Park lecture 1 Flashcards
What is endocrine signaling
Signaling molecule produced in specific organ, and diffuses across the whole body. Some cells have the receptor for this molecule and respond.
Juxtacrine signaling mechanism
Cell-Cell contact signaling.
Actual concentration of endocrine signaling is (high or low)?
Low (in Nm)
Paracrine signaling
Nearby cells release molecule and affects neighboring cells.
Synaptic signaling mechanism
Neurotransmitter travels very short distance (high local concentration)
Autocrine signaling
Made and functions in same cell
Cell surface receptor vs intracellular receptor
In cell surface receptor, signaling molecule does not enter the cell. It binds on the surface and activates 2nd messenger.
In intracellular receptors, some signaling molecules are hydrophobic enough to get into the cell (steroid hormones)
Steroid receptor mechanism of action once activated
They go into the nucleus and bind DNA, promoting expression of genes.
Precursor of steroid
Cholesterol
Remember cholesterol numbering system
In the planar form of cholesterol, bottom of plane is called
alpha (dash Dash)
Top of the plane in planar form
Beta (thick dark wedge)
main action of steroids
transcription regulation
what are the 3 sex and pregestational hormones
!7-B estradiol, testosterone, progestrone
What are the 2 adrenocortical hormones
Cortisol, aldosterone
Cortisol (glucocorticoids) use
Anti stress hormone and anti-inflammation
aldosterone(mineralocorticoids) use
Na+ uptake in kidney. Raises blood volume and blood pressure.
how would you tell cholesterol apart from other steroids
Cholesterol has a long chain at 17-C. (resembles fish)
How would you tell progesterone apart from other steroids
Has 20 and 21 carbons. and has 2 ketones.
How would you tell 17-B estradiol apart from other steroids
Aromatic group and 3-OH (di-ol= two hydroxy)
How would you tell testosterone apart from other steroids
Has a 3-ketone and 17-OH
How would you tell cortisol apart from other steroids (especially from aldosterone)
Bothe cortisol and aldosterone have 11-OH, but cortisol has a 17-OH
How would you tell aldosterone apart from other steroids(especially from cortisol)
has 11-OH, but no 17-OH
What are the 5 hormone receptors
Estrogen receptor, androgen receptor, corticosteroid receptor, aldosterone receptor, progesterone receptor. Sometimes there is cross reactivity
What are the two binding domains of steroid receptors
DNA binding domain
Hormone binding domain
How do hormones work
-Penetrate membrane and binds specific hormone receptor
-hormone receptor is surrounded by heat shock proteins (Protects the structure of hormone receptor)
-Once hormone is recognized by receptor they are activated and release heat shock proteins.
-hormone receptor is transported into nucleus
-dimer forms and binds to a specific part of DNA
-Activate transcription of genes
Once glucocorticoid receptors are activated, they bind to specific sequences called
Hormone response element (HRE)
Binding glucocorticoid to HRE alters the
rate of transcription
where is cortisol produced
Adrenal gland
What stimulates adrenal gland to release cortisol
ACTH (adrenocorticotropic hormone)
Where is ACTH produced
Pituitary
Production of ACTH is stimulated by
CTH (corticotropin hormone)
Where is CTH produced
Hypothalamus
What suppresses the release of CRH and ACTH
Cortisol (feedback)
First step of steroid hormone synthesis is catalyzed by
P 450 scc (side chain cleaving)
P 450 converts cholesterol to
pregnenolone
P 450 cleaves
long chain of cholesterol, converts to ketone.
How do we get progesterone from pregnenolone
3-B dehydrogenase isomerase adds a ketone on C-3 and a double bond between C4 and C5
Steps to go from pregnenolone to DHEA
17-a hydroxylase adds an OH to 17 carbon to form an intermediate 1. Intermediate 1 is acted on by 17,20 lyase removes 20, 21 carbon and there will be a ketone on 17
How is DHEA converted to andronstenedione
3b-dehydrogenase isomerase adds a ketone on C-3 and a double bond between C4 and C5
androstenedione will eventually lead to the formation of
Testosterone and estradiol
progesterone will eventually lead to formation of
aldosterone
intermediate 1 to intermediate 2 catalyzed by
3 B dehydrogenase isomerase
Intermediate 2 will lead to formation of
Cortisol
progesterone to intermediate 2 catalyzed by
17-a hydroxylase
Intermediate 2 to androstenedione catalyzed by
17,20 lyase
progesterone to aldosterone steps
21 hydroxylase adds OH to C-21
11 B hydroxylase adds OH to C-11 (aldosterone)
Intermediate 2 to cortisol steps
21 hydroxylase adds OH to C-21
11 B hydroxylase adds OH to C-11 (cortisol)
17-a- hydroxylase deficiency causes
Overproduction of mineralocortecoids and deficiency of corticosteroids and sex hormones
symptoms of 17-a-hydroxylase deficiency
Hypocortisolism—–> enlargement of adrenal gland
hyperaldosteronism
ambigous genitalia
Why does hypocortisolism cause enlargement of adrenal gland
Body will lack cortisol. Body releases CRH and ACTH to stimulate adrenal gland again and again, even though it can not produce cortisol. It gets bigger
21 hydroxylase deficient people can not produce
Can not produce either aldosterone or cortisol.
Only produce sex hormones (overproduction of sex hormones)
Symptoms of 21 hydroxylase deficiency
Hypocortisolism- no negative feedback, leads to overexpression of CRH and ACTH, leads to adrenal gland enlargement.
Hypoaldosteronism- lose sodium to urine, dangerous to infants.
premature androgen exposure
- hirsutism
-early epiphyseal closure
-ambiguous genitalia in female
Why is there an overexpression of sex hormones in 21 hyrdroxylase deficiency
21 hydroxylase not being sufficient causes all the intermediates to be sent to sex hormones instead of being made into cortisol and aldosterone.
Why is there an overexpression of sex hormones in 21 hydroxylase deficiency
21 hydroxylase not being sufficient causes all the intermediates to be sent to sex hormones instead of being made into cortisol and aldosterone.
Two possible routes of andronstenedione
Androstenedione is acted on by 17B-hydroxysteroid dehydrogenase to for testosterone.
It can also be acted on by aromatase to form an intermediate that is then acted on by 17B-hydroxysteroid dehydrogenase to form 17B-estradiol
How is testosterone converted into 17B-Estradiol?
Acted on by aromatase
Steroids are transported in blood by
Plasma transport proteins
What are some plasma transport proteins
Corticoid binding globulin (glucocorticoids and progesterone)
Sex hormone binding globulin (testosterone and 17B-estradiol)
Steroids are metabolized in
Liver
Where are the steroids excreted to after being metabolized by liver
Progesterone, androgen and glucocorticoids- Urine
Estrogen- Bile
Two drugs that control the synthesis of steroid hormones
Aminoglutethimide and ketoconazole
What does aminoglutethimide do?
Blocks steroid production in some hormone dependent tumors.
How does aminoglutethimide block steroid production
Inhibit P450SCC and aromatase
What does ketoconazole do?
Antifungal at low concentration
How does ketoconazole work
Block synthesis of ergosterol by inhibiting P450SCC, 17A-hydroxylase and 11B-hydroxylase
Two types of cells in testes
Leydig cells and sertoli cells
Leydig cells are stimulated by
Luteinizing hormone (LH)
Sertoli cells are stimulated by
Follicle stimulating hormone(FSH)
What do leydig cells produce
Testosterone
What do sertoli cells produce
Spermatogenesis
LH and FSH are released by what gland? What hormone activates this gland?
Anterior pituitary. GnRH.
What releases GnRH
Hypothalamus
FSH stimulates
Sertoli Cells
LH stimulates
Leydig cells
What are the two requirements for spermatogenesis in sertoli cells
FSH+testosterone
What are the two gonadotropins
LH
FSH
How is testosterone regulated in the body?
Feedback inhibition
What enzyme catalyzes testosterone at target cell
5a-reductase
What does 5a-reductase convert testosterone into
5a-dihydrotestosterone
Which one is more potent and has more activity out of testosterone and 5a-dihydrotestosterone
5a-dihydrotestosterone
How does 5a-reductase convert testosterone to 5a-dihydrotestosterone
Removes double bond from testosterone and adds an alpha hydrogen to position 5
In people with hypopituitarism, we can supplement them with testosterone. Would that make the person fertile?
No. FSH needed for sperm formation.
Why do we use synthetic androgens
Testosterone is metabolized too quickly
How is testosterone metabolized
oxidation of 17-hydroxy group
How will adding groups to 17-carbons affect testosterone?
longer half life
Name 3 synthetic androgens and their ROA
Methyltestosterone- ORAL
Testosterone enanthate-IM
testosterone cypionate-IM
What is the modification to methyltestosterone and what effect does it have?
17-alkyl addition. Makes it more orally active and longer half life
Testosterone enanthate and Testosterone cypionate structural changes compared to testosterone and what effects they have
Both have 17 esters with long hydrocarbon chains. Makes it more lipophilic. They are injected IM so they stay in injection site and slowly diffuse. Esters will hydrolyze and testosterone will form. SO they are prodrugs.
Adverse effects of testosterone in women
Hirsutism
deepening of voice
ammenorhea
clitoral enlargement
acne
Adverse effects of Testosterone in men
Acne
sleep apnea
gynecomastia
increased aggressiveness and psychotic symptoms
azoospermia and testicular atrophy
What are the two anti androgens
5a- reductase inhibitors
androgen receptor inhibitor
5a- reductase inhibitors action
Block conversion from testosterone to 5a-dihydrotestosterone
Androgen receptor inhibitors
Block binding of endogenous androgens to receptors
Example of 5a-reductase inhibitors
Finasteride and dutasteride
5a- reductase (Finasteride and dutasteride) pharmacologic uses
BPH and Male pattern baldness
androgen receptor inhibitor pharmacologic uses
cyproterone and spironolactone
Hirsutism in women
Acne
Excessive sex drive in men
