Exam 1 Steroid Synthesis

Question 1

How do cells communicate?

Answer 1

sender cells make certain chemicals and transmit them → diffuses through the body and receptors receive the chemicals and can decode and respond to them (but other cells don’t have decoders so they don’t understand the message and it means nothing to them)

Question 2

What are the different modes of cell-cell communication?

Answer 2

juxtacrine, endocrine, paracrine, synaptic/neuronal, and autocrine

Question 3

What is juxtacrine signaling?

Answer 3

direct physical contact → example is MHC and T cells

Question 4

What is endocrine signaling?

Answer 4

1. travels fairly far through the blood to reach target organ expressing receptors
2. low in concentration, high affinity receptor
3. minutes to hours

Question 5

What is paracrine signaling?

Answer 5

1. travels short distance and affects neighboring cells
2. fairly high local concentration, receptor with low affinity
3. rapid and localized communication → very fast

Question 6

What is synaptic/neuronal signaling?

Answer 6

1. involves neurotransmitters, travels a short distance
2. very high local concentration, dissociate rapidly
3. very rapid (millisecond) termination

Question 7

What is autocrine signaling?

Answer 7

1. made and functions in the same cell
2. similar to paracrine signaling so travels short distance affecting its own cell
3. high local concentration and low affinity receptor → rapid
4. cancer cells utilize this method to produce growth factors

Question 8

What is the difference between intracellular vs cell surface receptors?

Answer 8

intracellular → have to cross the membrane so molecules that bind to intracellular receptors are hydrophobic (have no charge)
cell surface receptor → outside of cell so don’t need to cross the membrane, molecules can be charged but the problem is absorption in the blood and crossing to BBB

Question 9

Steroid hormones have what kind of receptors?

Answer 9

they are intracellular so they have no charge

Question 10

What are steroid hormones?

Answer 10

1. synthesized from cholesterol
2. planar, rigid, hydrophobic (so can penetrate membrane) that tightly bind to receptors
3. exist in low concentrations in the body
4. bound to serum carrier proteins since solubility is not good
5. share the common mode of action → free hormones diffuse through the cell membrane and bind to specific receptor and regulate transcription of a specific set of genes

Question 11

What are the 5 major classes of steroid hormones?

Answer 11

1. sex and progestational hormones
   →progesterone (C21) → female menstrual cycle, pregnancy, embryogenesis
   →17beta-estradiol (C18) → estrogen, female hormone
   →testosterone (C19) → androgen, male hormone
2. adrenocortical hormones
   →glucocorticoids
   →→cortisol (C21) → anti-stress hormone, anti-inflammation
   →mineralocorticoids
   →→aldosterone (C21) → regulator of Na+ uptake in the kidney, raises blood volume and BP

Question 12

What happens if you don’t have aldosterone?

Answer 12

we would lose all of our Na+ in our urine → blood volume decreases → leads to hypotension

Question 13

What happens if aldosterone levels are too high?

Answer 13

we reuptake Na+ and water → blood volume increases and leads to hypertension

Question 14

Steroid hormones bind to what receptors?

Answer 14

to their respective receptors (ex. estrogen receptor, androgen receptor, corticoid steroid receptor, etc)

Question 15

Steroid receptors belong to what family?

Answer 15

nuclear receptor family → example include steroid receptors, thyroid hormone receptors, etc

Question 16

Steroid receptors contain what?

Answer 16

DNA binding domain and a hormone binding domain

Question 17

Where is the steroid receptor normally located?

Answer 17

in the cytoplasm

Question 18

What is the classic model of steroid action?

Answer 18

hormone enters the cell (with stabilization of heat shock proteins), enter the nucleus and bind to a specific region in DNA to induce transcription (transcription takes time so steroid drugs takes time to see the full effect)

Question 19

DNA binding domains of activated dimers bind to what?

Answer 19

bind to specific DNA sequences called hormone response elements (HRE) which is upstream of steroid responsive genes → binding alters the rate of transcription

Question 20

What is the negative feedback loop?

Answer 20

hypothalamus releases CRH from stress which activates pituitary glands to release ACTH that activates adrenal glands to release cortisol which can negatively regulate ACTH and CRH to make less if there are high cortisol levels

Question 21

How is cholesterol turned to pregnenolone?

Answer 21

extra chain is cleaved by P450scc (CYP11A1)

Question 22

Where do the universal steps of steroid hormone synthesis occur?

Answer 22

everywhere in the body (including adrenal glands, ovaries, and testes)

Question 23

What are the 3 major changes in the universal steps?

Answer 23

1. OH to ketone and double bond moves on progesterone from pregnenolone → makes aldosterone (then 17-alpha-hydroxylase can make substrate that will make cortisol then 17,20 lyase can make androstenedione that leads to testosterone and estradiol)
2. 17-alpha-hydroxylase makes substrate that adds OH on C17 → 17,20-lyase removes 2 extra carbons to make a ketone to make DHEA

Question 24

What is 17-alpha-hydroxylase deficiency?

Answer 24

1. rare form of congenital adrenal hyperplasia (5%)
2. caused by mutations in CYP17A1 which has both 17-alpha-hydroxylase and 17,20 lyase activities
3. overproduce mineralocorticoids and deficient in corticosteroids and sex hormones
4. symptoms: hypocortisolism (enlargement of adrenal glands), ambiguous genitalia, hyperaldosteronism →hypertension

Question 25

What does 21-hydroxylase do?

Answer 25

adds an OH group on carbon 21

Question 26

What is 21-hydroxylase deficiency?

Answer 26

1. major form of congenital adrenal hyperplasia (95%) 2. mutations in CYP21A2 which functions as 21-hydroxylase 3. symptoms → hypocortisolism (enlargement of adrenal glands), hypoaldosteronism (hyponatremia which can be fatal in infants), premature androgen exposure which leads to ambiguous genitalia in females, hirsutism, early epiphyseal closure (short stature)

Question 27

What is the main takeaway with 17-alpha-hydroxylase deficiency?

Answer 27

can still synthesize aldosterone but make more than normal but no sex hormones or corticosteroids

Question 28

What is the main takeaway with 21-hydroxylase deficiency?

Answer 28

can't make cortisol or aldosterone but have too much sex hormones

Question 29

What does aromatase do?

Answer 29

makes an aromatic ring structure (turns testosterone to 17-beta-estradiol)

Question 30

How are steroids transported and excreted?

Answer 30

1. transported in plasma by plasma transport proteins → corticoid binding globulin (transcortin) → glucocorticoids and progesterone → sex hormone binding globulin (SHBG) → testosterone and estradiol 2. metabolized in the liver to soluble forms by oxidation, sulfation, and glucoronidation that attach more hydrophilic groups to make it more soluble 3. then excreted in the bile or urine

Question 31

What is excreted in the bile?

Answer 31

estrogen → because of its aromatic ring

Question 32

What is excreted in the urine?

Answer 32

progesterone, androgens, and glucocorticoids

Question 33

What does aminoglutethimide do?

Answer 33

1. inhibits aromatase and P450scc | 2. used to block steroid production in some hormone dependent tumors (breast and prostate)

Question 34

What does ketoconazole do?

Answer 34

1. antifungal at low concentrations (blocks synthesis of ergosterol) 2. inhibits P450scc, 17-alpha-hydroxylase and 11beta-hydroxylase (is like 21-hydroxylase) 3. can treat hyperglucocorticoid states (Cushing's syndrome) → produce too much cortisol 4. may cause toxic side effects as it blocks synthesis of lots of hormones