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REI Written Boards 2024 - AK > Steroid Pathways and Enzyme Deficiencies > Flashcards

Steroid Pathways and Enzyme Deficiencies Flashcards

1
Q

Number of carbons in each type:
- Cholesterol
- Progestin
- Androgen
- Estrogen

A
  • Cholesterol (27)
  • Progestin (21)
  • Androgen (19)
  • Estrogen (18)
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2
Q

Basic structure of steroid hormone

A

3 x 6C rings
1 x 5C ring

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3
Q

Draw the structure of cholesterol

A

Include:
- 27 C
- 1 x OH group (C3)
- 1 x double bond (C5-C6)

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3
Q

What is a ketone group?

A

C=O (+ 2 methyl groups CH3)

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3
Q

What is a hydroxyl group?

A

CH3-OH

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3
Q

What is the structure of aromatic ring?

A

6C ring with 3 x double bonds

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4
Q

Draw estradiol

A

Include:
- 18 C
- 2 x OH groups (C3, C17)
- Aromatic ring (double bonds: 1-2, 3-4, 5-6)

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5
Q

Draw testosterone

A

Include:
- 19 C
- 1 x OH group (C17)
- 1 x ketone group (C3)
- 1 x double bond (C4-C5)

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6
Q

Draw progesterone

A

Include:
- 21 C
- 2 x ketone groups (C3, C20)
- 1 x double bond (C4-C5)

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7
Q

Types of enzyme reactions
- Desmolase
- Dehydrogenase
- Hydroxylation
- Removal of hydrogen
- Saturation (addition of hydrogen)

A
  • Desmolase: cleavage of a side chain
  • Dehydrogenase: conversion of ketone < > hydroxyl group
  • Hydroxylation: add hydroxyl group
  • Removal of hydrogen: creates double bond
  • Saturation (addition of hydrogen): reduces a double bond
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8
Q

Which enzymes in the steroid pathway work in the mitochondria?

In the endoplasmic reticulum?

A

All of the following are oxidases:

Mitochondria:
- P450scc
- P450 cyp 11 (11 beta hydroxylase)

ER:
- P450 cyp 17
- P450 cyp 21
- P450 aromatase

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9
Q

StAR (steroidogenic acute regulatory protein) function

A

Transport of cholesterol from outer > inner membrane of mitochondria

Rate-limiting step of steroid synthesis

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10
Q

What structural changes occur from cholesterol –> pregnenolone?

Enzyme?

A

Enzyme: P450scc

  1. Cleavage of cholesterol side chains C20-27
  2. Addition of C20-21 on to C17 (ketone on C20, methyl group on C21)
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11
Q

What structural changes occur from pregnenolone –> progesterone?

Enzyme?

A

Enzyme: 3B-HSD

  1. Change OH group to ketone at C3
  2. Switch double bond from C5-6 > C4-5
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12
Q

What structural changes occur from progesterone –> 11-deoxycorticosterone?

Enzyme?

A

Enzyme: 21 alpha hydroxylase

  1. Add OH group to C21
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13
Q

What structural changes occur from 11-deoxycorticosterone –> corticosterone?

Enzyme?

A

Enzyme: 11 beta hydroxylase

  1. Add OH group to C11
14
Q

What structural changes occur from corticosterone –> aldosterone?

Enzyme?

A

Enzyme: aldosterone synthase (both hydroxylase and dehydrogenase activities)

  1. Add OH group to C18
  2. Switch OH group to ketone at C18
15
Q

What structural changes occur from 17 OH pregnenolone –> DHEA?

Enzyme?

A

Enzyme: 17, 20-lyase

  1. Removes C20 and C21 > 19 C molecule
  2. Adds ketone group to C17
16
Q

What structural changes occur from pregnenolone –> 17 OH pregnenolone?

Enzyme?

A

Enzyme: 17 hydroxylase

  1. At C17: add OH group
17
Q

What structural changes occur from androstenedione –> testosterone?

Enzyme?

A

Enzyme: 17 beta HSD

  1. At C17: convert ketone > OH group
18
Q

Congenital adrenal hyperplasia
- Describe pathophysiology
- Most common enzyme deficiency?
- Phenotypes?
- Inheritance pattern?
- Diagnosis?
- Presentation?
- Treatment?

A

Pathophysiology:
- Deficient cortisol synthesis&raquo_space;
- Stimulates compensatory increase in pituitary ACTH production&raquo_space;
- Results in adrenal hyperplasia (due to over-stimulation of other hormones)
- Increased proximal steroid hormones (increased androgen production, “right shunt”)
- Virilization, ambiguous genitalia in females

  • Most common enzyme deficiency: 21 alpha hydroxylase (90% of cases)&raquo_space; build-up of progesterone and 17 hydroxyprogesterone

Phenotypes:
- Salt-wasting (homozygous): severe, presents in 1st 2 weeks of life due to deficient mineralocorticoid and glucocorticoid activity, FTT, poor feeding, lethargy, vomiting, fatigue, hyponatremia, hyperkalemia, increased renin (due to absent aldosterone), hypotension, hypovolemia, shock, ambiguous genitalia in females

  • Classic virilizing (homozygous)
  • Late onset (compound heterozygote, homozygous with some enzyme function)

Inheritance pattern: autosomal recessive

Diagnosis:
- 17-OHP measured in follicular phase > 200 ng/dL
- ACTH stimulation test reveals very high 17-OHP to confirm diagnosis
- Genotyping (will also show up on carrier screen)

Presentation:
- Ambiguous genitalia
- Chronic anovulation

Treatment:
- Glucocorticoid steroids to provide negative feedback&raquo_space; decrease pituitary ACTH release&raquo_space; decrease androgen production

19
Q

When does the male external genitalia develop?

A

9-14 weeks gestation

Exposure to excess androgens in female fetuses during this time (e.g. CAH) will result in ambiguous genitalia

20
Q

How are males diagnosed with CAH?

A

On newborn screening vs early salt wasting crisis

21
Q

What should you do first when a newborn is diagnosed with CAH?

A

CMP / electrolyte panel to assess Na+, K+ > address signs of salt wasting crisis

22
Q

What enzyme deficiency is the 2nd most common cause of CAH?

How does phenotype differ from 21 alpha hydroxylase deficiency?

A

11 beta dehydrogenase deficiency
5-8% of cases

Distinguishing features: because of the build-up of deoxycorticosterone which has some mineralocorticoid activity, NO salt-wasting, but rather:
- Hypertension
- Hypokalemia
- Low renin

Diagnosis: elevated deoxycorticosterone, elevated 11-deoxycortisol

23
Q

3B-HSD deficiency
- Which enzyme type results in CAH?
- Phenotypes?

A

Type 1 3B-HSD: placenta, peripheral tissues (skin, breast, prostate)
Type 2 3B-HSD: adrenal, ovary, testes

Type 2 3B-HSD deficiency results in CAH:
- High DHEA levels
- DHEA cannot be converted into androgens in the adrenal gland, but it can still get converted into testosterone and DHT in the periphery, resulting in hyperandrogenism

Phenotype:
- Salt-wasting
- Non-classic virilizing form (similar to PCOS: mild virilization in females)
- Under-virilized/hypospadias in males (because of inability to synthesize testosterone in adrenal gland)

Diagnosis:
- Elevated 17 hydroxypregnenolone on ACTH stim test

24
Q

stAR protein deficiency
- results in?
- phenotypic features?

A

stAR is the rate-limiting step of steroid biosynthesis (transport of cholesterol from outer > inner mitochondrial membrane

stAR deficiency&raquo_space; congenital lipoid hypoplasia (increased ACTH due to absent negative feedback > cholesterol/lipid accumulation)

Absence of all steroid hormones (no aldosterone&raquo_space; severe salt wasting, no cortisol, no androgens&raquo_space; undervirilized male)

Life-threatening if not treated with hormone replacement

25
Q

High aldosterone, 11-deoxycorticosterone > hypertension, hypokalemia

Decreased cortisol

Elevated 17 hydroxypregnenolone, 17 hydroxyprogesterone

Undervirilized males

Primary amenorrhea in females

A

17 alpha hydroxylase deficiency

26
Q

Male (XY) with female phenotype
No male external genitalia
No female internal genitalia
Virilization may occur with puberty

Condition?
Pathophysiology?
Inheritance pattern?

A

17 beta HSD deficiency
- Defect in Leydig cells of testes
- Deficient local testosterone production, which impairs male internal/external genitalia formation
- No AMH, so no female internal genitalia
- Virilization at puberty can occur with androstenedione conversion to testosterone & DHT in periphery
- AR inheritance

27
Q

Maternal hirsutism
Female fetus ambiguous genitalia

Primary amenorrhea
Hyperandrogenism
Absent breast development
High FSH, low E2
Multicystic ovaries

A

P450 aromatase deficiency
- Inability to synthesis androgens > estrogens (female fetus virilized)

28
Q

Primary amenorrhea
Hypertension
Hypokalemia
Low renin

A

11 beta hydroxylase deficiency

29
Q

Mitochondrial enzymes vs smooth ER enzymes

A

Mitochondrial enzymes:
- cyp450scc
- 11 beta hydroxylase
- aldosterone synthase

Smooth ER:
- the rest of them

REI Written Boards 2024 - AK (25 decks)

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