Biosynthesis of steroid hormones: 11

Question 1

What are the 5 types of cell-cell communication?

Answer 1

Juxtacrine signaling

Endocrine signaling

Paracrine signaling

Synaptic or neuronal signaling

Autocrine signaling

Question 2

What is juxtacrine signaling?

Answer 2

Direct physical contact

Question 3

What is endocrine signaling?

Answer 3

Travels fairly far through the blood to a target organ expressing receptors.

Low [ ] high affinity receptors

minutes to hours

Question 4

What is paracrine signaling?

Answer 4

Travels short distance and affect neighbor cells.

High local [ ] receptors with low affinity

Rapid and localized

Question 5

What is synaptic or neuronal signaling?

Answer 5

Neurotransmitters that travel a short distance.

Very high local [ ] dissociate rapidly

Millisecond termination

Question 6

What is autocrine signaling?

Answer 6

Made and functions in the same cell

EX: cancer cells use this to promote their own growth.

Question 7

What is important about intracellular receptors?

Answer 7

They have a high log P because they are hydrophobic enough to diffuse the membrane.

Question 8

What is important about cell surface receptors?

Answer 8

The first messenger will bind to a receptor on the surface of the cell generating a second messenger inside the cell to activate.

Question 9

Where do steroids bind?

Answer 9

Intracellular receptors found in the nucleus.

bind tight to receptors

Question 10

What do steroid hormones do in general once bound to specific hormone receptors?

Answer 10

Regulate transcription of a specific set of genes.

Question 11

How are the 5 steroid hormones divided up?

Answer 11

Adrenocortical hormones (adrenal hormones) -2

Sex and progestational hormones (gonadal hormones) -3

Question 12

What are the 3 gonadal hormones?

Answer 12

Progesterone (C-21): female menstrual cycle, pregnancy, embryogenesis

17-beta-estradiol (C-18): estrogen, female hormone

Testosterone (C-19): androgen, male hormone

Question 13

What are the 2 adrenal hormones?

Answer 13

Cortisol (C-21): glucocorticoid, anti-stress hormone, anti-inflammatory

Aldosterone (C-21): mineralocorticoids, regulator of Na+ in the kidney; raises blood volume and blood pressure

Question 14

What receptors do each of the 5 hormones bind to?

Answer 14

Testosterone binds to the androgen receptors

17-beta estradiol binds to the estrogen receptor

Aldosterone binds to the aldosterone receptor

Progesterone binds to the progesterone receptor

Cortisol binds to the corticosteroid receptor

Question 15

What family do steroid receptors belong to?

Answer 15

Nuclear receptor family

Question 16

What are the steps to the classic model of steroid action?

Answer 16

1. Penetrate the membrane
2. Bind hormone receptor
3. Activation
4. Transported to nucleus
5. Bind DNA
6. Regulate transcription of specific set of genes

Question 17

What is a hormone response element (HRE)?

Answer 17

A DNA binding domains of activated dimers bind to specific DNA sequences upstream of steroid response genes.

Once bound, rate of transcriptions is changed.

Question 18

What is an example of a negative feedback loop?

Answer 18

When cortisol levels end up getting too high, they will suppress ACTH and CRH leading to an eventual decrease of cortisol released the adrenal gland.

Question 19

Where does synthesis of steroid hormones start?

Answer 19

Cholesterol (C-27) is cleaved by p450scc (site chain cleaving) enzyme into Pregnenolone (C-21).

Question 20

What other molecules can pregnenolone create?

Answer 20

All 5 of the hormones.

Cortisol
Aldosterone
Progesterone
Estradiol
Testosterone

Question 21

What does the enzyme 17a-Hydroxylase do?

Answer 21

Adds a alpha hydroxyl group at carbon 17.

Converts Pregnenolone to intermediate.

Converts Progesterone to intermediate.

Question 22

What does the enzyme 17,20-lyase do?

Answer 22

Removes the 20 and 21 carbons and makes carbon 17 a ketone.

Converts the intermediate into DHEA.

Converts the intermediate into androstenedione.

Question 23

What does the enzyme 3B-Dehydrogenase Delta 5, Delta 4 isomerase do?

Answer 23

The isomerase enzyme will move the double bond from carbons 5-6 to carbons 4-5.
Additionally the dehydrogenase enzyme will change carbon 3 from a hydroxyl to a ketone.

Converts pregnenolone to progesterone. (leads to aldosterone too)

Converts intermediate to another intermediate. (leads to cortisol)

Converts DHEA to androstenedione. (leads to testosterone and estradiol)

Question 24

What happens with a 17a hydroxylase deficiency? RARE

Answer 24

Caused by mutations in CYP17A1 having both 17a-hydroxylase and 17,20 lyase activity.

Leads to overproduction of mineralocorticoids and deficiency of corticosteroids and sex hormones.

SX: Hypocortisolism (low cortisol, high CRH and ACTH) leads to enlarged adrenal glands

Ambiguous genitalia: intersex

Hyperaldosteronism: increased mineralocorticoid production causes high Na+ uptake leading to high blood volume and high BP

Question 25

What do the enzymes 21-hydroxylase and 11B-hydroxylase do?

Answer 25

Add a hydroxyl group to carbon 21 and a beta hydroxyl group to carbon 11.

Question 26

What happens with a 21 hydroxylase deficiency? More common

Answer 26

Mutations in CYP21A2 which functions as 21-hydroxylase.

SX: Hypocortisolism (low cortisol, high CRH and ACTH) leads to enlarged adrenal glands.

Hypoaldosteronism: decreased mineralocorticoid production causes less Na+ uptake leading to low blood volume and low BP

Premature androgen exposure…
Ambiguous genitalia in female
Hirsutism
Early epiphyseal closure because sex hormones promote the closure of the epiphyseal ends of long bones.

Question 27

What does the enzyme 17B-hydroxysteroid dehydrogenase do?

Answer 27

It will create convert a ketone on carbon 17 to a beta hydroxyl group.

Converts androstenedione to Testosterone.

Converts intermediate to Estradiol.

Question 28

What does the enzyme aromatase do?

Answer 28

It will create an aromatic ring structure in ring 1.

This enzyme activity is low in men and high in women.

Converts Testosterone to Estradiol.

Converts Androstenedione to to intermediate.

Question 29

How are steroids transported in the plasma?

Answer 29

Plasma transport proteins:

Transcortin (corticoid-binding globulin) moves glucocorticoids and progesterone around.

SHBG (sex hormone binding globulin) moves testosterone and estradiol around.

Question 30

How are steroids excreted?

Answer 30

Metabolism happens in the liver through oxidation, sulfation and glucuronidation to soluble forms.

Estrogen is excreted in the bile.

Progesterone, androgen and glucocorticoids are excreted in the urine.

Question 31

What is the aminoglutethimide (Cytadren) responsible for?

Answer 31

Inhibiting aromatase and p450scc.

Block steroid production in some hormone-dependent tumors (breast, prostate).

Lowers sex hormone production

Question 32

What is ketoconazole used for?

Answer 32

Antifungal at low concentrations by blocking synthesis of ergosterol found in fungus membrane.

At higher concentrations, inhibits p450scc, 17a=hydroxylase and 11B-hydroxylase.

Can treat hyper glucocorticoid states (cushing’s syndrome)