Estrogens

Exam 2

3 primary estrogens

1. estradiol 

2. estrone

3. estriol

which estrogen is the most active endogenous

estradiol

where is estrogen produced

ovaries and placenta

what is estradiol metabolized to

estrone

how is estradiol metabolized to estrone

17-B steroid dehydrogenase

Therapuetic use of estrogen

• menopausal symptoms 

• bleeding regulation

• ovarian development failure

• hypoestrogenism

• suppression of lactation

Use of anti-estrogens

estrogen receptor dependent breast cancer

why are estrogens conjugated

transport and metabolism

where does conjugation occur

liver

what are the primary conjugates

glucuronides and sulfates

what do conjugations form

sodium salts and increase water solubility

estrogens have a _____ half-life

long (~1day)

what type of bacteria can de-conjugate primary sulfates to allow for reabsorption

gut bacteria

how is estriol sulfate deconjugated

• in the intenstines

• by gut bacteria

why does estradiol have poor oral bioavailability?

first pass metabolism

how do you avoid first pass metabolism in estradiol

• micronized oral formulations (estrace)

• transdermal preparations (evamist)

this estrogen was originally obtained from pregnant mares’ urine

premarin

This is a mixture of 9 estrogenic hormone sodium salts that are synthesized from soy and yam derived sterols and is considered a substitute for premarin

synthetic conjugated estrogens A (Cenestin)

has nine estrogenic sulfates and 8,9 dehydroestrone sulfate and substitute for Premarin 

snythethic conjugated estrogens B (enjuvia)

Contains some of the same sulfate conjugates of estrogens, but ratios and minor comp components differ

Sodium estrone sulfate added to urine

subsitute for Premarin

menest

orally active estrogen that is equal to estradiol in potency by injection

substitution at C-17 prevents oxidation

undergoes sulfate conjugation and is recirculated

EE

These EEs must be dealkylated for activity 

3-methyl ether derivatives 

True or false: for non-steroid estrogens, the steroid nucleus is required

false

What is necessary for non-steroid estrogenic activity

• aromatic ring A and 3-OH

Distance between C_ and C_ hydroxyl is important for non-steroid estrogens

3, 17

What type of scaffolding is important in non-steroid estrogens

planar hydrophobic 

3rd ring stabilizes orientation on receptor

ethers must be metabolized for activty

note distance between C3 anad C17

chlorotrianisene

isoflavone found in soybeans and other plants

can interact with ERs and cause estrogen similar effects

genistein

This SERM is used as ovulation stimulant for women desiring pregnancy

clomiphene (clomid)

how does clomid work

blocks negative feedback by inhibiting ER in hypothalamus and increasing in GnRH leading to enhance release of LH and FSH

2 isomers of clomid

1. enclomiphene

2. zuclomiphene

this isomer has antagonist actions on uterine tissue

enclomiphenethi

this isomer has weak agonist activity on ALL tissues

zuclomiphene

SERM used for breast cancer or prevention of

tamoxifen

True or false: tamoxifen is a prodrug 

true

Where does tamoxifen have antagonist activity vs agonist

antagonist on breast tissue

agonist on endometrium, liver, CV tissue, bone

major ADR of tamoxifen

uterine cancer

this SERM contains benzothiophene and has a carbonyl hinge

raloxifen

what is the purpose of the carbonyl hinge 

causes differing actions 

has antag activity on breast and endometrium tissue and agonist on bone and CV tissue

primary use in prevention of osteoporosis in post-menopausal women

has better side effect profile

raloxifen

based on scaffold of estradiol

long substituted alkyl chain

when bound to ER the alkyl chain induces conformational change that blocks agonist action

fulvestrant

blocks and degrades ER and has no agonist effects 

used for women who have rapid disease progression after antiestrogen tx 

fulvestrant