Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR

DEPT. OF PHARMACOLOGYSSIMS & RC.

ESTROGENS AND ANTIESTROGENS

Natural estrogens

Estradiol (17-β-estradiol)-most potent –secreted by ovaries

Esterone –formed by extra-glandular conversion of androstenedione in peripheral tissues

Estriol is a conjugated metabolite of estrone and estradiol

Biosynthesis and Metabolism of Estradiol and Progesterone

OH

CH3

CH3

CH3CH3

CH3

OH

CH3

CH3

CH3 O

CH3

CH3OH

O

CH3OH

OH

OH

CH3

OH

O

CH3

OH

OH

cholesterol pregnenolone testosterone estradiol

estriol

Conjugation to glucuronides, sulfates, etc….

CH3

O

CH3

CH3

O

OH6a-hydroxymetabolite

CH3

O

CH3

CH3

OH

20a/b-hydroxy metabolite

CH3

OH

CH3

CH3

OH

H

5b-metabolite

estrone

CH3

O

CH3

CH3

O

progesterone

Estrogen preparations

Natural steroidal Estrogens Estradiol

benzoate/cypionate/valarate-IM Esterone and Esteriol

Synthetic steroidal Estrogens Ethinyl Estradiol-oral Mestranol-prodrug Quinesterol and Tibolone

Estrogen preparations

Synthetic nonsteroidal EstrogensDiethyl stilbestrol-oralDienestrol-topicalChlorotrainiseneMethallenesril

Synthetic Estrogens

CH3OH

RO

CHC

CH2

CH2OH CH3

CH3 OH

CH

CHOH

OH

CH3

CH3OMe

MeO

Cl

OMe

Ethinyl-estradiol R = H DiethylstilbestrolMestranol R = CH3

Chlorotrianisene Dienestrol

Distribution of ERα and ERβ

Estrogen Receptors Trigger Gene Activation

Estrogen Targets Tissues

Estrogen Replacement in Menopause

Therapeutic uses

Osteoporosis-conjugated equine estrogens-(0.625mg/day) or estradiol

Vasomotar symptoms-short term conjugated equine estrogen therapy

Cardiovascular disease-estradiol Esterified estrogens-sodium esterone sulfate Urogenital atropy-

Therapeutic uses

Neuroprotective and CNS effects- ins0mnia, fattigue-Tibolone-synthetic norsteroid derivative-estrogenic, progestrogenic, and weak androgenic properties

Dose-2.5mg OD

ERT in primary ovarian failure- Estrogens in cyclical pattern- Ethinyl estradiol-0.01mg- 3 wk for 4 m -0.02mg- 3wk for 1yr

Therapeutic uses

Dysfunctional Uretine Bleeding -Mainly progestins Dysmennorrhoea- mainly NSAIDS, cyclic estrogens

Acne and hirsuitism-cyclic estrogens

CH3Na+-O3PO

CH3 OPO3-Na+

Diethylstibesterol diphosphate - Stilphostrol®

CH3 OPO3Na2

ON

OCl

Cl Estermustine Sodium PhosphateEmcyt® - Pharmacia & Upjohn

Indications: inoperable prostate cancer

Absolute contraindication in women

MOA: Non-steroidal estrogen that binds to cytosolic estrogen receptor with the complex being transported to the nucleus where androgenic activity is antagonized by receptor competition

Primary hepatic metabolism with conjugated renally excreted

Contraindicated in men with cancer of the breast, any estrogen dependent neoplasm, thromboembolitic disorders

Estrogens – Prostate Ca

Estrogen adverse effects

Gynacomastia, Feminisation Prostatic Ca, Migraine, Breast tenderness Ammenorrhoea, Gall stones, hepatic dysfunctionC/I- diabetes, hepatic failure, thromboembolic disorder

Antiestrogens Block estrogen receptors Breast cancer ONLY All estrogen agonist/antagonists Selective Estrogen Receptor Modulators

SERM’s

Selective Estrogen Receptor Modulators (SERM)

Single Receptor Single Response …. May not be valid!

– Tissue specific activity …. Estrogenic for bone

growth; anti-estrogenic for uterine endometrial growth

N

SOH

O

O

OH

OH

NO

NO

Cl

CH3

CH3

Raloxifene Nafoxidine Toremifene

SERMs

Tamoxifen citrate - Nolvadex®

CH3

ON

CH3

CH3

Indications: Adjunctive treatment of breast cancer, prevention of breast cancer in genetically predisposed women and men

MOA: non-steroidal anti-estrogen that competes with estradiol for estrogen receptors in target breast tissues

Hepatic metabolism to conjugates that are renally excreted, hepatic failure possible, thromboembolism especially PE’s, have regular gynecologic exams, use only non-hormonal contraceptive methods

Tamoxifen citrate

Tamoxifen

Receptor deactivation can: Increase bone density Reduce LDL levels – bad lipids Increase HDL levels – good lipids Increase cancer risk▪ Endometrial carcinoma▪ Thromboembolism

Dose = 20 mg p.o. q.d.

Tamoxifen and Cancer

Toremifene citrate - Fareston®

ON

CH3

CH3

Cl

Toremefin citrate

Indications: Breast cancer ( ER + or unknown)

MOA: similar

Extensively metabolized by

CYP3A4, extensive enterohepatic

recirculation

Watch for thromboembolism,

leukopenia, may cause endometrial

hyperplasia, patients with metastatic

bone lesions may suffer hypercalcemia

Raloxifene

Developed for breast cancer for the treatment and prevention of osteoporosis in

postmenopausal women.

Tamoxifen and Raloxifene share antagonist properties in breast and agonist properties in bone,

but differ at the uterus in that tamoxifen acts as a partial agonist, while raloxifene is an antagonist.

In addition to the benefits in bone health, a 75% reduction in the development of new breast cancer in women who did not have a prior history of breast cancer was observed.

Raloxifene is as effective as Tamoxifen in breast cancer Chemoprevention .

Raloxifene

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