Steroid Pathways and Enzyme Deficiencies Flashcards by Ashley Kim

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

Cholesterol (27)
Progestin (21)
Androgen (19)
Estrogen (18)

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Basic structure of steroid hormone

3 x 6C rings
1 x 5C ring

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Draw the structure of cholesterol

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

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What is a ketone group?

C=O (+ 2 methyl groups CH3)

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What is a hydroxyl group?

CH3-OH

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What is the structure of aromatic ring?

6C ring with 3 x double bonds

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Draw estradiol

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

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Draw testosterone

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

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Draw progesterone

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

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

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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Which enzymes in the steroid pathway work in the mitochondria?

In the endoplasmic reticulum?

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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StAR (steroidogenic acute regulatory protein) function

Transport of cholesterol from outer > inner membrane of mitochondria

Rate-limiting step of steroid synthesis

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What structural changes occur from cholesterol –> pregnenolone?

Enzyme?

Enzyme: P450scc

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

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What structural changes occur from pregnenolone –> progesterone?

Enzyme?

Enzyme: 3B-HSD

Change OH group to ketone at C3
Switch double bond from C5-6 > C4-5

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

Enzyme?

Enzyme: 21 alpha hydroxylase

Add OH group to C21

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

Enzyme?

Enzyme: 11 beta hydroxylase

Add OH group to C11

What structural changes occur from corticosterone –> aldosterone?

Enzyme?

Enzyme: aldosterone synthase (both hydroxylase and dehydrogenase activities)

Add OH group to C18
Switch OH group to ketone at C18

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

Enzyme?

Enzyme: 17, 20-lyase

Removes C20 and C21 > 19 C molecule
Adds ketone group to C17

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

Enzyme?

Enzyme: 17 hydroxylase

At C17: add OH group

What structural changes occur from androstenedione –> testosterone?

Enzyme?

Enzyme: 17 beta HSD

At C17: convert ketone > OH group

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

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

When does the male external genitalia develop?

9-14 weeks gestation

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

How are males diagnosed with CAH?

On newborn screening vs early salt wasting crisis

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

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

What enzyme deficiency is the 2nd most common cause of CAH? How does phenotype differ from 21 alpha hydroxylase deficiency?

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

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

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

stAR protein deficiency - results in? - phenotypic features?

stAR is the rate-limiting step of steroid biosynthesis (transport of cholesterol from outer > inner mitochondrial membrane stAR deficiency >> congenital lipoid hypoplasia (increased ACTH due to absent negative feedback > cholesterol/lipid accumulation) Absence of all steroid hormones (no aldosterone >> severe salt wasting, no cortisol, no androgens >> undervirilized male) Life-threatening if not treated with hormone replacement

High aldosterone, 11-deoxycorticosterone > hypertension, hypokalemia Decreased cortisol Elevated 17 hydroxypregnenolone, 17 hydroxyprogesterone Undervirilized males Primary amenorrhea in females

17 alpha hydroxylase deficiency

Male (XY) with female phenotype No male external genitalia No female internal genitalia Virilization may occur with puberty Condition? Pathophysiology? Inheritance pattern?

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

Maternal hirsutism Female fetus ambiguous genitalia Primary amenorrhea Hyperandrogenism Absent breast development High FSH, low E2 Multicystic ovaries

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

Primary amenorrhea Hypertension Hypokalemia Low renin

11 beta hydroxylase deficiency

Mitochondrial enzymes vs smooth ER enzymes

Mitochondrial enzymes: - cyp450scc - 11 beta hydroxylase - aldosterone synthase Smooth ER: - the rest of them