L 12 and 13 estrogens Flashcards
estrogens
-Development and maintenance of female
reproductive tissues (ovaries, uterus, breast, vagina)
-Regulation in CNS (temperature, mood)
-Effects in peripheral tissues (bone, cardiovascular, liver)
progesterone
-Development and maintenance of female
reproductive tissues (uterus and breast)
-Maintenance of pregnancy
-Effects in other tissues (brain
17 beta estradiol
-Most potent estrogen in human
-Binds to the estrogen receptor and alters rate of transcription
-Produced mostly in the ovaries in premenopausal women.
-Synthesized most in the placenta during pregnancy.
-Plasma levels: 5 – 85 ng/dL
-Cyclically varies during the menstrual cycle.
-Mostly bound to sex hormone-binding globulin (SHBG) and albumin and only 2% free in circulation.
gransulosa cells produce
estrogen
corpus letum produces both
estrogen and progesterone
menstrual cycle
early follicular phase, late follicular phase, luteal phase
early follicular phase
Estrogen suppresses the production of
FSH.
late follicular phase
Estrogen stimulates the surge of LH and FSH –> ovulation and formation of corpus luteum
luteal phase
Estrogen and progesterone suppresses
the production of LH and FSH
if pregnancy does not occur
-corpus luteum degenerates.
-Production of estrogen and progesterone by corpus luteum declines. –> menstruation
if pregnancy occurs
-Fertilized egg/embryo secrets human chorionic gonadotropin (hCG).
-hCG acts like LH to stimulate corpus luteum to produce progesterone during the first trimester.
-Higher progesterone levels support maintenance of endometrium.
-Chromatographic immunoassays of hCG in the urine are used as pregnancy tests.
estrone and estriol are synthesized in the
liver and peripheral tissues
types of estrogens
-estrogenic activity is shared by large number of chemical substances
-natural estrogen
-synthetic estrogens
-phytoestrogens
-environmental estrogens
natural estrogens
-17β‐Estradiol – Most potent
-Estrone – Less potent
-Estriol – Less potent. Dominant form during pregnancy (synthesized in the placenta)
synthetic estrogens
drugs with estrogenic activities (steroidal and non-steroidal)
phytoestrogens
estrogen-mimetic compounds in plants (flavonoids)
environmental estrogens
compounds used in the manufacture of plastics (bisphenol, alkyl-phenols, phthalate products)
metabolism and excretion of estrogens
-Metabolized in the liver mostly and excreted to the bile and to the urine.
-Conjugated estrogens in the bile can be hydrolyzed in the intestine and reabsorbed (enterohepatic circulation).
-Orally administered estrogens have a high ratio of hepatic to peripheral effects; can be avoided by using a routes that avoid first-pass liver exposure
physical effects of estrogen on female maturation
-Development of the vagina, uterus, and uterine tubes
-Stromal development and ductal growth in the breast
-Accelerated growth phase and the epiphyseal closure
-Growth of axillary and pubic hair
-Alteration in the distribution of body fat to produce female body contours
-Pigmentation in the skin (nipples, areolae, and genital region)
physical effects of estrogen on endometrial effects
-Development of endometrial lining during menstrual cycles
-Prolonged exposure leads to hyperplasia of the endometrium and abnormal bleeding.
physiological effects of estrogen on metabolic and cardiovascular effects
-Decrease in the rate of resorption of bone
Estrogen deficiency can lead to osteoporosis.
-Stimulation of synthesis of transcortin and SHBG
-Alteration in the composition of plasma lipids
Increase in HDL
Decrease in LDL
physiological effects of estrogen on blood coagulation
enhancement of the coagulability of blood
physiologial effects of estrogen on CNS
mood
clinical uses of estrogen
-hormone replacement therapy in postmenopausal women
-osteoporosis
-hormonal contraception
-replacement therapy in patients with hypogonadism
hormone replacement therapy in postmenopausal women
-Relief of CNS disturbances – hot flashes, sweating, flushing
-Relief of symptoms resulting from urogenital atrophy - vaginal dryness, increased risk of infections
-Relief of psychological effects – mood swings, insomnia, depression, nervousness
osteoporosis
-For post-menopausal osteoporosis only
-Estrogens decrease the rate of bone resorption
replacement therapy in patients with primary hypogonadism
-Failure of development of the ovaries
-Chromosomal disorders
Turner syndrome – absence of one or all sex chromosomes
-Castration (oophorectomy)
adverse effects of estrogens
uterine bleeding
endometrial carcinoma
breast cancer
nausea, headaches, fluid retention, weight gain
uterine bleeding
-estrogen therapy is a major cause of postmenopausal uterine bleeding.
-Endometrial hyperplasia
-Estrogen should be given cyclically.
-Can be prevented by administration of a progestin in each cycle
endometrial carcinoma
concomitant use of progestin reduces risk
breast cancer
-Particularly for a long-term use
-Addition of a progestin does not have a protective effect.
17 alpha alkylated estrogens
-Ethinyl estradiol, Mestranol, Quinestrol
-17α-alkylation prevents conversion to estrone. –> enhances oral bioavailability and increases the half life.
-3-alkylated ether is quickly dealkylated in vivo.
estrogenic esters
-Esterification decreases solubility and slows the absorption.
-Slow absorption from the injection site (depot) prolongs the action.–> less frequent injections.
-Estradiol valerate, Estradiol cypionate
conjugated estrogens
-Usually collected from pregnant mares’ urine (Premarin ®).
-Mixture of estrogens
50-60% estrone sulfate
20-30% equilin sulfate
Other estrogenic substances
diethylstilbestrol
-Used in 1940 – 1970 to prevent miscarriage.
-increased risk of vaginal adenocarcinoma in women exposed in utero.
-Used in advanced prostate cancer.
chlorotrianisene
-Postpartum breast engorgement
-Menopause symptoms
-Prostate cancer
selective estrogen receptor modulators
-SERM
-“Designer estrogens”
-Partial estrogen agonists
Block the action of stronger estrogens.
-Estrogenic in some tissues and antiestrogenic in others
-Mostly nonsteroidal estrogens
-Hold promise as the alternative for estrogen replacement therapy.
structural basis of SERM actvity
-Ligand binding domain with an agonist (diethyl stilbestrol) bound
-Helix 12 conformation allows for coactivator binding.
-Ligand binding domain with a selective estrogen receptor modulator (tamoxifen) bound
-Helix 12 conformation blocks coactivator binding.
tamoxifen
-Prodrug; oxidized in vivo.
-Partial estrogen agonist
-Antiestrogen actions
Treatment of breast cancer
Prevents breast cancer in high risk women.
-Estrogenic actions
Weak estrogen agonist at endometrial cells
increase the risk for thromboembolic events.
Prevents osteoporosis.
toremifene
-Structurally similar to tamoxifen
-SERM
-Used to treat advanced breast cancer
ospemifene
-Structurally similar to toremifene
-SERM
-Estrogenic effects on the vaginal epithelium
-Used to treat dyspareunia in post-menopausal
women
raloxifene
-SERM; partial estrogen agonist
-Tissue-specific activities
-Bazedoxifene is a recently approved analog with similar
activities
raloxifene estrogen actions
-Estrogen actions
-Prevents osteoporosis in postmenopausal women
(approved).
- Decreases LDL levels in blood.
-increases the risk for blood clots.
raloxifene antiestrogen actions
Decreases the risk for breast cancer (approved).
Does not stimulate endometrial cells.
May cause hot flashes.
clomiphene
-SERM; partial estrogen agonist
-Increases secretion of FSH and LH by inhibiting negative estradiol feedback.
-Used to stimulate ovulation in women with oligomenorrhea or amenorrhea and ovulatory dysfunction (frequently from polycystic ovary syndrome).
-Polycystic ovary syndrome (PCOS)
-7% of women of reproductive age
-Gonadotropin-dependent ovarian hyperandrogenism
-Anovulation and infertility
fulvestrant
-Selective estrogen receptor downregulator (SERD)
-Pure estrogen receptor antagonist for the treatment of breast cancer
-Somewhat more effective than SERM in patients who have become resistant to tamoxifen
aromatase inhibitors
-Block the biosynthesis of estrogens.
-Effective in some patients whose breast cancer has become resistant to tamoxifen.
-Ovulation induction (off-label use)
-Gynecomastia
17α‐alkylated estrogens (too many brand
names)
-Ethinyl estradiol
-Mestranol
-Quinestrol
estrogenic esters
-Estradiol valerate (Progynova® )
-Estradiol cypionate (Depo-Estradiol® )
conjugates estrogens
Estrone sulfate/equilin sulfate (Premarin ® )
nonsteroidal estrogen agonist
-Diethylstilbestrol (Stilphostrol ® )
-Chlorotrianisene (Tace ® )
selective estrogen receptor modulators (SERMs)
-Tamoxifen (Nolvadex® , Soltamox ® )
-Toremifene (Fareston ® )
-Ospemifene (Osphena® , Senshio® )
-Raloxifene (Evista® )
-Bazedoxifene (Conbriza® ,Viviant ® )
-Clomiphene (Clomid® )
selective estrogen receptor downregulator (SERD)
Fulvestrant (Faslodex®)
aromatase inhibitor
-Anastrazole (Arimidex ®)
-Letrozole (Femara® )
-Exemestane (Aromasin® )
