

21
Q

How does the predominant glucocorticoid differ between humans and rodents? Why?

A

Corticosterone is main GC in rodents, Cortisol in humans, because humans have more 17a-hydroxylase activity

22
Q

Which hormone stimulates steroid synthesis? How is this hormone regulated?

A

Adrenocorticotropic hormone (ACTH) release from anterior pituitary stimulates steroid synthesis. Glucocorticoids are the only steroid that feeds back to inhibit ACTH & CRH

23
Q

Which carrier proteins does cortisol bind? How much is unbound? What is its half life?

A

Cortisol binds CBG, some albumin
8% free
1.5-2hr half life

24
Q

Which carrier proteins does corticosterone bind? How much is unbound? What is its half life?

A

Binds CBG weakly

half life <1hr

25
Q

Which carrier proteins does aldosterone bind? How much is unbound? What is its half life?

A

Binds Albumin & CBG (both weak)
36% free
Half life <15 min

26
Q

Which carrier proteins does DOC bind? How much is unbound? What is its half life?

A

Binds albumin, CBG

4% free

27
Q

How does the role of the adrenal glands differ between males and females?

A

Males: testes most important source of androgens
Females: Adrenal glands most important source of androgens

28
Q

How does 17a-hydroxylase enable synthesis of androgens & estrogens? How does this affect where they can be produced?

A

17-hydroxyl group is necessary to allow cleavage of C17 side chain.
-Since z glomerulosa lacks 17a-hydroxylase, androgens/estrogens can only be made in fasciculata & reticularis

29
Q

What is the major androgen produced in the adrenal gland? What is the mechanism of production?

A

Dehydroepianrosterone (DHEA)

-Produced by cleavage of C17 side chain by C17-20 lyase (found in adrenals & gonads)

30
Q

What is a common modification of DHEA and why is it significant?

A

1) DHEA is often sulfated at the 3 position
2) DHEA-3-sulfate binds tightly to SHBG
3) Very long half life

31
Q

What hormone can be derived from DHEA? Where does this occur? Which enzymes are involved?

A

In peripheral tissue, DHEA is converted to androstenedione (more potent) via 3b-hydroxylase and d5-4 isomerase

32
Q

Which hormones can be derived from androstenedione? Which enzymes are involved?

A

1) Androstenedione reduced at C17 to testosterone via 17b-hydroxysteroid DH
2) Testosterone to 17b-estradiol via aromatase

33
Q

Describe Addison’s Disease.

A

Adrenal unable to produce sufficient glucocorticoids

  • Intolerant to stress, extremely sensitive to insulin
  • Increased pigmentation from increased ACTH and other POMC peptides
34
Q

Describe secondary adrenal insufficiency.

A

Lack of ACTH. Intolerant to stress, extremely insulin-sensitive, no increased pigmentation

35
Q

Describe Cushing’s syndrome:

  • Cause
  • 5 physical traits
  • 3 systemic effects
  • 3 vascular symptoms
A

Excess of glucocorticoids

  • Due to excess ACTH production by pituitary or adrenal tumor. Pituitary = cushing’s disease
    1) Truncal obesity, buffalo hump, striae, thin legs, virilization
    2) high gluconeogenesis, decreased immune system, low inflammatory response
    3) Mineralocorticoid function of cortison –> hypertension, edema, alkalosis
36
Q

Describe Conn’s syndrome.

A

Mineralocorticoid excess:

  • due to adenomas of glomerulosa cells
  • hypertension, edema, alkalosis
  • low renin & angiotensin levels
  • aka primary aldosteronism
37
Q

Describe secondary aldosteronism

A

Renal artery stenosis decreases perfusion pressure sensed via juxtaglomerular cells, results in elevated renin & angiotensin
-leads to hyperplasia and hyperfunction of juxtaglomerular cells

38
Q

Describe congenital adrenal hyperplasia (CAH).

A

-AKA congenital adrenogenital syndrome
-Due to deficiency in steroidogenic enzymes
(90% due to lack of 21-hydroxylase, most others 11b-hydroxylase)
-Overproduce ACTH & adrenal androgens
-Increased body growth, virilization, ambiguous external genitalia

39
Q

What are ACE inhibitors and how do they work?

A

Angiotensin-converting-enzyme inhibitors:
Downregulates conversion of angiotensin 1 to 2 & 3
Lowers BP!

40
Q

What is the main estrogen in post-menopausal women? In pregnant women?

A

1) Estrone

2) Estriol (not main but made during pregnancy)

MNE Exam 2 (9 decks)

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