Lecture 13: Estrogens

Question 1

Requirements of estrogen activity

Answer 1

-aromaticity in A ring
-hydroxyl at 3 position
-17B OH group

Question 1

Hydroxyl of estrogen

Answer 1

-can be masked as ether derivative
-ether hydrolyzed in vivo

Question 2

17a-ethynyl substituent on estrogen

Answer 2

-blocks metabolism
-allows oral activity

Question 3

17B OH group of estrogen

Answer 3

-required
-can be temporarily blocked by ester for drug delivery

Question 4

16-OH on estrogen

Answer 4

-decreases activity

Question 5

17a-alkylated estrogens

Answer 5

-prevents conversion to ESTRONE
=enhances bioavailability
=inc half life
-3-alkylated ether is dealkylated in vivo

Question 6

17a-alkylated estrogen examples

Answer 6

-ethinyl estradiol
-mestranol
-quinestrol

Question 7

Estrogenic esters

Answer 7

-esterification decreases solubility
=slow absorption
=prolong action
=less frequent injections

Question 8

Estrogenic ester examples

Answer 8

-estradiol valerate
-estradiol cypionate

Question 9

conjugated estrogens

Answer 9

-usually collected from pregnant horse piss
-mixture of estrogens
-50-60% estrone sulfate
-20-30% equilin sulfate
-other estrogenic substances

Question 10

Nonsteroidal estrogen structure requirements

Answer 10

-OH group
-rigid core
-hydroxyl (enhances)

Question 11

Nonsteroidal estrogen structure requirements for ANTAgonist activity

Answer 11

-amine side chain
-aromatic ring

-both interfere with helix-12

Question 12

Non-steroidal estrogens

Answer 12

-diethylstilbestrol
-chlorotrianisene

Question 13

diethylstilbestrol

Answer 13

-non-steroidal estrogen
-used 1940s-70s to prevent miscarriage
-increased risk of vaginal adenocarcinoma in women exposed in utero
-used in advanced prostatic cancer

Question 14

chlorotrianisene use

Answer 14

-postpartum breast engorgement
-menopause symptoms
-prostate cancer

Question 15

Selective estrogen receptor modulators (SERM)

Answer 15

-“designer estrogens”
-partial estrogen agonists
-estrogenic or antiestrogenic depending on tissue
-mostly nonsteroidal estrogens
-maybe alternative for estrogen replacement therapy

Question 16

Structural basis of SERM activity

Answer 16

-bind ligand binding domain
-Helix 12 conformation BLOCKS coactivator from binding

Question 17

Tamoxifen

Answer 17

-prodrug, oxidized in vivo
-partial estrogen agonist

Question 18

partial estrogen agonist

Answer 18

-block potent estrogen agonists from binding
-change helix12 conformation

Question 19

Tamoxifen antiestrogenic actions

Answer 19

-treat breast cancer
-prevent breast cancer

Question 20

tamoxifen estrogenic actions

Answer 20

-weak estrogen agonist at endometrial cells
-inc risk for thromboembolic events
-prevents osteoporosis

Question 21

Toremifene

Answer 21

-similar structure to tamoxifen
-SERM
-treat advanced breast cancer

Question 22

Ospemifene

Answer 22

-structurally similar to toremifene
-SERM
-estrogenic effects on vaginal epithelium
-treat dysparenunia in post-menopausal women

Question 23

Raloxifene

Answer 23

-SERM
-partial agonist
-tissue-specific activity

Question 24

Raloxifene estrogen actions

Answer 24

-prevent osteoporosis in postmen women
-decrease LDL
-inc risk of blood clots

Question 25

Raloxifene antiestrogen actions

Answer 25

-dec risk of breast cancer
-does NOT stimulate endometrial cells
-may cause hot flashes

Question 26

Bazedoxifene

Answer 26

-raloxifene analog

Question 27

Clomiphene

Answer 27

-SERM, parial agonist
-inc FSH and LH secretion (inhibits feedback)
-stimulate ovulation in women with amenorrhea and ovulatory dysfunction (PCOS)

Question 28

polycystic ovary syndrome (PCOS)

Answer 28

-7% of women
-gonadotropin-dependent ovarian hyperandrogenism
-anovulation and infertility

Question 29

Fulvestrant

Answer 29

-SERD (downregulator)
-pure estrogen ANTAgonist for breast cancer treatment
-more effective than SERM in patients resistant to tamoxifen

Question 30

Aromatase inhibitors

Answer 30

-block synthesis of estrogens
-effective in breast cancer patients resistant to tamoxifen
-ovulation induction (off-label)
-gynecomastia

Question 31

Aromatase inhibitor examples

Answer 31

-anastrozole
-letrozole
-exemestane