Steroids Slide Set 1

What is the basic steroid skeleton?

Take a minute and count the Carbons (up to 27) for Cholesterol

What is the basic estrogen structure? (defining features)

Look out for the aromatic ring!

5a-cholestane

What does the "alpha" designation mean in a given steroid structure?

steroid nomenclature:

alpha = downwards (dotted lines)

https://iupac.qmul.ac.uk/steroid/3S01.html

What does the "beta" designation mean in a given steroid structure?

beta = UPwards (solid lines)

https://iupac.qmul.ac.uk/steroid/3S01.html

5a-androstane

5a-pregnane

5a-estrane

5a-androst-8-ene

starts, ene, starting

steroid nomenclature: double bonds

double bonds are specified with the number of the position from which its ____ followed by -____.

if the bond can only be drawn in only 1 direction, or if it goes to the next highest position, only the _____ position needs to be specified.

5b-estr-9(11)ene

5a-estr-9-ene

What are the 2 female sex hormones?

estrogen and progestogen (and their respective derivatives)

What is the term for male sex hormones?

androgens (including testosterone etc)

What are the 3 categories of adrenocorticoids?

GLUCOcorticoids, MINERALOcorticoids, Sex hormones

What steroid hormone(s) have unsaturated ketone within its A ring?

progestins

Mineralocorticoids, Glucocorticoids do as well

What are the 2 key features of Androgen steroid structures, differentiating them from the rest?

19 methyl + 17b-OH combo

What steroid structure contains a progestin-like ring A, as well as a 21-OH or 21-Ac attached?

mineralocorticoids

What steroid structure contains a progestin-like ring A, as well as a 17-alpha-OH and 11-beta-OH group?

glucocorticoids

transcriptional

free steroid hormones diffuse through the cell membrane + bind to high affinity receptors where they act as ______ factors by interaction with specific DNA sites

3b-dehydrogenase

21-hydroxylase

11b-hydroxylase

17-estradiol, estrone, estriol

what are the 3 main estrogens?

17b-estradiol

which estrogen is produced in the greatest amount in the body?

estrone (ketone version of 17b-estradiol)

which estrogen has the highest conc in the plasma?

estriol

which estrogen has its highest conc in the urine?

metabolite conjugates (glucuronide, sulfate)

how are insoluble estrogens and other steroids cleared from the plasma?

false

T/F. estrogens can only be used in women

estradiol

estradiol

(estrogenic)

most potent natural estrogen

ROA: oral, transdermal patch, vaginal ring

indication:

- vasomotor symptoms associated with menopause

- vulvar/vaginal atrophy associated with menopause (topical only)

ADME:

- poor OBA (5%)

- conjugate in intestine + eliminated

estradiol cypionate

(estrogenic)

SAR: ester prodrug

- deposited in tissue + slowly release into blood where it is hydrolyzed to estradiol

ROA: IM injection -- dosed monthly

indication: hypogonadism

- mod-severe vasomotor symptoms associated with menopause

BBW; inc risk of endometrial carcinoma in postmenopausal women

endometrial carcinoma

the BBW for estradiol cypionate has an increased risk of what?

ethinyl estradiol

ethinyl estradiol

(estrogenic)

more potent + more stable than estradiol

ROA: PO, injection

indication: hypogonadism

- moder-severe vasomotor symptoms associated with menopause

SAR: metabolically more stable than estradiol due to C17 ethynyl group preventing oxidation

ADME:

- rapid + complete absorption after oral admin

- first pass metabolism to O-glucuronide and sulfate derivatives + enterohepatic circulation

what is the function of the C17 ethynyl group in ethinyl estradiol that increases its stability?

prevents oxidation

mestranol

mestranol

(estrogenic)

ROA: oral, injection, topical

- once daily dosing

indication: oral contraceptive in combo formulation

- treat hypogonadism

ADME: ether prodrug that is dealkylated in vivo via hepatic oxidative O-demethylation

quinestrol

quinestrol

(estrogenic)

ROA: oral

- once weekly dosing

indication: oral contraceptive in combo formulation

ADME: prodrug that gets dealkylated in vivo

what are 2 unique estrogenic compounds excreted in the urine of pregnant mares?

equilenin, equilin

premarin

(conjugated estrogen)

combo of sodium estrone sulfate + sodium equilin sulfate

ROA: oral, IV, IM

- poor OBA

indication: uterine bleeding

BW: may cause endometrial cancer, breast cancer, or CV disorders

diethylstilbestrol (DES)

diethylstilbestrol (DES)

(non steroidal estrogen)

DISCONTINUED due to causing severe birth defects + rare tumors

SAR: E-isomer is much more active

indication: reduce risk of pregnancy complications + losses

tamoxifen, toremifene, clomiphene, raloxifene

what are the 4 anti-estrogen SERMS?

tamoxifen

estrogen agonist or antagonist (depending on target organ and duration)

what is a selective estrogen receptor modulator (SERM)?

tamoxifen

(anti-estrogen -- SERM)

ROA: oral

MOA: estrogen receptor antagonist in breast tissue

indication: estrogen-dependent breast cancer in women

ADME:

- minor metabolite, 4-hydroxy-N-methyltamoxifen (endoxifen) = more potent than parent

resistance: occurs after 5 years of therapy, and then agonist property takes over

5

after how many years of tamoxifen therapy will the activity switch from being an antagonist to an agonist?

toremifene

toremifene

(antiestrogen -- SERM)

MOA: selective estrogen antagonist

indication: breast cancer

ADME: N-desmethyl toremifene = active metabolite

BBW: QTc prolongation

clomiphene

clomiphene

(anti estrogen -- SERM)

SAR: 1:1 mixture of enclomiphene and zuclomiphene

ROA: oral

MOA: zuclomiphene has estrogenic activity while enclomiphene has anti-estrogenic activity

indication: ovulation stimulant (fertility drug)

- polycystic ovary syndrome

ADME: readily absorbed from GIT, half life of 5 days

clomiphene

what is the most commonly used fertility drug?

raloxifene

raloxifene

(anti estrogen -- SERM)

MOA: estrogen agonist on receptors of osteoblasts/clasts + antagonist at breast and uterine estrogen receptors

indication: treat + prevent osteoporosis in postmenopausal women

- dec risk of breast cancer in postmenopausal women w osteoporosis or high risk women

PK: 60% absorption, low OBA (2%), rapid phase 2 metabolism, enterohepatic circulation

- dec risk of thromboembolic events + cataracts

- less resistance than tamoxifen

less

raloxifene has (less/more) resistance than tamoxifen

agonist, antagonist

raloxifene is an estrogen ____ on receptors in osteoblasts and osteoclasts but is an _____ in breast and uterine estrogen receptors.

demethylate, aromatize

what are the chemical transformations that aromatase carries out?

_____ the C10 methyl group and _____ the A-ring

anastrozole, letrozole, exemastane

what are the 3 aromatase inhibitors?

anastrozole

anastrozole

(aromatase inhibitor)

ROA: oral

MOA: competitive inhibitor that binds the heme portion of the enzyme

indication: 1st line for hormone receptor positive breast cancer and for relapse following tamoxifen therapy

- more effective than tamoxifen in treating breast cancer

SAR: related to non-steroidal aromatase inhibitors

advantage: no limitation on duration usage, where tamoxifen can only be used for 5 years

letrozole

letrozole

(aromatase inhibitor)

ROA: oral

MOA: competitive inhibitor that binds the heme portion of the enzyme

indication: 1st line for hormone receptor positive breast cancer and for relapse following tamoxifen therapy

- more effective than tamoxifen in treating breast cancer

SAR: related to non-steroidal aromatase inhibitors

advantage: no limitation on duration usage, where tamoxifen can only be used for 5 years

exemastine

exemastine

(aromatase inhibitor)

ROA: oral

MOA: irreversible aromatase inhibitor (suicide substrate)

- forms covalent bond with cysteine

indication: estrogen +ve breast cancer in post menopausal women

- risk reduction for invasive breast cancer in post menopausal women

oral

what is the ROA for aromatase inhibitors?