ESTROGENS & PROGESTINSHormnal contraceptives

SUHARTI K. SUHERMANDept. 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 doesn’t have major effects on CHO-metab

• lipids slightly serum Tg & T-Chol

LDL & HDL

from 2 large trials of HRT

E+P or E–only regiments don’t 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

Phar’kinetics

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

• INDICATIONS : contraceptives orally or injectable ( + progestin )

HRT : prevention & th/ of osteoporos , urogenital atrophy ( vaginal dryness & itching , pain during sexual intercourse), vasomotor symptoms

Failure of ovarian development ( Turner’s syndrome) or hypogona dism

• functional uterine bleeding ( no organic diseases) hormonal imbalance

• Adverse reactions & contraindications = hormonal contraceptions

• 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

INDUCTION OF OVULATION

• 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

* don’t 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 H-H - O axis, still in reproductive age

• Tamoxifen inhibits proliferation of human’s breast cancer cells the size & number of cancer cels ;

but stimulates proliferation of endometrial cells & causes endometrial thickness = estrogenic activity

TAMOXIFEN • The activity depend upon the tissue

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

Phar’kinetics

• 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)

Preparations• MPA (oral & injectable)

• 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