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Glucocorticoid Synthesis Flashcards

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1
Q

What are Glucocorticoids also called?

A

Corticosteroids

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2
Q

What do Glucocorticoids regulate?

A

Carbohydrate, Protein, and Fat metabolism.

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3
Q

What effects do glucocorticoids have on metabolism?

A

Promote Gluconeogenesis.
Increase BG
Promote protein & fat catabolism in peripheral tissues.
“oppose insulin”

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4
Q

What is the primary glucocorticoid in man?

A

Cortisol (hydrocortisone)

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5
Q

Where is Cortisol synthesized?

A

Zona Fasciculata of Adrenal Cortex.

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6
Q

What is the outermost zone of the adrenal gland called and what does it produce?

A

Zona glomerulosa

Aldosterone

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7
Q

What is the innermost zone of the adrenal gland called and what does it produce?

A

Zona reticularis

Androgens (DHEA)

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8
Q

What controls synthesis of Cortisol and where does it come from?

A 
Adrenocorticotrophic hormone (ACTH)
Anterior Pituitary
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9
Q

How is ACTH secretion regulated?

A

by the Hypothalamus through corticotropin releasing hormone (CRH)

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10
Q

How is CRH and ACTH release inhibited?

A

By negative feedback through Cortisol.

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11
Q

What are glucocorticoids synthesized from?

A

Cholesterol

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12
Q

Where is cholesterol obtained from?

A

Diet
Intracellular Cholesterol esters
Synthesis de novo in adrenals

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13
Q

Where is cholesterol transported to for glucocorticoid synthesis?

A

Mitochondria

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14
Q

What enzyme cleaves the side chain of cholesterol to pregnenolone?

A

CYP11A1 (P450scc)

RATE LIMITING STEP

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15
Q

What is the reason for patients who are unable to produce ANY of the steroids?

A

They lack the CYP11A1 enzyme or the Cholesterol Transport Protein (StAR)

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16
Q

What is characteristic of congenital lipoid adrenal hyperplasia?

A

Lack Cortisol, Aldosterone, Testosterone, Estradiol.

Exhibit –> hyponatremia and hyperkalemia (salt wasting) Female genitalia.

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17
Q

What converts pregnenolone to 17 alpha hydroxyprogesterone and androstenedione?

A

CYP17 ( steroid 17 alpha hydroxylase)

and 3beta-hydroxysteroid dehydrogenase.

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18
Q

What happens when patients lack CYP17?

A

Unable to synthesize glucocorticoids and sex steroids.

  • Lack Cortisol, Testosterone, Estradiol
  • Exhibit elevated aldosterone levels –> Na retention and hypertension.
  • Lack of sexual development (phenotypic females) and inability to mature sexually.
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19
Q

Why is CYP17 not required for aldosterone synthesis?

A

Because CYP17 is not expressed in zona glomerulosa where mineralcorticoids are synthesized.

-Lack of CYP17 causes increased production of aldosterone as glucocorticoids and sex steroids cant be made.

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20
Q

What does CYP21 convert hydroxyprogesterone to?

A

11-deoxycortisol.

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21
Q

When patient lack CYP21 what happens?

A

Unable to synthesize aldosterone and cortisol. BUT can still make sex steroids.

-CYP21 not expressed in Gonads cause increased sex steroids in people who lack it.

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22
Q

What is the most common form of Congenital Adrenal Hyperplasia (CAH)?

A

CYP21 Deficiency.

  • 1:14,000
  • Ranges from severe to mild
  • Require hydrocortisone replacement therapy, and in severe cases mineralcorticoid supplementation.
  • typically exhibit virilization
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23
Q

What is virilization?

A

Masculinization/precocious puberty

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24
Q

What does CYP11B1 (steroid 11beta-hydroxylase) convert 11-deoxycortisol to?

A

Cortisol

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25
What happens when patients lack CYP11B1?
Unable to synthesize Cortisol. -Aldosterone and Sex steroid synthesis remains intact b/c CYP11B1 is not expressed in Gonads and the Zona glomerulosa has a CYP11B2.
26
What does CYP11B1 deficiency result in?
1. Androgen Excess 2. Aldosterone Excess in some patients - Na retention and hypertension. 3. frequency of 1:250,000.
27
What is the principal mineralcorticoid?
Aldosterone.
28
What is the role of Aldosterone?
1. Regulates Na balance in body | 2. Promotes K loss in urine in EXCHANGE for Na.
29
What does CYP11B2 do to Corticosterone to make Aldosterone?
Oxidizes C18 methyl group to aldehyde.
30
Where is the only place CYP11B2 found?
Zona glomerulosa of adrenal cortex (outermost zone)
31
What does a CYP11B2 deficiency cause?
VERY RARE | -Salt wasting (Na loss) but NO effect on cortisol or sex steroids.
32
What and how much is cortisol bound to?
Plasma Proteins, 90% bound.
33
What is characteristic of Corticosteroid Binding Globulin (CBG, Transcortin)?
High Affinity and Low Capacity. -Normal conditions 80% of plasma cortisol is bound to CBG.
34
What is characteristic of Albumin?
Low Affinity and High Capacity. -normal conditions 10% of plasma cortisol is bound to albumin.
35
What is the half life of Cortisol?
~100 min.
36
What does reduction of the 4-5 double bond of cortisol cause?
Inactive Metabolites -Can happen extra-hepatically or in the liver.
37
What does reduction of the 3-keto group of cortisol cause?
Tetrahydrocortisol. -Happens in the liver.
38
What happens when Tetrahydrocortisol is conjugated at the 3-position?
Yields Glucuronide or Sulfate Metabolite. -Excretion is via URINE.
39
Where are synthetic glucocorticoids metabolized?
In the Liver. -P450 mediated hydroxylations at various positions (CYP3A4, 2C9, 2C19) -Subsequent conjugation to glucuronic acid or sulfate. -Biliary or renal excretion.
40
What do steroids bind to and activate?
The Glucocorticoid Receptor.
41
What is the action of the glucocorticoid receptor?
Either Increase or Decrease the Transcription of responsive genes. -results in delayed onset of response (4-12hr)
42
What may activation of the glucocorticoid receptor involve?
induction/activation of histone deacetylases.
43
What does steroid binding to receptors cause?
1. Release of heat-shock proteins 2. Translocation of receptor to nucleus. 3. Binding of receptor to GRE-sequences in promoter responsive genes, altering mRNA transcription.
44
What are the required features of glucocorticoids?
1. Ketone at C3 (3beta-HSD) 2. Double bond at 4-5 of A ring (3beta-HSD) 3. Hydroxyl at C11 (CYP11B1)
45
Presence of a ketone at the C11 position on glucocorticoids is on what and what is required to activate to create a hydroxyl?
Prednisone, Cortisone 11Beta-Hydroxysteroid dehydrogenase (type1)
46
Where is 11B-hydroxysteroid dehydrogenase (type 1) mainly found?
Predominantly in the liver.
47
Which form of glucocorticoids is best for topical applications?
Hydroxylated
48
Which form of glucocorticoids is best for patients w/ liver dysfunction or 11-HSD1 deficiency?
Hydroxylated
49
What protects the kidney from Cortisol?
11B-Hydroxysteroid Dehydrogenase
50
The mineralocorticoid receptor is ancestral to what receptor?
Glucocorticoid receptor. | -GR evolved from MR by gaining selectivity for cortisol.
51
What does the mineralocorticoid receptor bind?
Aldosterone & Cortisol w/ equal affinity.
52
Which receptor has selectivity for cortisol?
Glucocorticoid.
53
What is the action of 11B-HSD (Type 2) in kidney cells?
Catalyzes oxidation of Cortisol to Cortisone. - Cortisone doesnt bind to MR or GR. - Protects renal tubule from circulating cortisol (more abundant than aldosterone)
54
Where is the 11B-HSD (Type 2) found?
ONLY in aldosterone sensitive cells.
55
Why is aldosterone not oxidized by 11B-HSD?
Because of the C-18 Aldehyde.
56
What reactivates cortisone to cortisol and where?
11B-HSD (Type 1) | Liver
57
What is a rare disease associated with deficiency in 11B-HSD?
Apparent Mienralcoritcoid Excess. -HTN despite complete lack of aldosterone.
58
What does licorice contain and what does it cause?
two compounds that inhibit 11B-HSD (type2) allows cortisol to stimulate MR resulting in HTN.
59
What are the features which ENHANCE glucocorticoid potency/selectivity?
1. Addition of a double bond at 1-2 position. 2. Addition of a methyl group to C6 3. Addition of a hydroxyl or methyl group of C16. 4. Addition of a fluorine to C9. 5. Combination of above.
60
What does addition of a double bond at 1-2 do?
Enhances glucocorticoid potency 4-5 fold without affecting mineralocorticoid potency. -Slows metabolism
61
What are examples of glucocorticoids that have a double bond at 1-2 position?
Prednisone (Deltasone) | Prednisolone.
62
What does addition of a methyl group to C6 do?
Further enhances glucocorticoid potency 1-2 fold and reduces mineralocorticoid potency by half.
63
What are examples of glucocorticoids with a methyl group added to C6?
Methylprednisone/ Methylprednisolone (medrol)
64
What does addition of a hydroxyl or methyl group at C16 do?
Enhances potency by 2.5 fold. | -Eliminates mineralocorticoid effect!!!
65
What does addition of a Fluorine to C9 do?
Increases BOTH glucocorticoid (10 fold) and mineralocorticoid activity (125 fold) -Used in Aldosterone replacement therapy.
66
What is an example of a glucocorticoid with a Fluroine added to C9?
Fludrocortisone (Florinef)
67
What does a combination of enhancing features do?
Yields highly potent glucocorticoids with NO mineralocorticoid activity.
68
What are examples of glucocorticoids that have a combination of changes?
1. Dexamethasone (Decadron) 2. Triamcinolone (Aristocort) 3. Betamethasone (Diprosone)
69
What is an example of a short acting glucocorticoid?
Cortisol.
70
What are examples of intermediate acting glucocorticoids?
1. Prednisolone 2. Methylprednisolone 3. Triamcinolone 4. Fludrocortisone
71
What are examples of long acting glucocorticoids?
1. Bethamethasone | 2. Dexamethasone
72
What is the G/M potency/activity of Cortisol?
1/1
73
What is the G/M potency/activity of Prednisolone?
4/0.8 -1,2-ene
74
What is the G/M potency/activity of Methylprednisolone?
5/0.5 | -1,2-ene, C6-Me
75
What is the G/M potency/activity of Triamcinolone?
5/0 | -1,2-ene, C16-OH, 9-F
76
What is the G/M potency/activity of Betamethasone and Dexamethasone?
25/0 | -1,2-ene, C16-Me, 9-F
77
What is the G/M potency/activity of Fludrocortisone?
10/125 | -9-F

Endocrine (9 decks)

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