Pharm Block II Estrogens

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natural estrogens: -17 beta estradiol (most potent), estrone, estriol
-aromatized steroid A ring
-produced in ovary in premenopausal women, testis and adrenal for males, adipose in postmenopausal women
regulation of female steroids: -cyclical secretion due to LH and FSH
-early phase feedback inhibition on GnRH, LH and FSH
-late phase high levels of estrogen stimulate LH and FSH surge
-progesterone only does feedback inhibition
estrogen pharmacokinetics: -67% bound to albumin or sex steroid binding globulin
-estradiol converted to estrone and estriol in liver
-liver conjugates with sulfuric acid for excretion in the urine
effects of estrgen: -primary and secondary female sex characteristics
-skin and blood vessel structure
-increased coagulability
-increases HDL/LDL, decreases cholesterol
-edema by Na and water retention
-modulation of sympathetic smooth muscle control
mechanism of estrogen action: -nuclear receptors alpha and beta
-distribution leads to differential gene expression
-also a 7 transmembrane G protein receptor
natural estrogens in use: -given as lipophilic esters in oil, in transdermal patches, or in oral micronized preparations
-also used sulfate esters of equine esstrone and equilin
other estrogen in use: -orally active synthetics and non-steroidals
-ethinyl estradiol (synthetic) is most potent
-mastranol converts to ethinyl estradiol in body
-diethylstilbestrol (DES) first cheap potent non-steroidal
-different plant estrogens
common threapeutic uses of estrogens: -hormone replacement (HRT): most effective in early menopause
--used to prevent osteoporosis, vasomotor symptoms, urogenital atrophy
--CV effects still controversial
-oral contraception
estrogens in contraceptives: oral contraceptives usaully include ethinyl estrdiol or mastranol
estrogens for menopause relief: -small doses of conjugated estrogens or ethinyl estradiol
-SERMs (selective estrogen receptor modulators) are more selective an may be better
other therapeutic uses of estrogens: -female hypogonadism
-ovarian dysgenesis
-dysmenorrhea or amenorrhea
-hirsutism
estrogens in cancer therapy: -superceded by anti-estrogen therapy
-high doses block GnRH for protatic adenocarcinoma
--now continuous GnRH preferred
adverse effects and toxicity of estrogens: -common: nausea/vomit, vaginal bleeding, breast tenderness, endometrial hyperplasia/carcinoma
-risk of thromboembolic disease, stroke, migraine, cholestasis, gall bladder disease
-breast cancer risk still controversial
contraindications of estrogen use: -pregnancy
-estrogen-dependent breast/uterine cancer
-idiopathic genital bleeding
-thrombophlebitis or thromboembolic disorder
tamoxifen citrate: SERM
-competative estrogen inhibitor in breast tissue BUT agonist in bone and on lipid metabolism
-treatment of metastatic breast cancer in postmenopause with tumors with estrogen receptors
-induce ovulation
--may cause hot flashes, nausea/vomit, uterine cancer, thromboemoblic events
Raloxifene: -orally active non-steroidal SERM
-agonist in bone and lipid
-antagonist in uterus
-treat/prevent postmenopause osteoporosis
-may cause: hot flashes, abdominal pain, infertility, peripheral edema, teratogenesis, thromboembolism, weight gain
Clomiphene citrate (enclomiphene): -orally active non-steroidal anti-estrogen (possible SERM)
-first choice to stimulate ovulation
-blocks estrogen negative feedback of GnRH
-also a weak agonist is some responsive tissues
side effects of clomiphene: -risk of ovarian hyperstimulation syndrome
-overian cysts or enlargement
-abdominal discomfort
-abnormal uterine bleeding
-breast tenderness
-blurred vision
Danazol: -17 β alkyl testosterone derivative
-pure estrogen inhibition to block LH/FSH surge
-blocks steroidoenic enzymes
-also binds to androgen, progesterone, and glucocorticoid receptors (same superfamily)
-only androgen activity is relevant
Danazol pharmacokinetics: -long, 15 hr half life
-mainly used for endometriosis
-causes: weight gain, edema, breast reduction, hot flashes, headache, cramps, hirsutism, ance, deep voice
Anti-aromatase drugs: -aminoglutethimide
-exemestane
-imidazole inhibitors
Exemestane: -orally active
-steroidal enzyme inhibitor
Aminoglutethimide: -also inhibits P450scc at high doses
Imidazole Inhibitors: -anatrozole and letrozole
-orally active, rapid onset
-total estrogen suppression
-no angrogen effects
Progesterone synthesis: -cholesterol to pregnenolone to progesterone
-metabolized in liver
Progesterone Pharmacokinetics: -only natural progestin
-short, 5 min half life
-inactivated by conversion to pregnanekiol and pregnanolone then conjugation with glucuronic acid
-index of production is total 3α,20α pregnanediol
Mechanism of Progestin Action: -one gene gives two receptors: A and B
-bind progesterone equally
-A inhibits B action
Progestins: -17α hydroxyprogesterone metabolites
-19 nortestosterone derivatives
17α hydroxyprogesterone metabolites: -hydroxyprogesterone caproate
-medroxyprogesterone acetate (MPA)
-megestrol acetate
19 nortestosterone derivatives: -nerethindrone
-ethylnodiol diacetate
-norgesterol (gonanes)
-least androgenic
Synthetic progenstin pharmacokinetics: -orally active
-long half lives
--norethindrone 7 hr
--nergestrel 16 hr
--MPA 24 hr
Progestin effects in Females: -changes endometrium from proliferative to secretory
-decreases myometrial contractility
-alveolobular development in mammary gland
-high doses inhibit ovulation
General effect of Progestin: -raise body tempurature (not in synthetics)
-weak aldosterone antagonist leading to Na, Cl, and water loss
-synthetics have estrogenic, androgenic, anabolic, anti-estrogenic, and anit-androgenic properties
-potent progestins may decrease HDL
Therapeutic Uses of Progestins: -usually used with estrogens
-prevent postmenopausal symptoms
-oral contrceptives
-progesterone and hyproxyprogesterone caproate suppress ovary function
--stop uterine bleeding
--treat dysmenorrhea
--treat endometriosis (continuous application)
--treat hirsutism
Toxicity of Progestin: -increase blood pressure
-reduce HDLs by androgenic and anti-estrogenic effects
Mifepristone: -competative antagonist of progestin
-used to terminate pregnancy
-high doses block glucocorticoid binding
Norplant Contraceptive system: -implanted rubber capsule
-uses levonorgesterol
-lasts up to 5 years
-reguires local anesthesia
-early in use may cause: breakthrough bleeding, dermatitis, breast discharge, weight gain, anorexia, hirsutism
Depo-Provera: -medroxyprogesterone acetate
-150 mg every 3 months
-may lead to amenorrhea for up to a year after discontinuing
-increased osteoperosis risk
Lunelle: -monthly injections
Preven: -emergency contraceptive
-ethinyl estradiol (50ug x4 tablets)
-OR levonorgesterol (0.25mg x4 tablets)
-contraindicated in pre-existing pregnancy (WHY??)
Plan B: -emergency contraceptive
-levonorgestrol (0.75mg x2 tablets
-first dose within 72 hrs
-next dose 12 hr later
Actions of Oral Contraceptives: -thicken cervical mucus
-alter endometrium
-decrease motility and secretions of fallopian tubes
**to block implantation
-progestin minipills don't block ovulation
Other uses of Oral Contraceptives: -treat dysmenorrhea or endometriosis that don't respond to estrogen or progestins alone
-delay menses in hemolytic or hemorrhagic anemia
Adverse effects of Oral Contraceptive: -first cycle effects:
--nausea/vomit, headache, dizziness, fatigue
--abdominal cramps, backache
--breakthrough bleeding
--increased appetite, fluid retention, weight gain
-6% develop clinical depression
-low doses have low risk of side effects
-low risk of MI and hypertension
-increase in thromboembolism
-amenorrhea may last up to 12 mo, but is responsive to clomiphene
-high dose may lead to hepatic dysfunction
-breast cancer risk controversial
-decrease in ovarian and endometrial cancer
Contradindications for Oral Contraceptives: -thromboembolic disease
-cerebral vascular disease
-MI or coronary artery disease
-congenital hyperlipidemia
-hormone-sensitive carcinoma
-idiopathic vaginal bleeding
-pregnancy (for real??)
-liver dysfunction or tumor
Contraindications for Progestrin-only Preparations: FROM PILLS
-undiagnosed vaginal bleeding
-liver disease
-breast cancer

DEPOT
-thrombophlebitis
-thromboembolic disorders
Risk factors with Contraceptives: -risk of CV problems if over 35 and heavy smoker
-hypertension
-migraines
-breast cancer

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