Lecture 13: Estrogens Flashcards
Requirements of estrogen activity
-aromaticity in A ring
-hydroxyl at 3 position
-17B OH group
Hydroxyl of estrogen
-can be masked as ether derivative
-ether hydrolyzed in vivo
17a-ethynyl substituent on estrogen
-blocks metabolism
-allows oral activity
17B OH group of estrogen
-required
-can be temporarily blocked by ester for drug delivery
16-OH on estrogen
-decreases activity
17a-alkylated estrogens
-prevents conversion to ESTRONE
=enhances bioavailability
=inc half life
-3-alkylated ether is dealkylated in vivo
17a-alkylated estrogen examples
-ethinyl estradiol
-mestranol
-quinestrol
Estrogenic esters
-esterification decreases solubility
=slow absorption
=prolong action
=less frequent injections
Estrogenic ester examples
-estradiol valerate
-estradiol cypionate
conjugated estrogens
-usually collected from pregnant horse piss
-mixture of estrogens
-50-60% estrone sulfate
-20-30% equilin sulfate
-other estrogenic substances
Nonsteroidal estrogen structure requirements
-OH group
-rigid core
-hydroxyl (enhances)
Nonsteroidal estrogen structure requirements for ANTAgonist activity
-amine side chain
-aromatic ring
-both interfere with helix-12
Non-steroidal estrogens
-diethylstilbestrol
-chlorotrianisene
diethylstilbestrol
-non-steroidal estrogen
-used 1940s-70s to prevent miscarriage
-increased risk of vaginal adenocarcinoma in women exposed in utero
-used in advanced prostatic cancer
chlorotrianisene use
-postpartum breast engorgement
-menopause symptoms
-prostate cancer
Selective estrogen receptor modulators (SERM)
-“designer estrogens”
-partial estrogen agonists
-estrogenic or antiestrogenic depending on tissue
-mostly nonsteroidal estrogens
-maybe alternative for estrogen replacement therapy
Structural basis of SERM activity
-bind ligand binding domain
-Helix 12 conformation BLOCKS coactivator from binding
Tamoxifen
-prodrug, oxidized in vivo
-partial estrogen agonist
partial estrogen agonist
-block potent estrogen agonists from binding
-change helix12 conformation
Tamoxifen antiestrogenic actions
-treat breast cancer
-prevent breast cancer
tamoxifen estrogenic actions
-weak estrogen agonist at endometrial cells
-inc risk for thromboembolic events
-prevents osteoporosis
Toremifene
-similar structure to tamoxifen
-SERM
-treat advanced breast cancer
Ospemifene
-structurally similar to toremifene
-SERM
-estrogenic effects on vaginal epithelium
-treat dysparenunia in post-menopausal women
Raloxifene
-SERM
-partial agonist
-tissue-specific activity
Raloxifene estrogen actions
-prevent osteoporosis in postmen women
-decrease LDL
-inc risk of blood clots
Raloxifene antiestrogen actions
-dec risk of breast cancer
-does NOT stimulate endometrial cells
-may cause hot flashes
Bazedoxifene
-raloxifene analog
Clomiphene
-SERM, parial agonist
-inc FSH and LH secretion (inhibits feedback)
-stimulate ovulation in women with amenorrhea and ovulatory dysfunction (PCOS)
polycystic ovary syndrome (PCOS)
-7% of women
-gonadotropin-dependent ovarian hyperandrogenism
-anovulation and infertility
Fulvestrant
-SERD (downregulator)
-pure estrogen ANTAgonist for breast cancer treatment
-more effective than SERM in patients resistant to tamoxifen
Aromatase inhibitors
-block synthesis of estrogens
-effective in breast cancer patients resistant to tamoxifen
-ovulation induction (off-label)
-gynecomastia
Aromatase inhibitor examples
-anastrozole
-letrozole
-exemestane
