Steroid Pathways and Enzyme Deficiencies Flashcards
Number of carbons in each type:
- Cholesterol
- Progestin
- Androgen
- Estrogen
- Cholesterol (27)
- Progestin (21)
- Androgen (19)
- Estrogen (18)
Basic structure of steroid hormone
3 x 6C rings
1 x 5C ring
Draw the structure of cholesterol
Include:
- 27 C
- 1 x OH group (C3)
- 1 x double bond (C5-C6)
What is a ketone group?
C=O (+ 2 methyl groups CH3)
What is a hydroxyl group?
CH3-OH
What is the structure of aromatic ring?
6C ring with 3 x double bonds
Draw estradiol
Include:
- 18 C
- 2 x OH groups (C3, C17)
- Aromatic ring (double bonds: 1-2, 3-4, 5-6)
Draw testosterone
Include:
- 19 C
- 1 x OH group (C17)
- 1 x ketone group (C3)
- 1 x double bond (C4-C5)
Draw progesterone
Include:
- 21 C
- 2 x ketone groups (C3, C20)
- 1 x double bond (C4-C5)
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
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
StAR (steroidogenic acute regulatory protein) function
Transport of cholesterol from outer > inner membrane of mitochondria
Rate-limiting step of steroid synthesis
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)
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
What structural changes occur from progesterone –> 11-deoxycorticosterone?
Enzyme?
Enzyme: 21 alpha hydroxylase
- Add OH group to C21
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»_space;
- Stimulates compensatory increase in pituitary ACTH production»_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)»_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»_space; decrease pituitary ACTH release»_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»_space; congenital lipoid hypoplasia (increased ACTH due to absent negative feedback > cholesterol/lipid accumulation)
Absence of all steroid hormones (no aldosterone»_space; severe salt wasting, no cortisol, no androgens»_space; 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
