Steroid Hormones and some Repro Hormones! (Week 5--Edwards) Flashcards Preview

Block 3: GI, Endocrine, Reproductive > Steroid Hormones and some Repro Hormones! (Week 5--Edwards) > Flashcards

Flashcards in Steroid Hormones and some Repro Hormones! (Week 5--Edwards) Deck (49):
1


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!)

2


Which glands synthesize and secrete steroid hormones?


Adrenal glands (cortisol, aldosterone, androgens)

Testes (androgens)

Ovary (estrogen/progerterone)

3


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)

4


What are the steroid receptors (homodimers) that we see?


GR for glucocorticoids

MR for mineralcorticoids

PR for progesterone

AR for androgen

ER for estrogen

5


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

6

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

7


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)

8

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

9


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

10


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

11


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

12


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

13


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)

14


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

15


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

16


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

17


Addisons Disease


Destruction of adrenal cells (because of TB or autoimmune) causes loss of cortisol and aldosterone

Treatment: lifelong replacement of cortisol and aldosterone

18


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

19


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)

 

20


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

21


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)

22


Steroid Diabetes


When you have too much cortisol (due to Cushing's), have too much gluconeogenesis which causes too much glucose in the blood

23


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

24


RXR heterodimer


Bound to DNA but inactive until ligand enters nucleus and binds nuclear receptor to activate transcription

25

Drugs to decrease blood pressure

ACE inhibitors

Angiotensin II receptor blockers (ARBs)

Aldosterone receptor antagonists

Beta blockers

Ca2+ channel blockers

Diuretics (Thiazide)

Renin inhibitors

26


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

27


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)

28


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

29


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

30


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

31


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

32

What else activates the MR pathway by inhibiting SD?


Black licorice and chewing tobacco are inhibitors of SD

33


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)

34


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)

35


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

36


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

37


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)

38


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

39


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

40


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)

41


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)

42


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

43


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!

44


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

45


Where is aromatase expressed in men and women?


Women: adipose and breast tissue

Men: adipose tissue and Leydig cells

46


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?

47


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

48


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

49


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!