Biosynthesis of steroid hormones: 11 Flashcards
What are the 5 types of cell-cell communication?
Juxtacrine signaling
Endocrine signaling
Paracrine signaling
Synaptic or neuronal signaling
Autocrine signaling
What is juxtacrine signaling?
Direct physical contact
What is endocrine signaling?
Travels fairly far through the blood to a target organ expressing receptors.
Low [ ] high affinity receptors
minutes to hours
What is paracrine signaling?
Travels short distance and affect neighbor cells.
High local [ ] receptors with low affinity
Rapid and localized
What is synaptic or neuronal signaling?
Neurotransmitters that travel a short distance.
Very high local [ ] dissociate rapidly
Millisecond termination
What is autocrine signaling?
Made and functions in the same cell
EX: cancer cells use this to promote their own growth.
What is important about intracellular receptors?
They have a high log P because they are hydrophobic enough to diffuse the membrane.
What is important about cell surface receptors?
The first messenger will bind to a receptor on the surface of the cell generating a second messenger inside the cell to activate.
Where do steroids bind?
Intracellular receptors found in the nucleus.
bind tight to receptors
What do steroid hormones do in general once bound to specific hormone receptors?
Regulate transcription of a specific set of genes.
How are the 5 steroid hormones divided up?
Adrenocortical hormones (adrenal hormones) -2
Sex and progestational hormones (gonadal hormones) -3
What are the 3 gonadal hormones?
Progesterone (C-21): female menstrual cycle, pregnancy, embryogenesis
17-beta-estradiol (C-18): estrogen, female hormone
Testosterone (C-19): androgen, male hormone
What are the 2 adrenal hormones?
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
What receptors do each of the 5 hormones bind to?
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
What family do steroid receptors belong to?
Nuclear receptor family
What are the steps to the classic model of steroid action?
- Penetrate the membrane
- Bind hormone receptor
- Activation
- Transported to nucleus
- Bind DNA
- Regulate transcription of specific set of genes
What is a hormone response element (HRE)?
A DNA binding domains of activated dimers bind to specific DNA sequences upstream of steroid response genes.
Once bound, rate of transcriptions is changed.
What is an example of a negative feedback loop?
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.
Where does synthesis of steroid hormones start?
Cholesterol (C-27) is cleaved by p450scc (site chain cleaving) enzyme into Pregnenolone (C-21).
What other molecules can pregnenolone create?
All 5 of the hormones.
Cortisol
Aldosterone
Progesterone
Estradiol
Testosterone
What does the enzyme 17a-Hydroxylase do?
Adds a alpha hydroxyl group at carbon 17.
Converts Pregnenolone to intermediate.
Converts Progesterone to intermediate.
What does the enzyme 17,20-lyase do?
Removes the 20 and 21 carbons and makes carbon 17 a ketone.
Converts the intermediate into DHEA.
Converts the intermediate into androstenedione.
What does the enzyme 3B-Dehydrogenase Delta 5, Delta 4 isomerase do?
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)
What happens with a 17a hydroxylase deficiency? RARE
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
What do the enzymes 21-hydroxylase and 11B-hydroxylase do?
Add a hydroxyl group to carbon 21 and a beta hydroxyl group to carbon 11.
What happens with a 21 hydroxylase deficiency? More common
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.
What does the enzyme 17B-hydroxysteroid dehydrogenase do?
It will create convert a ketone on carbon 17 to a beta hydroxyl group.
Converts androstenedione to Testosterone.
Converts intermediate to Estradiol.
What does the enzyme aromatase do?
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.
How are steroids transported in the plasma?
Plasma transport proteins:
Transcortin (corticoid-binding globulin) moves glucocorticoids and progesterone around.
SHBG (sex hormone binding globulin) moves testosterone and estradiol around.
How are steroids excreted?
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.
What is the aminoglutethimide (Cytadren) responsible for?
Inhibiting aromatase and p450scc.
Block steroid production in some hormone-dependent tumors (breast, prostate).
Lowers sex hormone production
What is ketoconazole used for?
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)
