Estrogens
Estrogens are synthesized mainly in the ovaries, the placenta, and the
adrenal glands. A minute amount of estradiol is synthesized in the testes.
Physiological actions of estrogens:
Action
Category
Growth and development of muscular and mucosal
Uterus&tube
elements of
Elements
of the uterus and the fallopian tubes.
Myometrium
Stimulate the growth of the myometrium at puberty and
during pregnancy.
Endometrium
Increase the endothelium and rebuild the endometrim
In the proliferative phase
Vagina
Development of the epithelial layer & enhance glandular
secretion.cornification and deposition of glycogen.
Increase
Participate in duct formation & with other hormones in
preparation of the breast for lactation at puberty and pregnancy.
Incresebindingof t4then decrease free →physiological goiter.
Inhibits bone resorption [ ppt of calcium]
Increase HDL & triglyceride but decrease LDL & cholesterol.
Increase synthesis of coagulation factors
Large doses decrease FSH &LH[feed back mechanism]
Beast
Thyroid
Bone
Lipids
Blood
Pituitary
Pharmacokinetic
Natural estrogen : their esterified or or conjugated derivatives are
absorbed through GIT, skin and mucous membranes. Estradiol is rapidly
metabolized and partially inactivated by microsomal enz. Of the liver.
Micronized estradiol as N. estradiol but first pass metabolism not
sufficient to lessen effectiveness when taken orally.
Synthetic estrogen: these compound as ethinyl estradiol are well
absorbed. Mestranol demythylated to ethinyl estradiol [fat soluble]are
stored in adipose tissues. They are slowly released. The synthetic have a
prolonged action and higher potency compared to N estrogen.To avoid
first pass metabolism may be administrated transdermal[patch,topical
gel,sprayand topical emulsion]transvaginal [tab, cream ring] or by
injections. Its metabolites execreted in bile and urine.
Estrogen preparations:
They are divided into:
 Natural: Estradiol, Estrone and Estriol
 Semisynthetic: they include
- Conjugated estrogens (ethinyl estradiol &piprazine estrone
sulfate)
- Esterified estrogens (estradiol cypionate , valerate )
 Non steroid estrogen that include:
- Synthetic: dienestrol, diethylstilbestrol, benzestrol, hexestrol,
methestrol, methallenestril, and chlorotrianisene
- Plant products with estrogenic activity are called
phytoestrogens.
- Those produced by fungi are known as mycoestrogens.
Therapeutic uses:
1-Replacement therapy in cases of postmenopausal , surgical [used with
progesterone to decrease risk of endometrial carcinoma associated
unopposed estrogen]
 1ry hypogonadism & 1ry amenorrhea, 1ry infertility.
 Delayed puberty & hypopitutrism & castration
 Menopausal syndrome[ shortest time lowest dose] ,Premature
menopause, surgical menopause
Bleeding,dysmenorrhea
 Atrophic vaginitis, osteoporosis.
2-Supression of ovulation in cases of:
 Dysmenorrhea ,dysfunction uterine bleeding
 Contraceptive pills
3-Suppress excessive androgen secretion to treat acne valgaris &
hirsutism.&cancer prostate in males.
4-Suppression of postpartum lactation
NB:They was used in the treatment of atherosclerosis but they are now
obsolete due to high side effects.
Adverse effects:
 Breakthrough bleeding.
 Breast tenderness.
 Thromboembolic disorders.
 Hypertension.
 Cholestasis.
 Increase incidence of certain types of cancer eg cancer breast ,
endometrium and vaginal adenocarcinoma in young women
whose mothers were treated with diethylstilbestrol in an effort to
prevent miscarriage.
 Nausea ,peripheral edema ,headach.
Commonly Used Estrogens.
Preparation
Average Replacement Dosage
Ethinyl estradiol
0.005–0.02 mg/d
Micronized estradiol 1–2 mg/d
Estradiol cypionate
2–5 mg every 3–4 weeks
Estradiol valerate
2–20 mg every other week
Estropipate
Semisythetic
1.25–2.5 mg/d
Conjugated, esterified, or mixed estrogenic substances:
Oral
0.3–1.25 mg/d
Injectable
0.2–2 mg/d
Transdermal
Patch
Quinestrol
0.1–0.2 mg/week
Chlorotrianisene
12–25 mg/d
Methallenestril
Mestranol
3–9 mg/d
0.05 mg/d
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Antiestrogens
1-Estrogen receptor antagonists[pituitary gonadal axis must be
intact]
Partial agonists: [non stroid]
Clomophene (clomid) and tamoxifen (nolvadex) modify or inhibit the
action of estrogens.
Pure antagonists: Fulvestrant
Mechanism of action:
a. They bind to the cytoplasmic estrogen receptors that are then
translocated to the nucleus so, interfering with the physiologic
action of estrogens in pitutary.
b. By interfering with the normal hypothalamic and hypophyseal
feedback inhibition of estrogen synthesis, these agents cause
increased secretion
of luteinizing honnone-releasing hormone, follicle-stimulating
hormone-releasing bonnone, and gonadotropines.
This leads to ovarian stimulation and ovulation.
Therapeutic uses
• Clomiphene is a partial agonist, a weak estrogen that also acts as a
competitive inhibitor of endogenous estrogens It has found use as an
ovulation-inducing agent in treatment of female infertility due to overian
causes.Side effect:polycyctic ovary,multiple pregnancy,hot flushes
• Tamoxifen a competitive partial agonist inhibitor of estradiol at the
estrogen receptors [ more agonist] .It is extensively used in the palliative
treatment of breast estrogen sensetive cancer in postmenopausal women
and is approved for chemoprevention of breast cancer in high-risk women
in a dose of 10–20 mg twice daily, vaginal tumour .Side effects Hot
flushes and nausea vomiting, osteoporosis and increase incidence of
cancer in contralateral breast if used for more than 5 years.
 Toremifene is a structurally similar compound with very similar
properties, indications, and toxicities.It increase incidence of
cancer uterus due to agonist effect on endometrium.
 Raloxifene is another partial estrogen agonist-antagonist It has
similar effects on lipids and bone but appears not to stimulate the
endometrium or breast.
 Fulvestrant is used in treatment of cancer breast.
2-Inhibitors of estrogen synthesis
 Anastrozole & Letrozole & Fadrozole are non steroidal inhibitor
of aromatase enzyme
 Exemestane, a steroid molecule, is an irreversible inhibitor of
aromatase