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4 ESTROGENS
- ESTRADIOL
- CONJUGATED ESTROGENS
- ETHINYL ESTRADIOL
- DIETHYLSTILBESTROL (DES)
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ESTRADIOL MOA
Natural steroidal estrogen
ALL estrogens interact w/ intracellular receptors to alter gene tsc & thus protein synth
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CONJUGATED ESTROGENS MOA
Composed of phytoestrogen
Contains same 3 major & 6 minor estrogens as Premarin
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ETHINYL ESTRADIOL
Synthetic steroidal estrogens
Ethinyl group added to 17 position of steroid ring →rev 1st pass metab → incr:
- --bioavailability
- --potency
- --t1/2
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DIETHYLSTILBESTROL (DES) MOA
Synthetic non-steroidal estrogen
- teratogenic (1st trimester)
- --♀ fetus: clear cell adenocarc of vagina in late teens-20s
- --♂ fetus: undesc testes, epidydymal cysts &
- azoospermia
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PHARMACOLOGICAL EFFECTS OF ESTROGENS
Nl sexual maturation of ♀
Dev of 2o sex char
Distrb fat to hips & breasts
Accel growth phase & epiphyseal closure at puberty
Maintenance of nL struct of skin, mucosa & blood vessels
- Stim hepatic synth of:
- --TBG, SHBG, transcortin, transferrin, renin substrate & fibrinogen →
- --incr circ levels (thyroxine, estrogen, testosterone, Fe, Cu, etc.) but free conc ≤
- nL
Stim synth clotting factors 2, 7, 9, 10 → incr likelihood of thromboembolic disease
- Antag PTH → decr rate of bone resorption by osteoclasts
- --reason for postmenopausal bone loss
Incr HDL & TG
Decr LDL & total chol
Facilitate mov of fluid from plasma to ECF → edema (Kidney has compensatory salt/H2O retention)
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PHARMACOKINETICS OF ESTROGENS
Pharmacokinetics (of estrogens):
1. Enterohepatic recirc → greater effect on liver than periphery
2. Apply drugs topically (cream) for periph action to minimize hepatic effects
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THERAPEUTIC USES OF ESTROGENS
Primary hypogonadism
- Post-menopausal HRT
- --> dec LDL & HDL & TGs
- --> “Perfect” HRT:
- ----Agonistic (+) at bone, skin & mucous membranes, CNS & plasma lipid profile.
- ----Antagonistic or no effect at breast, uterus & liver
- Contraception (***combo w/ progestin to prevent endometrial hyperplasia caused by
- estrogen)
“Morning after” contraception
Dysmenorrhea
Dysfunctional uterine bleeding
OCP’s decr Sx of benign breast dz
- Hirsuitism
- --Combo w/ finasteride, flutamide & spironolactone may prevent
- --Eflornithine applied topically → irrev inhb ornithine decarboxylase → prevent hair growth
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ADVERSE S/E OF ESTROGENS
1. n/v
2. Diarrhea
3. Breast tenderness
- 4. Endometrial hyperplasia
- (post-meno dec via co-admin progestin)
5. Salt & H2O retention
6. HTN
7. Gallbladder disease
8. Chol jaundice (very rare)
9. Thromboembolic disease
10. Post-meno bleeding
11. Headache
- 12. Hyperpigmentation
- (Chloasma or melasma)
- DES:
- teratogenic (1st trimester)
- --♀ fetus: clear cell adenocarc of vagina in late teens-20s
- --♂ fetus: undesc testes, epididymal cysts &
- azoospermia
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CONTRAINDICATIONS FOR ESTROGEN USE
- Relative:
- 1. Fam hx of breast or uterine malign
- 2. Severe varicose veins
- 3. Hx of hepatic dz
- 4. HTN
- Absolute:
- 1. Estgn-dep breast or uterine cancer
- 2. UnDx abnl genital bleeding
- 3. Hx of severe thromboembo dz
- 4. Acute hepatic dz
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SERMS
(selective estrogen receptor modulators)
CLOMIPHENE
TAMOXIFEN
RALOXIFEN
- Acts as estrogen agonist (+) in some tissues
- & estrogen antagonist (-) in other tissues
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CLOMIPHENE MOA AND PHARM EFFECTS
SERM
Orally active non-steroidal
- 1. BLOCKS estgn rec in hypothal → interrupts nl feedback inhb of GnRH &
- gonadotropin secretn
2. Incr GnRH secrtn → incr FSH & LH
- 3. Incr FSH & LH → gametogenesis & estgn
- --------------------------
Induce ovulation in ♀ w/ amenorrhea or anovulatory cycles
(-) CNS (nl sleep & temp regltn)
(+) liver: protein synth
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TAMOXIFEN MOA AND PHARM EFFECTS
SERM
Orally active non-steroid comptv estgn receptor antag (-) w/ partial agon (+) in some pts
1. Estgn receptor antag (-) in BREAST
- 2. Agonist (+) in liver & uterus*** → S/E
- --DVT or PE in high risk pts
- --Prolonged tx: endometrial hyperplasia → endometrial cancer
- Pre-meno ♀: Tamox antag (-)
- estgn receptors in hypothal & pit
- → incr GnRH → incr LH → incr estgn → (-) tamox effects.
- ----Prev the incr estgn w/ GnRH analog
Post-meno ♀: Same as pre-meno but ovaries quit making estgn → doesn’t matter
-----------------------------------------------
- (-) breast
- (-) CNS (nl sleep & temp regltn)
- (-) skin/mucous membr
- (+) bone density
- (+) plasma lipids
- (+) liver: protein synth
- (+) uterus: hyperplasia***
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RALOXIFENE MOA AND PHARM EFFECTS
SERM
Estrogen receptor AGONIST (+) on:
- 1. Bone: decr bone resorption by osteoclasts
- 2. Plasma lipid profile
- 3. Hepatic protein syn
- ANTAGONIST (-) on:
- 1. Uterus***
- 2. Breast
- -------------------------------------
- (-) breast
- (-) CNS (nl sleep & temp reg)
- (-) skin/mucous membr
- (-) uterus: hyperplasia***
- (+) bone density
- (+) plasma lipids
- (+) liver: protein synth
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CLOMIPHENE THERA AND ADVERSE S/E
SERM
Want to be pregnant!!!!
Induce ovulation in ♀ w/ amenorrhea or anovulatory
- Poss:
- 1. Multiple births
- 2. Stillbirths
- 3. Ovarian enlargement
- ------------------------------------
ADVERSE
- 1. Ovarian enlargement
- 2. Temp scintillating scotomata
- (blurred spots or flashes)
- 3. Sx of menopause (hot flashes, etc.)
- Contraindicated in pts w/ thromboembo
- d/o b/c acts as an estrogen receptor (+) in liver → incr clot factor synth
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TAMOXIFEN THERA AND ADVERSE S/E
SERM
1. Tx E(+) breast cancer
2. Breast cancer prophylaxis in high risk ♀
- 3. Post-meno ♀: same (+) agonistic
- (good) effect on bone density & lipids as estrogen
- ----------------------------------
ADVERSE
- 1. n/v
- 2. Hot flashes
- 3. Less freq vag bleeding & menstrual irreg
- 4. Comp prevents metab of warfarin → incr PT
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RALOXIFENE THERA AND ADVERSE S/E
1. Decr size of uterine leiomyomas in post-meno ♀
2. Maint post-meno bone density
3. Decr incid of vertb fractures by 30-40% (but effctv < HRT w/ conjugated estrogens)
4. Decr breast cancer in high risk ♀
- 5. Decr Tc & LDL. No incr HDL
- (like HRT w/ estgn)
- ------------------------------------
- ADVERSE
- 1. Hot flashes
- 2. Flu-like sx
- 3. Arthralgia
- 4. Thromboembo (inc hep clot factor synth)
- 5. p.o. → prev bene of topical estradiol in post-meno ♀ w/ atropic vaginitis
- (dec estrogen → vaginal itching & dryness)
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AROMATASE INHIBITORS
ANASTROZOLE
LETROZOLE
(Block synth of ALL estrogen in body)
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AROMATASE INHIBITORS MOA AND PHARM EFFECTS
Prevents conversion of androgens to estrogens
- LH → thecal cells make Androstenedione (ASDN) →
- granulosa cells take up ASDN → testn → [aromatase (fat cells)] → estradiol
- Aromatase (CYP450 enz) converts andgns → estgns (testn → estradiol & DHEA → estrone)
- --------------------
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AROMATASE INHIBITOR THERA AND ADVERSE S/E
Tx breast cancer in post-meno ♀:
- 1. Estro receptor (+) cancer
- 2. Advanced or metastatic breast cancer
- 3. NOT responded to tamoxifen
- 4. Been on tamoxifen for 5 years
- ----------------------------
ADVERSE:
- 1. MENOPAUSAL Sx
- 2. MSK PROBS
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LIST OF PROGESTINS
PROGESTERONE
NORETHINDRONE
NORGESTIMATE
NORELGESTROMIN
DROSPIRENONE
MEDROXYPROGESTERONE
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PROGESTERONE MOA
PROGESTIN
ANTI-MINERALOCORTICOID
ANTI-ANDROGENIC
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NORETHINDRONE MOA
PROGESTIN
FAMILY OF DERIVATIVES OF 19-MORTESTOSTERONE
SOME ANDROGENIC EFFECTS
LACK ANTI-MINERALOCORTICOID ACTIVITY
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NORGESTIMATE & NORELGESTOMIN MOA
PROGESTINS
- Norelgestromin = 17-deacylated norgestimate
- = actv metabolite of norgestimate
- 1. Does NOT stim androgen receptors
- → NOT (-) antagonize estrogen effect on plasma HDL conc
- ---- NO stim of sebum prodn → good skin (No acne)
2. Combo w/ ethinyl estradiol (OCP) → 3x incr serum conc of SHBG → 50% decr in serum free testosterone conc
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DROSPIRENONE MOA
PROGESTINS
Spironolactone derivative
1. Stim (+) progesterone rec
2. Blocks (-) androgen & mineralocorticoid rec
3. Block mineralocorticoid rec → CV benefits ♥
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MEDROXYPROGESTERONE MOA
PROGESTIN
I.M. DEPO PROVERA
COMPLETE AMENORRHEA --> CONTRACEPTION LASTING 3 MONTHS
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THERAPEUTIC USES OF PROGESTINS
Uses of OCPs
1. Contraception: combo w/ ethinyl estradiol
- 2. Acne
- --Estgn inhb hypothal & pit → decr LH → decr testn
- prodn by ovaries
--Incr hepatic synth of SHBG → decr free testn conc
--Decr free testn → decr sebum prodn in skin
- 3. HRT for post-meno (esp drospirenone***)
- --Constant estgn w/ cyclic or intermittent progestin
- --Const estgn & progestin
- --Ethinyl estradiol + drospirenone: Drospirenone has
- anti-androgenic and anti-mineralocorticoid effects
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PROGESTIN ADVERSE EFFECTS
- NORETHINDRONE
- --LOW ANDROGENIC ACT --> INC SEVUM PROD --> ACNE
- --Tx w SPIRONOLACTONE
- MEDROXYPROGESTERONE
- --NO RISK OF THROMBOEMBOLIC Dz BUT UNPREDICTABLE MENSTRUAL BLEEDING
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LIST OF PROGESTIN ANTAGONISTS
MIFEPROSTONE (RU-486)
ULIPRISTAL
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MIFEPRISTONE MOA AND THERAPEUTIC USES
PROGESTIN ANTAG
GLUCOCORTICOID REC ANTAG
OUTPATIENT ABORTION OF FETUS < 49 DAYS
- INTERRUPTS PREG
- --2 DAYS LATER GIVE SYNTH PG DINOPROSTONE --> CONTRACTS UTERINE SMOOTH MUSC
- ---------------------------------------
THERA
1. Prevent implantation of fertilized egg
2. Alleviate sx of endometriosis
3. Tx non-resectable meningiomas
4. Tx uterine leiomyomas
5. Tx Cushing’s syndrome (b/c also glucocorticoid receptor antag)
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ALENDRONATE & IBANDRONATE
BISPHOSPHONATES
INH BONE REABS BY STIM OSTEOBLASTS
- BINDS TO REMODELING BONE SURFACES
- --> INH OSTEOCLASTS
- PREVENT POST-MENO BONE LOSS
- -------------------------------------
ADVERSE
- Esophagitis:
- --Pts should take drug w/ 8 oz of H2O & remain upright for 30 min.
- --If drink too much or lie down (before 1st
- meal of the day) → level of drug reaches LES → damage
Osteonecrosis of the jaw (mostly w/i.v.)
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