Mne Lecture 31 - Adrenal Steroid Synthesis

Front 1

21 carbons

Back 1

pregnane

Front 2

-ane

Back 2

= 0 double bonds

Front 3

18 carbons

Back 3

estrange

Front 4

-ene

Back 4

= 1 double bond

Front 5

19 carbons

Back 5

androstane
eg. aldosterone

Front 6

-diene

Back 6

= 2 double bonds

Front 7

prefix:
hydroxyl-


suffix:

Back 7

-ol


chemical name:

Hint 7

alcohols (also diol etc.)

Front 8

prefix:
oxo-


suffix:

Back 8

-one


chemical name:

Hint 8

ketones (also dione etc.)

Front 9

prefix:
deoxy-


characteristic:

Back 9

lacking a hydroxyl group

Front 10

prefix:
dehydro-


characteristic:

Back 10

removal of 2 hydrogens to give a double bond

Front 11

Describe the nucleus of all steroid hormones:

Back 11

-17 carbon cycopentanoperhydrophenanthrene nucleus
-this has three 5-carbon rings (A, B, C) and one five carbon ring (D).
-additional carbons can be present at positions 10 and 13 or as a side chain at position 17

Front 12

prefix:
dihydro-


characteristic:

Back 12

addition of 2 hydrogens to a double bond

Front 13

pregnene

Back 13

21 carbons, 1 double bond

Front 14

where is the double bond in a delta 4 steroid?

Back 14

-double bonds are named by the number of the preceding carbon

eg. delta 4 = double bond between c4 and c5

Front 15

-the angular methyl groups C19 and C18 at positions C10 and C13 project in front of the ring and serve as reference points.

Substitutions in the same plane as these groups are termed ___, those that project behind the plane are termed ___.

Back 15

Substitutions in the same plane as these groups are termed cis or B respectively, those that project behind the plane are termed trans or a respectively

Front 16

Additional carbons can be present at positions ___ or as a side chain at position ___ on the cyclopentanoperhydrophenanthrene nucleus

Back 16

Additional carbons can be present at positions 10 and 13 or as a side chain at position 17 on the cyclopentanoperhydrophenanthrene nucleus

Front 17

The cholesterol biosynthetic pathway is controlled by the activity of?
What does this enzyme need to work?
Where is it located?
What is a negative feedback control of this enzyme?

Back 17

HMG CoA Reductase

-uses NADPH specifically (from the pentose phosphate shunt)

-HMG CoA reductase is an intrinsic membrane protein of the endoplasmic reticulum; its C-terminal active site lies in the cytoplasm
-Cholesterol negatively feeds back on HMG CoA reductase

Front 18

What is the source of all the carbons in cholesterol?

(briefly run through the pathway)

Back 18

Acetyl coA

acetyl coA + acetyl coA --> acetoacetyl coA --> HMG coA --> mevalonate --> active isoprene
isoprene + isoprene --> geranyl pyrophosphate --> + isoprene --> farnesyl pryophosphate

Farnesyl pyrophosphate + farnesyl pyrophosphate --> squalene ----> lanosterol ----> CHOLESTEROL

Front 19

Name some cholesterol lowering drugs.

How do they work?

Back 19

-lovastatin
-simvastatin
-pravastatin
-fluvastatin
"the statins"

fluvies simply love parada

inhibit HMG CoA reductase

Front 20

How many carbons in:
progesterone
cortisol
alsodosterone
testosterone
estradiol

Back 20

PAC TE (for school!)

progesterones 21

cortisol 21

alsodosterone 21

testosterone 19
-->21 carbon steroids can be converted to SMALLER MOLECULES
--> comes from cholesterol, through pregnenolone and progesterone. gets smaller as you start processing

estradiol 18
-->18 carbons the a ring is now AROMATIC (when you have an aromatic A ring you have to lose carbon at c 19

Front 21

progesterone
cortisol
alsodosterone
testosterone
estradiol

how do they compare in terms of -OH's and stuff?

Back 21

Front 22

How do you get rid of steroids?

Back 22

make them hydrophilipic!!!

steroids bind to carrier proteins so they can’t be secreted unless they’re in the free form
-->stop binding to carrier proteins make hydrophilic to get rid of them

-the liver modifies steroids to make them more hydrophilic
-get rid of dbl bond at 3 position to make dihydro- derivative
-then put H across double bond O at 3 position (reduce the 3-ketone group to hydroxy derivative) to get the TETRAHYDRO FORM
**this is the form that is used to be excreted
-can also add other groups --sulfates or glucuronic acid -- to any available OH group usually at 3 position

**these modified steroids are more hydrophilic, bind less well to carrier proteins and are excreted more rapidly

Front 23

Steroids are synthesized from ___.

Back 23

cholesterol obtained mainly from the plasma. Some is synthesized in sity from acetyl-coA via mevalonate and squalene.

Front 24

Cholesterol is stored as

Back 24

an ester in cytoplasmic lipid droplets.

Front 25

pregnenolone

what is it?
how do you make it?
what is the rate limiting step?
what helps stimulate this synthesis?

Back 25

- is an INACTIVE precursor 
- 21 carbons

Take cholesterol convert into 1st step of steroid biosynthesis --> conversion to pregnenolonec

1. Cholesterol made in the liver. LDL gets cholesterol into cells as droplets, now we have to mobilize these droplets from the stored form. In tissues that make steroids, take those droplets and mobilize it
**Use an esterase, which removes the fatty acid from the 3 position

2. Then take cholesterol from cytosol and move it into the mitosol
**STAR is the protein that does this ** THIS IS THE RATE LIMITING STEP NOT P450 SIDE CHAIN CLEAVAGE

3. Cleavage itself takes the side chain at C17 and takes off 6 carbons. A cytochrome P-450 side chain cleavage enzyme (P-450scc) performs this reaciton. This reaction is activated by cAMP
-->most steroid biosynthesis rxns activated by cAMP, but this one especially
--> produced from many different receptors.
A. In the testes where you have luteinizing hormone (LH) activating androgen synthesis, LH will activate cAMP and activate the reaction.
B. In the adrenal cortex where you’re making glucocorticoids ACTH will do the same thing. It will bind to its receptor, increase cAMP levels and increase cleavage.) 
C. Angiotensin II

4. get pregnenolone, 21 C and isocaproaldehyde (6 c)

***all steroid hormones in mammals are formed from cholesterol and pregnenolone

Front 26

What do mutations in StAR lead to?

Back 26

-Congenital lipoid adrenal hyperplasia (salt wasting, hyponatremia, hypovolemia, hyperkalemia, acidosis, and death in infancy unless treated)

Front 27

THe lipoid adrenal hyperplasia phenotype is the result of two separate events:

Back 27

1. Decreased steroidogenesis due to mutation in the StAR gene is the primary cause

2. Subsequent increased loss of steroidogenesis due to cellular damage from accumulated cholesterol esters in the adrenal cortex is a secondary cause

Front 28

What's a good inhibitor of steroid biosynthesis ?

Back 28

Aminoglutethimide

**it inhibits P-450 scc

**Aminoglutethimide is most effective in the adrenal. It is not very specific; it inhibits armoatase activity and increases the turnover of some steroids

Front 29

Back 29

Adrenal cortex on top of kidney

two areas: medulla center and cortex on outside

adrenal cortex makes:
mineralocorticoids,
glucocorticoids,
and weak androgens

medulla makes:
epinephrine and norepinephrine

Front 30

Back 30

-adrenal cortex

**the enzymatic content of these three zona, the pathways inside the cells, can almost think of these as 3 different tissues instead of 3 different zonas/cell types

Front 31

zona glomerulosa

Back 31

mineralocorticoticoids

Hint 31

ARE NOT controlled by pituitary hypothalamus. they ARE controlled by renin-angiotension system 
*main control lies outside of pituitary and hypothalamus

Front 32

zona fasciculata

Back 32

glucocorticoids

Hint 32

controlled by ACTH

Front 33

zona reticularis

Back 33

weak androgens

Hint 33

controlled by ACTH

Front 34

Glucocorticoids bind tightly to which receptors in vitro?
Are they supposed to do that?
If not, how do you prevent it form happening?

Back 34

Glucocorticoids bind tightly to the mineralocorticoid receptor in vitro.

Mineralocorticoid responsive tissues protect themselves from glucocorticoids by enzymatically inactivating glucocorticoids.

11-b hydroxysteroid dehydrogenase (11-b HSD) removes a hydrogen from the 11-hydroxy of glucocorticoids to give an inactive ketone derivative.

Front 35

Mineralocorticoids

Back 35

-21 carbon steroids
-the main mineralocortiocoid is ALDOSTERONE which is only made in the zona glomerulosa

Front 36

Transport and excretion of aldosterone

-metabolic products?
-half life?

Back 36

-aldosterone does not have a specific carrier protein but binds weakly to albumin and cortisol binding globulin (CBG)

-aldosterone is rapidly metabolized by the liver, which forms tetrahydroaldosterone 3-glucuronide and other metabolic products

-the weak interaction with albumin gives aldosterone a serum t1/2 of less than 15 minutes

-tetrahydroaldosterone 3-glucuronide is excreted in urine (unconjugated aldosterone that is filtered by the kidney is mainly reabsorbed)

-11-deoxycorticosterone (DOC) and corticosterone aslo have some miceralocorticoid activity

Front 37

Aldosterone in circulation

Back 37

Albumin: 47%

CBG: 17%

Free: 36%

Front 38

if you were to take adrenal cortex what hormones are present in blood coming from it?

Back 38

You’d find scores of steroids
Because they're lipid soluble you cant keep them in one place. As soon as you make it it’s either going to be used up by the next enzyme in the reaction pathway or its going to diffuse somewhere else, like the bloodstream
see progesterone leaving, for instance rate of reaction is such that it usually goes straight through the pathway to its end product!

Front 39

Addison's disease

Back 39

-inability of the adrenal to produce sufficient glucocorticoids

-intolerance to stress, extreme sensitivity to insulin

-overproduction of ACTH and other POCM peptides results in increased pigmentation

can see pigmentation throughout the body
mostly even
palms of hands, esp in creases, scars, gums around teeth

-adrenal cortex stops functions --> most commonly because of autoimmune attack on adrenocortical cells that results in deficiency of cortisol --> ADDISONS disease

with Addison's disease
-lack of cortisol cant manage stress response
-hypoglycemic
-hypovolemic (low na+ levels too)
**no adrenal gland producing cortisol

If addison’s disease is untreated, person under stress can die of sudden loss of blood pressure --> collapse of blood supply in the brain (think of rats in cages)
-pigmentation is from excess output of ACTH / a-MSH from POMC molecule of pituitary which is no longer under negative feedback restraint from cortisol because he lacks cortisol

Front 40

Secondary adrenal insufficiency

Back 40

-lack of ACTH
-symptoms same as addisons (intolerance to stress, extreme sensitive to insulin, increased pigmentation)

Front 41

Conn's Syndrom

Back 41

-primary aldosteronism

-mineralocorticoid excess due to adenomas of the glomerulosa cells

-symptoms include hypertension, edema, and alkalosis

-renin and angiotensin II levels are depressed

Front 42

Secondary aldosteronism

Back 42

-hyperplasia and hyperfunction of juxtaglomerula cells due to renal artery stenosis and the attendent decrease in perfusion pressure results in elevated levels of renin and angiotensin

Front 43

Congenital adrenal hyperplasia (congenital adrenogenital syndrome)

treatment??

Back 43

-due to deficency in steroidogenic enzymes

-90% are due to 21-hydroxylase deficiency, others mainly an 11b-hydroxylase deficiency

-overproduction of ACTH

-overproduction of adrenal androgens leading to increased body growth, virilization, and ambiguous external genitalia

__

the issue goes back to synthesis .. 21a hydroxylase deficiency, there is backup of precursor substrate that gets shunted to androgen pathway
- removes negative feedback on ACTH .. More pours out drives conversion to androgenic compounds at excess levels
-because of that you get virilization of patient.

At first glance might look like penis but it’s an enlarged clitoris because of excess androgens in the situation

patient was treated, what is the most logical treatment?

Give cortisol 
a. cant live w/o cortisol.
B. cortisol by giving and restoring back to normal concentration reinstates negative feedback on ACTH to let them come back to normal this then restores androgen back to normal lower concentration release virilizing effect

this girl as an adult woman reverts to normal female appearance

Front 44

Cushing's disease

Back 44

1. excess production of ACTH (usually due to tumor, could be located in pituitary or elsewhere in body)
-excess ACTH drives oversynthesis of cortisol by adrenal cortex
-excess cortisol has consequences

-individual has Cushing’s disease
-it is a result of patient having a pituitary tumor that is over secreting ACTH driving excess cortisol production
-excess cortisol accounts for appearance of patienta. Patients often develop swollen face called a moon face or sometimes called moon facies 

-might just say oh this is someone who is fat, but this is not the situation
-excess cortisol not only just raises blood sugar (these patients are hyperglycemic --> can lead to insulin resistance and diabetes)
-swelling in face is an EDEMATOUS swelling, caused by Na+ reabsorb by mineralocorticoid action in kidneys. Draws water into vascular system

-FAT:
-get deposition of fat on back of neck dorsal cervical deposition of fat --> buffalo hump
- also on trunk : centripetal distribution of fat
-BUTT --> when you look at buttock that is the site where the fat has left, can be reduced from thighs as well. Getting redistribution of fat. High cortisol levels break down fat from buttocks and thighs. -Pancreas and b-cells respond to these high levels of FA by releasing insulin which targets the back of neck and trunk for the uptake of those free FA and incorporation into the fat cells in those locations. **Get interesting redistribution of fat going on.

-See here what you might call stretch marks but they aren't just stretch marks. Those are stretch marks created by breakdown of connective tissue under influence of high cortisol levels 

-the patients’ high cortisol levels may ultimately inhibit synthesis of pituitary hormones by patient except for tumor produced ACTH. May see more breakdown of bone, osteoporosis, whole host of normal physiological processes that might be disrupted under high cortisol levels

Front 45

Cushing's syndrome

Back 45

-not the same as Cushing’s disease --> depends on where the site of defect arises
-Cushing’s syndrome arises at the adrenal gland itself --> starts overproducing cortisol autonomously (usually due to an adrenal gland tumor) which creates the same appearance and symptoms as cushing’s disease
-note moon face, cenetripetal deposition of fat, also on back of neck-patient is also hyperglycemic, insulin resistance

-in this slide can see surgery was performed to remove the adrenal gland tumor. By removing tumor cortisol levels come back to normal and symptoms revert back to normal.

-look at ACTH levels: Cushing’s syndrome patient has low ACTH levels because the excess cortisol is providing negative feedback to the hypothalamus.
-in Cushing’s disease, the patient has HIGH ACTH because the tumor is overproducing ACTH and driving cortisol.