ESTROGENS & PROGESTINS Hormnal contraceptives

SUHARTI K. SUHERMAN
Dept. of Pharmacology & Therapeutics, Medical Faculty , University of Indonesia

ESTROGENS
Sources : ovarium, testis, placenta, adrenal cortex Steroidal estrogen are formed from androstenedione or testosterone Catalyzed by aromatase or CYP 19

ESTROGEN PREPARATIONS

natural : estradiol, estrone, estriol (esters estradiol : valerate , cypionate parenterally) synthetic: ethinyl estradiol (EE), mestranol, diethylstilbestrol (DES) others : conjugated equine estrogens (sulfate esters of estrone & equilin)

Metabolic / non reproductive effects anabolic action edema estr alone slightly fasting glucose & insulin but doesnt have major effects on CHO-metab lipids slightly serum Tg & T-Chol LDL & HDL

 from 2 large trials of HRT E+P or Eonly regiments dont provide any protection from cardiovasc disease est chol secrtion & bile acid secretion leads to saturation of bile with cholst risk of gallstone formation

 bones estr regulate & stimulates osteoblast production & activity ; the numbers & activity of osteoclasts post menop osteoblast activity osteoclast > actives osteoporosis HRT stimulates osteoblast activity & induced osteoclast apoptosis

Pharkinetics oral, parenteral, topical complete absorption ;hepatic metabolism, CYP 3A4 natural estr > rapid synthetic (longer t1/2, 13 17 hrs & duration of action) & bind to SSBG, EE bind to albumin, 2% free ;excretion urine & feces

 Esters : valerate / enanthate long acting

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 INDICATIONS : contraceptives orally or injectable INDICATIONS ( + progestin ) HRT : prevention & th/ of osteoporos , urogenital atrophy ( vaginal dryness & itching , pain during sexual intercourse), vasomotor symptoms Failure of ovarian development ( Turners syndrome) or hypogona dism

 functional uterine bleeding ( no organic diseases) hormonal imbalance Adverse reactions & contraindications = hormonal contraceptions

INDUCTION OF OVULATION Anovulations : amenorrhea & infertility disfunctional bleeding 15 25 % infertility caused by anovulations Preparations : Clomiphene tab 50mg

Kinetic : * orally well absorbed, metabolized by the liver * excretion feces

 Indications * infertility woman with normal H - H - O axis , no ovarian cysts except patient with polycystic syndrome Contra indications *pregnancy, abnormal liver functions , hypersensitivity, abnormal uterine bleeding of undetermined origin

 Dosage : 50 mg/day 5 7days at the 5th days of bleeding or at any time if there no uterine bleeding before 1 cycle * dont use more than 3 cycles since it may cause adverse reactions : ovarian cyst, epigasctric pain, multi ple pregnancy, visual disturbances

Epimestrol = 17 Epiestriol
Estrogenic activity: 1/100 - 1/200 - EE Potent antiestrogenic activity Inhibited estrogen at the receptor site Orally - well absorbed, metabolism unknown Urinary excretion

Human chorionic gonadotropin(HCG)

Sources : placenta ; activity ~ FSH glycoprotein parenterally Indications : + human menopausal gonadotropin (HMG ~ FSH & LH) induction of ovulation 1500 IU/day if there is a ripening of follicle HCG to induce ovulation

 Indications : infertility with normal HH - O axis, still in reproductive age

Tamoxifen inhibits proliferation of humans breast cancer cells the size & number of cancer cels ; but stimulates proliferation of endometrial cells & causes endometrial thickness = estrogenic activity

 The activity depend upon the tissue TAMOXIFEN selective estrogen receptor modulator (SERM) Orally well absorbed ; excretion : feces & urine Indication : palliative treatment of advanced breast cancer, with ER positive (raloxifen)

 Contraindications : hypersensitivity, pregnancy

Dosage : 20-40 mg/day Adverse reactions : Hot flushes, vaginal bleeding, skin rash, light edema, headache, ovarian cyst & thromboembolism have been reported in some patients raloxifen

Progestins
Sources of natural progesteron = Estrogen progesterone a precursor of steroidal hormones synthetic 19-nor testosterone derivatives

 metabolic effects : stimulate lipopro tein lipase activity fat deposition; prog & MPA may LDL

the 19 nor progestin derivatives have > effects on plasma lipids

Pharkinetics
natural progest orally rapid metabolism low bioavailability short duration of action esters form longer action : medroxyprogesterone acetate (MPA) hidroxyprogeston caproate I.M.

 MPA, megestrol acetate (MA) & po tent 19- nor compound ( norethin drone, levonorgestrel, desogestrel ) orally slow hepatic metabolism longer duration of action Prog. bound to albumin & CBG ; the 19 - nor compound binds to SSBG & albumin, MPA bind to albumin Excretion : urine & feces

 Indications : - contraceptions - + estrogen HRT - endometrial cancer (MPA) - secondary amenorrhea - breast cancer (MA)

 MPA (oral & injectable) Preparations Levonogestrel (150 g), desogestrel (150 g), linestrenol (0.5 mg), gestodene (75 g) 3 - ketodesogestrel = etonogestrel (68 mg)

 ADR & Contra-indications = hormonal contraceptions

Hormonal contraceptives Contraception : to prevent conception Methods : coitus interruptus -IUD mini operation hormonal prepara tions * oral pill : estrogen dervt + progestin dervt * injectab (long acting) MPA 150 mg/12 weekly, & MPA 50mg + estradiol cypionate 5mg /4 weekly

# 6 implants inserted subdermally ( 6 x 36mg levonogestrel ) slow release ,longterm contraceptive action (5 yrs) # 2 implants 75mg levonorgs for 3 yrs # 1 implant 68 mg etonogestrel 3 yrs

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pill / oral contraceptives

Combination pill gestodene 75ug + EE 30ug lynestrenol 2.5mg + EE 50ug desogestrel 150ug + EE 30ug or 20ug levonorgestrel 150ug +EE 30ug Progestin only pill lynestrenol 50ug 350 ug of norethindron

Route of administration Oral pill 1st day of menst bleeding Injectable & implantable 5th day of menst bleeding

 Mechanisme of actions: # E + P negative feed back mechan, secretion of GnRH & GnH inhibit ovulation # secretion of endocervics glands & more scanty inhibit sperm penetration # disturbs of fallopian tube movement # imbalance of E & P inhibit nidation of the fertilized egg

Adverse reactions

Bleeding irregularities, long term amenorrhea, nausea & edema, or BW, migraine headaches , vertigo, hypertension, TC & thrombosis (deep veins thromboembolism, especially in smoker & diabetic women ), varices , Alterations in - lipids & glucose - blood coagulation risk of cardiovasc diseases

Contraindications
Pregnancy , DM , hyperlipidemia ,hypertension varices , women > 40 yrs old or > 35 yrs + smoker , migrain , cardiovascular diseases , liver diseases , heart diseases , obesity , asthmatic , ever have any cancer of reproductive system or mammary gland , thromboembolic diseases, undiagnosed vaginal bleeding , jaundice , endometrial hyperplasia

Drug interactions
with : barbiturates, hydantoin , carbamazepine , rifampicin (CYP3A4), certain laxative , activated charcoal irregular bleeding or effectiveness