Steroid Biosynthesis

Question 1

How are steroid hormones derived?

what is the pathway to the precursor for all steroid hormones? (include the most important enzyme)

Answer 1

from cholesterol

desmolase converts cholesterol to pregnenolone –> leading to progesterone

progesterone is the precursor to all of the steroid hormones

Question 2

Where is desmolase found?

what does it do?

What’s good to know?

Answer 2

in all steroid producing tissues (Adrenal, Testes, Ovary, Placenta)

Catalyzes the first step of hormone synthesis from cholesterol to pregnenolone

RATE LIMITING STEP

Question 3

What is desmolase positively regulated by?*****

Answer 3

ACTH

Question 4

What is interesting to note about the structural changes of cholesterol to pregnenolone?

Answer 4

27 carbons to 21 carbons

Question 5

ACTH.. what is it also called?

What creates ACTH (pathway)

What does the final product do for feedback?

Answer 5

in the hypothalamus, corticotropin releasing hormone (CRH) is released, signals the pituitary gland to secrete ACTH, goes to adrenal glands to make cortisol.

accumulation of cortisol: It’ll negatively regulate the anterior pituitary from making ACTH and negatively regulate the hypothalamus from making CRH

Question 6

Short term actions of ACTH?

Answer 6

stimulates lipoprotein uptake into cortical cells in the adrenal cortex. (gets fat inside the cells where its needed to make hormones)

Cholesterol availability in the adrenal cortex increases

Question 7

What are the long term actions of ACTH?

Answer 7

stimulates the transcription of genes conding for steroidogenic enzymes

P450scc –> catalyzes the first step of steroidogenesis that is cleavage of the side chain of cholesterol

Question 8

ACTH and cancer:

what does a normal cell do without a stimulus? with a stimulus?

tumor cell?

Answer 8

in certain tumors, the production fo cortisol is uncoupled from acth.

if you imagine a tumor in your body doesn’t have to be in your adrenal glands that is making tons of cortisol that’s going to have a huge effect.

in a normal, inactive cell, you have inactive PKA, no proliferation, no cortisol.

In a normal cell + ACTH signaling, PKA is activated and you get cell proliferation and cortisol production in a REGULATED MANNER

in a tumor cell, the stimulation of ACTH is no longer required due to a mutation in the receptor, so you get a constitutively active PKA which leads to wild cell proliferation and massive cortisol production

Question 9

What does P450scc do normally?

Answer 9

P450scc responds to ACTH and other signals to mobilize cholesterol into a mitochondria.

AND through the actions of hydroxysteroid dehydrogenase (HSD) –> you get progesterone, which then splits to Aldosterone and cortisol

Question 10

Between Progesterone, cortisol, and aldosterone is what?

Answer 10

a bunch of CYPs, or Cytochrome P450

Question 11

what does cortisol bind to?

what does it do metabolically and for blood pressure? anything else good to note?

Answer 11

cortisol binds and activates the glucocorticoid receptor (GR) –> increases GNG and blood pressure and AMAZINGLY anti-inflammatory.

Question 12

Glucocorticoids and Infant Respiratory Distress Syndrome?

normal births?

what about in premature births??

what do you give the mother knowing it’s going to be a premie?

Answer 12

normal infants:

during delivery the mother has a burst of glucocorticoids.. this alters the lung structure and stimulates the production of surfactant allowing for lung expansion!

Premature this whole process is defective, and it leads to infant respiratory distress syndrome.

if you know the baby is going to be premature, give the mothers glucocorticoids so the baby can breathe (betamethasone, dexamethasone)

Question 13

What does aldosterone bind do?

Answer 13

Binds and activates Mineralcorticoid receptor (MR)

increase Na and H2O retention to raise your blood pressure

Question 14

What does Testosterone bind do?

Answer 14

Binds to the Androgen Receptor (AR)

male sex hormone

Question 15

What is Congenital Adrenal Hyperplasia?

1) what do women present with when having mild congenital adrenal hyperplasia?(3)
2) what happens if a fetus has this? how do you know before the baby is born?

Answer 15

Women present with “Hirsutism” = excessive body hair.

also infrequent or very light menstruation = General Oligomenorrhea

Infertility

fetus with this will have excess cortisol precursors in the amniotic fluid.. we know through using human leukocyte antigen haplotype

Question 16

Congenital Adrenal Hyperplasia types? (Classical)

Answer 16

2 kinds:

“simple virilizing” –> in females gives rise to ambiguous genitalia (21-a-hydroxylase)

“salt wasting” –> dehydration, vomiting, diarrhea. without treatment can be fatal (11-a-hydroxylase)

Question 17

What is the nonclassical Congenital Adrenal Hyperplasia?

what causes it?

what happens during puberty?

what about males and this?

Answer 17

Milder than classical CAH

caused by an excess of androgen which can cause precocious puberty

males often undiagnosed and asymptomatic

Question 18

Even mild congenital adrenal hyperplasia can result in what?

how do you treat it?

Answer 18

life threatening sinus infections, pulmonary infections, shortened stature, severe acne

Hormone Replacement Therapy –> what hormone depending on what mutation the patient presents

Question 19

What is CAH caused by?

what is the gene involved in this?

Answer 19

excessive or deficient production of sex steroids

90-95% of the cases are due to 21-hyroxylase

5% is 11B-Hydroxylase

Question 20

Explain the 11b-hydroxylase mutant in Congenital Adrenal Hyperplasia

What’s going to accumulate?

Answer 20

11B hydroxylase is a genetic block, blocking aldosterone production and cortisol production.. thus you get excess androgen production

you get the massive movement to the right side of the cascade.

11-Deoxycorticosterone (aldosterone path)

11-Deoxycortisol (Cortisol path)

Question 21

What’s interesting to note about 11-deoxycorticosterone?

Answer 21

high affinity for mineralcorticoid receptor… it’s an MR AGONIST!

because it still has affinity and it’s in high concentrations, it promotes Na and water retention while lowering plasma K+ concentrations.

so patients will have dysregulated salt/water balance.

all due to the abnormal accumulations

Question 22

Overall, what’s going to happen with someone with a 11-B-Hydroxylase Deficiency?

what two things are going to be increased, what are they both going to do but what one predominates?

Answer 22

Increase levels of any of these compounds would cause increased Na+ absorption in the kidneys and, hence, hypertension.

ONLY 11-DEOXYCORTICOSTERONE AND 11-DEOXYCORTISOL LEVELS would increase due to this enzyme deficiency… and 11-deoxycorricosterone has a much higher affinity for MR to produce hypertension

Question 23

the more common Congenital Adrenal Hyperplasia (CAH) is due to 21-a-hydroxylase deficiency.. what is this going to decrease?

why is it called hyperplasia?

what 3 things are going to be higher levels?

what does this lack of(hormones) lead to?

What happens in females?

Answer 23

decrease cortisol synthesis and hyperplasia of the adrenal cortex due to the idea that low cortisol levels will upregulate ACTH

Progesterone
17,A-hydroxyprogesterone
17a-hydroxypregnenolone

Leads to salt wasting –> lack of aldosterone, high rate of sodium loss in the urine

females have obvious genital ambiguity

Question 24

How do hormones get around in the blood (2 transporters)

include what they transport

which one is different in men and women?

where are both proteins made? what happens if this is off?

Answer 24

Corticosteroid-binding protein (CBG) –> transports glucocorticoid hormones and progesterone

Sex steroid-binding Globulin (SHBG) –> transports testosterone, dihydrotestosterone, estradiol

SHBG is different in women because it’s only partially saturated, in men it’s fully saturated because there is tons of testosterone.

both made in the liver, so if you have a sick liver good luck transporting this around

Question 25

Pregnenolone is the precursor for what hormones?

Answer 25

Progesterone
Aldosterone
Cortisol
Testosterone
Estradiol

Question 26

what are the three possible mutations that can lead to the down regulation of some steroid hormones being produced from Pregnenolone?

Answer 26

Cyps (11-b dehydroxylase, 21a ex)

HSDs (hydroxysteroid dehydrogenases)

Lyases

Question 27

What happens if we have a mutation in CYP17A1 (also known as 17,20-Lyase/17a-hydroxylase) only and not a double?

Answer 27

this enzyme is a gateway from progesterone to all sex steroids

unlike the case of combined 17a-hydroxylase/17,20lyase deficiency… if you only have 17,20-lyase it doesn’t affect your glucocorticoid production, so therefore it does NOT present with adrenal hyperplasia or hypertension.

Question 28

what should you know about 17,20 lyase/17a-hydroxylase.

Answer 28

from progesterone to go over to the sex hormones, you have to go through 17,20 lyase.. so it’s the gatekeeper

mutation would lead to low testosterone, but it won’t lead to hypertension and glucocorticoid loss

Question 29

What are the 3 regulated steps in cholesterol to pregnenolone, formation of estrone, and estradiol in women?

Answer 29

Desmolase is regulated by ACTH and LH!

FSH stimulates aromatase in females to produce Estrone

FSH also unregulated aromatase to change testosterone to estradiol in women.

Question 30

What’s regulating the production of GnRH in males and females?

Answer 30

in females, progesterone regulates the production of GnRH

in males, testosterone regulates the production of GnRH

Question 31

How is vitamin D synthesized?

1) what tissues are involved?

Answer 31

Skin, Liver, Kidney, Intestine

Question 32

how do we get vitamin d and what does it start in each scenario and what is it changed to?

what happens to creating active vitamin D in the kidney and what is the active form also called?

Answer 32

we get vitamin D through our diet (Ergocalciferol is changed to cholecalciferol (vitamin D2)

Through the skin, it’s converted from 7-dehydrocholesterol via radiation to cholecalciferol

1-a hydroxylase in the kidney change it from 25-hydroxycholecalciferol to 1,25 which is the active form (Calcitriol)

Question 33

When we have Cholecalciferol from our skin or from our diet.. it makes it to the liver before going systemically.. what’s going to happen to it?

so if we have a bad liver, what’s going to happen?

Answer 33

it’s going to be processed to 25-hydroxycholecalciferol through an enzyme 25-hydroxylase which is encoded by the CYP2R1 gene!!!

this is why it’s formed exclusively in the liver!

we won’t be able to form 25-hydroxycholecalciferol