Steroid Hormones and some Repro Hormones! (Week 5--Edwards) Flashcards
How are steroid hormones made?
Steroid hormones are all synthesized from cholesterol
(cleavage of side chain and changes to ring structure)
Specifically, synthesis starts from cholesterol ester-rich (CE) lipid droplets in tissues –> lipase cleaves to cholesterol and fatty acid –> desmolase cleaves to pregnenolone –> pregnenolone is a precursor that goes to tissues to produce the steroid hormones (using organ-specific enzymes!)
Which glands synthesize and secrete steroid hormones?
Adrenal glands (cortisol, aldosterone, androgens)
Testes (androgens)
Ovary (estrogen/progerterone)
What type of receptor do steroid hormones activate?
Nuclear receptors (ligand-activated transcription factors that have a DNA binding motif and a ligand binding motif)
Steroid hormones pass through the plasma membrane into the cell and bind soluble nuclear receptors in the cytoplasm –> then they go together into the nucleus and bind DNA to activate transcription of target genes (or, in the case of GCs on GR, can repress transcription too)
What are the steroid receptors (homodimers) that we see?
GR for glucocorticoids
MR for mineralcorticoids
PR for progesterone
AR for androgen
ER for estrogen
What are some non-steroid nuclear receptors (heterodimers of R and RXR together) we see?
T3R for thyroid hormone (synthetic T4)
VDR for 1,25-(OH)2-VD (aka, vitamin D!)
PPAR-alpha for fatty acids/fibrates
PPAR-gamma for TZDs (thiozolidinedione–not used anymore)
PXR/SXR for xenobiotics
What are some common applications for steroid hormones?
Glucocorticoids/cortisol: anti-inflammatory
Estrogen/progesterone: birth control pill; osterporosis
SERMs (selective estrogen receptor modulators–means diff actions in diff tissues): treatment for breast cancer
Androgens (testosterone)/estrogens: hormonal replacement; important in cancers
Androgen antagonists (blockers): treatment for prostate cancer
Hormonal replacement: normal treatment for various steroid deficiencies (Ex: cortisol given for Addisons)
TZDs: (activate PPAR-gamma) treatment for diabetics (not used anymore)
Fibrates: (activate PPAR-alpha): lowers TGs (for people with hypertriglyceridemia)
Vitamin D: (increase Ca2+ absorption from gut to decrease bone loss) osteoporosis and bone loss in pts with dialysis
Adrenal gland structure and what is made here
Cortex has 3 layers:
Zona glomerulosa: thin, outermost, has columnar cells; makes mineralocorticoids (aldosterone–salt)
Zona fasciculata: thick, middle, has cells with lipid droplets; makes glucocorticoids (cortisol–sugar)
Zona reticularis: thin, inner zone; makes sex steroids (androgens–sex)
Medulla is just one layer: makes catecholamines (epi and NE)
General feedback mechanism for CRH, ACTH, cortisol
CRH released from hypothalamus in response to sleep, cold, pain, emotions, hemorrhage, exercise, hypoglycemia, infection, trauma, toxins
CRH stimulates anterior pituitary to release ACTH
ACTH binds cell surface receptor on adrenal gland to activate synthesis of cortisol
Cortisol is secreted into the blood and affects tx of genes in target cells; Cortisol also represses ACTH release from anterior pituitary and CRH release from hypothalamus
How is ACTH generated?
In the pituitary, POMC (pro-opimelanocortin) is synthesized and then cleaved by endopepsidases
ACTH and other proteins are some of the cleavage products
Why do patients with Cushing’s disease have darkening of the skin?
Cushing’s disease is when ACTH is produced by a pituitary tumor so get high levels of ACTH in the blood
High levels of ACTH cause parallel increase in levels of MSH (melanocyte stimulating hormone) because ACTH is cleaved to create MSH, and this causes darkening of skin
How does ACTH cause production of cortisol from adrenal glands?
ACTH binds cell surface receptor and actiavtes cAMP –> PKA –> activates lipase (CE droplet –> cholesterol) and desmolase (cholesterol –> pregnenolone) –> cortisol is synthesized then secreted immediately (because they’re not stored, they just go straight out to bloodstream)
At the same time, HDL (and sometimes LDL) binds to its receptor on adrenal cell surface –> brings CE droplet INTO the cell, and CE droplet is the source of cholesterol
How do plasma cortisol and ACTH levels vary?
Diurnally (highest when you wake up, lowest at midnight)
Increase in pregnancy (because of this, can get hyperglycemia/Gestational Diabetes)
Note: it is ACTH that increase, and peaks in cortisol follow that
Congenital Adrenal Hyperplasias (CAHs)
These diseases are now called by their specific enzyme defect:
21-alpha-hydrozylase deficiency (>90% of CAHs)
11-beta-hydrozylase deficiency (5% of CAHs)
21-hydroxylase deficiency
Too much testosterone!
>90% of CAHs; 1 in 15,000 births
Pathway to cortisol is blocked, so low/zero cortisol –> high ACTH because no negative feedback –> lipase and desmolase high –> progesterone is converted to androgens instead of cortisol or aldosterone
What are the effects of 21-hydroxylase deficiency?
75% have mineralocorticoid deficiency (salt wasting; hypotension) thus increased neonatal mortality
In utero, high ACTH increases steroid intermediates that are converted to androgens (cause virulizing effect)
Genetically female (46XX) babies may be called boys at birth or have “ambiguous” genitalia because of exposure to increased androgens (testosterone) during DEVELOPMENT, but then at puberty, develop breasts (because DO have ovaries, so start secreting a lot of estrogen?)
Males can start going through puberty very early (4-6), stunted bone growth
11-hydroxylase deficiency
Too much testosterone!
Virulization/masculinization occurs similar to 21-hydroxylase deficiency because same pathways blocked (just further downstream in this case)
Patients also have hypertension because loss of 11-hydroxylase results in accumulation of 11-deoxycorticosterone (DOC) which promotes Na+ reabsorption in kidney
Addisons Disease
Destruction of adrenal cells (because of TB or autoimmune) causes loss of cortisol and aldosterone
Treatment: lifelong replacement of cortisol and aldosterone
Cushing’s Syndrome
High levels of cortisol caused by:
Pituitary tumor producing ACTH (and MSH) (Cushing’s DISEASE)
Exogenous tumors (in lung, thymus, pancreas) that produce ACTH
Tumor of adrenal producing cortisol (no increased pigmentation, but yes increased blood sugar–steroid diabetes)
Tumors that produce CRH
Taking glucocorticoid drugs long term
What is special about glucocorticoids/GR receptor?
Can activate or REPRESS transcription
If there is inflammation, glucocorticoids bind pro-inflammatory TFs (NFkB) and INHIBIT them from transcribing inflammatory genes
If no inflammation, stimulates transcription like usual (to do things like gluconeogenesis, etc)
Cushing’s Disease
Defined as overproduction of ACTH by pituitary tumor
Leads to increased cortisol
Clinical manifestations:
Steroid Diabetes (increased glucose in blood)
Muscle wasting/thin arms and legs (protein catabolism)
Loss of peripheral adipose but increase in visceral fat (fat, heart, between shoulders = buffalo hump)
Moon facies
Weak bones
High BP
Normal pathway for adrenal steroid synthesis
ACTH binds receptor –> stimulates lipase and desmolase which bring CE to cholesterol to pregnenolone –> mostly turned to cortisol but also aldosterone by 21-hydroxylase
Also very little bit turned to adrenal androgen (androstenedione) that is secreted –> in peripheral tissues, converted to testosterone –> estrogen (via aromatase in adipose tissue, and this is how post-menopausal woman gets estrogen)
Steroid Diabetes
When you have too much cortisol (due to Cushing’s), have too much gluconeogenesis which causes too much glucose in the blood
What happens if you take glucocorticoid medication for a long time?
Will have very high cortisol levels because of giving it exogenously
Ex of drugs: hydrocortisone, prednisone, dexamethasone
ACTH production repressed in pituitary by excess cortisol –> synthesis/release of cortisol from adrenal cells is very low –> adrenal cells atrophy
Problem is if you suddenly stop steroids, can die because no cortisol produced by your own adrenals in response to stress –> must taper off steroids to allow adrenal cells to recover
Give GCs long term only if patient has disease where you have to use GCs to treat–asthma, rheumatoid arthritis, lupus, IBD, allergies
RXR heterodimer
Bound to DNA but inactive until ligand enters nucleus and binds nuclear receptor to activate transcription
Drugs to decrease blood pressure
ACE inhibitors
Angiotensin II receptor blockers (ARBs)
Aldosterone receptor antagonists
Beta blockers
Ca2+ channel blockers
Diuretics (Thiazide)
Renin inhibitors
How does the RAAS system work?
1) Liver secretes angiotensinogen
2) Kidney secretes renin (when gets signal that there was decrease in renal perfusion from JGA), which cleaves angiotensinogen to angiotensin I
3) ACE cleaves angiotensin I to angiotensin II
4) Angiotensin II acts through angiotensin I receptor (weird!) to increase sympathetic activity, increase tubular reabsorption of Na, Cl, H2O (increase K+ retention), stmulate adrenal cortex to secrete aldosterone, vasoconstrict, stim posterior pituitary to secrete ADH
Which cells have the angiotensin I receptor?
1) Cells of the zona glomerulosa in the adrenal cortex (this is where angiotensin II binds and acts to increase aldosterone secretion)
2) Vascular smooth muscle cells (causes vasoconstriction)
How does angiotensin II work at the adrenals?
Binds AT1 receptor on cell surface –> stimulates lipase to do CE to cholesterol –> stimulates desmolase to do cholesterol to pregnenolone –> simulates other enzymes to do pregnenolone to aldosterone
How does angiotensin II work at the vascular smooth muscle cells?
Angiotensin II binds AT1 receptor on vascular smooth muscle cell surface –> increase IP3 that increases intracellular Ca2+ –> vasoconstriction
How does aldosterone work on the kidney?
Cells of the distal tubule/collecting duct have mineralocorticoid receptors (MR) in their cytoplasm –> aldosterone enters these cells and binds to MR to cause MR/aldosterone complex to translocate to nucleus and increase target gene expression –> more Na+ channels inserted into lumenal membrane so more absorption of Na, H2O
How could cortisol be involved in the aldosterone pathway?
MR is promiscuous and can also be activated by cortisol!
Cortisol is 1000x more concentrated in the blood
There is an enzyme, 11BOH steroid dehydrogenase (SD) that usually inactivates cortisol (to cortisone) so it can’t bind MR.
But if SD is mutated, cortisol will activate the aldosterone pathway with MR a LOT, and this will cause a ton of Na, H2O retention and increase blood pressure
What else activates the MR pathway by inhibiting SD?
Black licorice and chewing tobacco are inhibitors of SD
Diseases that can lead to increased BP because of increased aldosterone
Primary aldosteronism (adrenal tumor, overproduction of aldosterone)
Malignant hypertension (renal damage leads to loss of control of renin secretion and increased plasma renin levels)
Liver disease (aldosterone not degraded normally)
Diseases that can lead to decreased BP because of decreased aldosterone
Addisons disease (destruction of adrenals so no source of aldosterone)
CAH Type II (mutation in 11 hydroxylase so can’t make aldosterone–NOTE: STEP 1 BOOK says hypertension because 11-deoxycorticosterone builds up and stimulates MR)
How is testosterone produced?
LH from anterior pituitary binds to cell surface receptor on Leydig cells of interstitum of seminiferous tubules in testis –> stimulates lipase to do CE to cholesterol –> stimulates desmolase to do cholesterol to pregnenolone –> other enzymes convert pregnenolone to testosterone
How is dihydrogentestosterone (DHT) made?
Testosterone enters target cell –> if target cell has 5-alpha reductase enzyme, testosterone converted to DHT –> DHT can bind nuclear androgen receptors and act here
What do testosterone and DHT do?
Testosterone: gonadotropin regulation, spermatogenesis, Wolffian stimulation (internal: epididymis, vas deferens and seminal vesicle formation)
DHT: external virilization, sexual maturation at puberty (prostate, penis, scrotum)
What does it mean that DHT is “stronger” steroid?
DHT binds more tightly than testosterone to its AR
DHT/AR complex can bind more efficiently to chromatin
But note: both T and DHT bind to same AR, so even if you don’t have DHT (with 5-alpha reductase deficiency), enough T will cause external virilization, etc
What would happen if an XY child doesn’t have AR for testosterone of DHT?
Would appear female because no development of any male characteristics
Increase T but doesn’t do anything because AR not working
Get increased estradiol
Never “turn into” boy because no AR
What would happen if an XY child has mutation in 5-alpha reductase?
Would look female at birth because no external virilization (but would get male sexual maturation at puberty because enough T binds AR)
This child would get INTERNAL male organs from actions of testosterone
“Penis at 12”
Note: could have mutation that causes only 10% activity of 5alpha reductase, and could have slight virilization but infertile, etc (intermediate phenotypes)
Diseases/mutations involving sex steroids
1) Mutation of 5alpha reductase
2) Mutation of AR
3) Defective testosterone synthesis
4) Prostate cancer: androgen-dependent and androgen-independent
5) A different 5-alpha reductase gene is expressed in the scalp and causes male-pattern bladness (inhibitors are on the market)
Consequences of steroid abuse
Abusers use up to 40 times the therapeutic dose
There are no “muscle-specific” androgens–all steroids will be converted to androgen and act via androgen receptor
Overuse causes: increased muscle mass, increased BP, increases LDL lowers HDL, increased risk of liver and heart damage, gynecomastia, increased risk of prostate cancer, acne, shrunken testicles, reduced sperm count, mood swings/aggressive behavior
How do steroid abusers prevent estrogen production that causes gynecomastia?
Take aromatase inhibitors to prevent conversion of testosterone to estradiol (in adipose tissue)
Note: men DO have aromatase and thus estrogens!
How is estrogen produced?
LH binds to cell surface receptor on theca cells of ovary –> stimulates lipase to do CE to cholesterol –> stimulates desmolase to do cholesterol to pregnenolone –> pregnenolone converted to 17-alpha-hydroxy steroids then to androstenedione –> androstensdione goes into granulosa cells of ovaries –> FSH has bound to cell surface receptor on granulosa cells to stimulate aromatase –> aromatase stimulates androstenedione to estradiol and estrone
Where is aromatase expressed in men and women?
Women: adipose and breast tissue
Men: adipose tissue and Leydig cells
What are androgen-dependent cancers?
Some breast cancers have estrogen receptors that when stimulated cause cancer cells to grow; can treat with estrogen receptor blocker or aromatase inhibitor
Some prostate cancers have testosterone receptors that when stimulated cause cancer cells to grow; can treat by blocking testosterone?
What happens differently in pre- vs. post-menopausal women regarding estrogen production?
Pre-menopausal women’s primary source of estrogen is the ovaries (theca cells and granulosa cells)
Post-menopausal women don’t secrete estrogen from ovaries anymore (ovaries dead) so their only source of estrogen is androstenedione from adrenal glands that is converted by aromatase in adipose and breast tissue into estrogen
Why are aromatase inhibitors (AI) used to treat breast cancer in post-menopausal but not pre-menopausal women?
AIs block estrogen synthesis in peripheral tissues but not in the ovary, so pre-menopausal women would still be secreting a ton of estrogen from their ovaries
Functions of cortisol
BBIIG!
Maintains blood pressure (upregulates alpha1 receptors)
Decreases bone formation
Anti-Inflammatory
Decreases immune function
Increases gluconeogenesis, (increases lipolysis, proteolysis to get substrates for making more glucose via gluconeogenesis!
