This is in brief about estrogens and antiestrogens

1. ESTROGENS AND
ANTIESTROGENS

2.  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

3. Biosynthesis and Metabolism of Estradiol and Progesterone
OH
CH3
CH3
CH3
CH3
CH3
OH
CH3
CH3
CH3 O
CH3
CH3
OH
O
CH3
OH
OH
OH
CH3
OH
O
CH3
OH
OH
cholesterol pregnenolone testosterone estradiol
estriol
Conjugation to glucuronides, sulfates, etc….
CH3
O
CH3
CH3
O
OH
6a-hydroxy
metabolite
CH3
O
CH3
CH3
OH
20a/b-hydroxy
metabolite
CH3
OH
CH3
CH3
OH
H
5b-metabolite
estrone
CH3
O
CH3
CH3
O
progesterone

4. Natural steroidal Estrogens
 Estradiol benzoate/cypionate/valarate-IM
 Esterone and Esteriol
Synthetic steroidal Estrogens
 Ethinyl Estradiol-oral
 Mestranol-prodrug
 Quinesterol and Tibolone

5. Synthetic nonsteroidal Estrogens
Diethyl stilbestrol-oral
Dienestrol-topical
Chlorotrainisene
Methallenesril

6. Synthetic Estrogens
CH3
OH
RO
CHC CH2
CH2
OH CH3
CH3 OH
CH
C
HOH
OH
CH3
CH3
OMe
MeO
Cl
OMe
Ethinyl-estradiol R = H Diethylstilbestrol
Mestranol R = CH3
Chlorotrianisene Dienestrol

11. CH3
Na+-O3
PO
CH3
OPO3-Na+
Diethylstibesterol diphosphate -
Stilphostrol®
CH3 OPO3Na2
ON
O
Cl
Cl Estermustine Sodium Phosphate
Emcyt® - 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
conjugation and renal excretion
Contraindicated in men with cancer of
the breast, any estrogen dependent
neoplasm, thromboembolic disorders
Estrogens – Prostate Ca

12.  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-

13.  Neuroprotective and CNS effects- insomnia, 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

14.  Dysfunctional Uretine Bleeding
 -Mainly progestins
 Dysmennorrhoea-
 mainly NSAIDS, cyclic
 estrogens
 Acne and hirsuitism-cyclic estrogens

15.  Gynacomastia, Feminisation
 Prostatic Ca,
 Migraine, Breast tenderness
 Amenorrhea,
 Gall stones, hepatic dysfunction
C/I- diabetes, hepatic failure, thromboembolic
disorder

16.  Block estrogen receptors
 Breast cancer ONLY
 All estrogen agonist/antagonists
 Selective Estrogen Receptor Modulators
 SERM’s

17. 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
N
O
N
O
Cl
CH3
CH3
Raloxifene Nafoxidine Toremifene

19. Tamoxifen citrate - Nolvadex®
CH3
O
N
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 Pulmonary Embolisms
Patients should have regular gynecologic examint’ns
Patients should use only non-hormonal contraceptive
methods
Tamoxifen citrate

20.  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.

22. Toremifene citrate - Fareston®
O
N
CH3
CH3
Cl
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

23.  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 .

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