Estrogens - 13,14 Flashcards
Estrogens
- development and maintenance of female reproductive tissues (___, uterus, breast, ___)
- regulation in ___ (temp, mood)
- effects in ___ tissues (bone, cardiovascular, liver)
- ovaries, vagina
- CNS
- peripheral
Progesterone
- development and maintenance of female reproductive tissues (___ and ___)
- maintenance of ___
- effects in other tissues (__)
- uterus, breast
- pregnancy
- brain
17β-Estradiol
- most potent estrogen
- produced mostly in the ___
- synthesized most in the __ during pregnancy
- plasma levels ___ ng/dL
- ___ varies during the menstrual cycle
- mostly bound to ___ and ___ only ___ free in circulation
- ovaries
- placenta
- 5-85 ng/dL
- cyclically
- sex-hormone binding globulin (SHBG), albumin, 2%
Regulation of estrogen synthesis
- hypothalamus: ___
- anterior pituitary: ___ and __
- Ovaries: ___ and ___ → physiological functions and positive/negative feedback loop
- GnRH
- FSH and LH
- estrogens and progesterone
Menstrual cycle
- Granulosa cells produce ___
- Corpus luteum produces ___ and ___
- estrogen
- estrogen and progesterone
Menstrual cycle
Early follicular phase
* Estrogen suppresses the production
of ___.
FSH
prevents multiple eggs fro being released
Menstrual cycle
Late follicular phase
* estrogen stimulates surge of __ and __ → ovulation and formation of ___
- LH and FSH
- corpus luteum
Menstrual cycle
Luteal phase
* estrogen and __ suppresses the production of ___ and ___
- progesterone
- LH and FSH
Menstrual cycle
- corpus luteum ___ if pregnancy does not occur
- when production of estrogen and progesterone by the ___ declines, ___ occurs
- degenerates
- corpus luteum, menstruation
Menstrual cycle
if pregnancy occurs
* fertilized egg secretes ___, whichs acts as ___ to stimulate corpus luteum to produce ___ during the first trimester.
* higher ___ levels support maintenance of endometrium
* ___ is what is detected during a pregnancy tests.
- human chorionic gonadotropin (hCG), LH, progesterone
- progesterone
- hCG
corpus luteum doesnt degrade, sticks around to make progesterone
Biosynthesis of estrogens
- Step 1: Androstenedione can be converted to ___ by aromatase, or it can be converted to ___ by 17B-hydroxysteroid dehydrogenase.
- Step 2: estrone is then converted to 17B-estradiol by ___, or testosterone is converted to 17B-estradiol by ___
both estrone and 17B-estradiol are converted into ___, a weak estrogen
- estrone, testosterone
- 17B-hydroxysteroid dehydrogenase, aromatase
- estriol
estrone & estriol - synthesized in the liver and peripheral tissues
Types of estrogens
Natural estrogens
* 17B-estradiol - ___ potent
* estrone - ___ potent
* estriol - less potent (dominant form during ___, synthesized in the ___)
- most
- less
- pregnancy, placenta
types of estrogens
Synthetic estrogens
2 types: ___ and ___
steroidal, non-steroidal
types of estrogens
Phytoestrogens
Estrogen-mimetic compounds in ___
plants (flavonoids)
types of estrogens
Environmental estrogens
Compounds used in the manufacture of ___
plastics (bisphenols, alkylphenols, phthalate phenols)
Metabolism and excretion of estrogen
- Metabolized in the ___ mostly and excreted to the ___ and to the ___
- Conjugated estrogens in the bile can be ____ in the ____ and reabsorbed (____ circulation).
- ___ administered estrogens have a ___ ratio of hepatic to peripheral effects; can be avoided by using routes that avoid ___ liver exposure.
- liver, bile, urine
- hydrolyzed, intestine, enterohepatic
- orally, high, first pass
Physiologic effects of estrogen
Female maturation
* development of vagina, uterus, and ___
* ___ development and ___ growth in the breast
* accelerated growth phase and ___ closure
* growth of ___ and ___ hair
* body fat distribution
* ___ in the skin (nipples, areolae, and genital region)
- uterine tubes
- stromal, ductal
- epiphyseal
- axillary, pubic
- pigmentation
Physiologic effects of estrogen
Endometrial effects
* development of ___ lining during menstrual cycles
* prolonged exposure leads to ___ of the endometrium and abnormal bleeding
- endometrial
- hyperplasia
Physiological effects of estrogen
Metabolic and cardiovascular effects
* decrease in ___ resorption (estrogen deficiency can lead to ___)
* synthesis of ___ and ___
* alteration in the composition of ___ lipids (increase in ___, decrease in ___)
* blood ___
* CNS: ___
- bone, osteoporosis
- sex-homrone binding globulin (SHBG), transcortin
- plasma, HDL, LDL
- coagulation
- mood
Clinical uses of estrogens
Hormone replacement therapy in postmenopausal women
* relief of ___ disturbances: ___, sweating, flushing
* used to treat symptoms of ____: vaginal dryness, increased risk of infections
* relief of psychological effects: ___, ___, depression, nervousness
- CNS, hot flashes
- urogenital atrophy
- mood swings, insomnia
Clinical uses of estrogens
Osteoporosis
* for ___ osteoporosis only
* estrogen decrease the rate of ___ resorption
- post-menopausal
- bone
Clinical uses of estrogens
hormonal ___
contraception
Clinical uses of estrogens
Replacement therapy in patients with primary ___
* failure of ___ development
* chromosomal disorders: ___ syndrome - absence of 1 or all ___ chromosomes
* ___ (ovarian cancer)
hypogonadism
* ovary
* Turner, sex
* oophorectomy
Adverse effects
Uterine bleeding
* estrogen therapy is major cause of ___ uterine bleeding
* endometrial ___
* estrogen should be given ___
* can be prevented by the administration of a ___ in each cycle
- postmenpausal
- hyperplasia
- cyclically
- progestin
Adverse effects
Endometrial ___
* use of progestin reduces the risk
carcinoma
Adverse effects
Breast cancer
* particularly ___term use
* addition of progestin does not have a ___ effect
- long-term
- protective
Adverse effects
general adverse effects of estrogen (think PUP)
- Nausea
- headache
- fluid retention
- weight gain
Structure-activity relationship
- ___ in A ring is required
- ___at the 3 position is essential for activity
- the 3-OH can be masked as a ___ derivative which is ___ in vivo
- 16-OH ___ activity
- 17a-ethynyl ___ metabolism and allows for ___ activity
- ___ group at the 17B position required for activity. (can be temporarily blocked by an ___ for drug delivery)
- aromaticity
- hydroxyl
- ester, hydrolyzed
- decreases
- blocks, oral
- hydroxyl
17α-alkylated estrogens
examples
- ethinyl estradiol
- mestranol
- quinestrol
17α-alkylated estrogens
17α-alkylation prevents conversion to ___
* enhances ___ bioavailability and increases ___
* 3-alkylated ether is quickly ___ in
vivo
- estrone
- oral, half life
- dealkylated
Estrogenic esters
Esterification ___ solubility and ___ the absorption
* example: ___ absorption from the injection site (depo-provera) ___ the action → ___ frequent injections
* 2 examples: ___ and ___
- decreases, slows
- slow, prolongs, less
- Estradiol valerate
- Estradiol cypionate
Conjugated estrogens
- Premarin is collected from ___
- mixture of estrogens: ___ estrone sulfate, ___ equilin sulfate, other estrogenic substances
- pregnant mares’ urine
- 50-60%, 20-30%
Structure-activity relationship in nonsteroidal estrogens
- an ___-substituted side chain blocks ___ and leads to antagonist/SERM activity
- A rigid ___ is required to maintain proper space between 2 or 3 aromatic rings
- ___ group required for agonist activity; should be ___ angstroms from other OH group.
- the other hydroxyl enhances activities (___ is oxidized in vivo)
- amine, helix-12
- core
- OH, 10-12
- tamoxifen
Non-steroidal estrogens
Diethyl stilbestrol (DES®)
* Used in 1940 – 1970 to prevent ___.
* Increased risk of vaginal ___ in women exposed in ___.
* Used in advanced ___.
- miscarriage
- adenocarcinoma, utero
- prostate cancer
Non-steroidal estrogens
Chlorotrianisene (Tace®)
* postpartum breast ___
* ___ symptoms
* ___ cancer
- engorgement
- menopause
- prostate
Selective estrogen receptor modulators (SERM)
- “___” estrogens
- ___ estrogen agonists
- Estrogenic in some tissues and ___ in others
- mostly ___ estrogens
- alternative for estrogen ___ therapy.
- designer
- partial
- antiestrogenic
- nonsteroidal
- replacement
Structural basis of SERM activity
- Helix 12 conformation allows for ___ binding.
- coactivator
Tamoxifen (Novaldex)
- prodrug; oxidized in ___
- ___ estrogen agonist
anti-estrogen actions
* treatment of ___ cancer
* ___of breast cancer in high risk women
estrogenic actions
* weak estrogen agonist at ___ cells
* increases the risk for ___ events
* prevents ___
- vivo
- partial
- breast
- prevention
- endometrial
- thromboembolic
- osteoporosis
Toremifene (FarestonTM)
- structurally similar to ___
- SERM
- Used to treat advanced ___
- tamoxifen
- breast cancer
Ospemifene (OspenaTM)
- Structurally similar to ___
- SERM
- Estrogenic effects on the ___
- Used to treat ___ in post-
menopausal women.
- toremifene
- vaginal epithelium
- dyspareunia
Raloxifene (EvistaTM)
- SERM; ___ estrogen agonist
- tissue-specific activities
estrogen actions
* prevents osteoporosis in ___ women
* decreases ___ levels in blood
* increases the risk for ___
anti-estrogen actions
* decreases the risk for ___
* does not stimulate ___ cells
* may cause ____
- partial
- postmenopausal
- LDL
- blood clots
- breast cancer
- endometrial
- hot flashes
Bazedoxifene
Bazedoxifene is a recently approved analog with
similar activities to ___
Raloxifene
Clomiphene (Clomid)
- SERM; partial estrogen ___
- increased secretion of ___ and ___ by inhibiting negative estradiol feedback
- used to stimulate ___ in women with oligomenorrhea of amenorrhea and ovulatory dysfunction (polycycstic ovary syndrome)
- agonist
- FSH, LH
- ovulation
Polycystic ovary syndrome (PCOS)
* __% of women of reproductive age
* gonadotropin-___ ovarian hyperandrogenism
* anovulation and infertility
- 7%
- dependent
Fulvestrant (Faslodex)
- selective estrogen receptor ___ (SERD)
- pure estrogen receptor ___ for the treatment of breast cancer
- more effective than ___ in patients who have become resistant to ___
- downregulator
- antagonist
- SERM, tamoxifen
Aromatase inhibitors
- Block the ___ of estrogens
- Effective in some patients whose ___ has become resistant to ___.
- ___ induction (off label use)
- Gynecomastia
3 examples: ___, ___, and ___
- biosynthesis
- breast cancer, tamoxifen
- ovulation
- Anastrozole, Letrozole, Exemestane
What is this?
17B-Estradiol
What is this?
anastrozole
aromatase inhibitor
What is this?
androstenedione
What is this?
Bazedoxifene
SERM
What is this?
Chlorotrianisene
Non-steroidal estrogen
What is this?
Clomiphene
SERM
What is this?
diethyl stilbestrol
Non-steroidal estrogen
What is this?
Equilin sulfate
Conjugated estroge
What is this?
Estradiol cypionate
Estrogenic esters
What is this?
Estradiol valerate
Estrogenic esters
What are these molecules?
estrone and estriol
What is this?
Estrone Sulfate
Conjugated estrogens
What is this?
Ethinyl estradiol
17α-alkylated estrogen
What is this?
Exemestane
Aromatase inhibitor
What is this?
Fulvestrant
Selective estrogen receptor downregulator (SERD)
What is this?
Letrozole
Aromatase inhibitor
What is this?
Mestranol
17α-alkylated estrogen
What is this?
Ospemifene
SERM
What is this?
progesterone
What is this?
Quinestrol
17α-alkylated estrogen
What is this?
Raloxifene
SERM
What is this?
Tamoxifen
SERM
testosterone
What is this?
Toremifene
SERM
