PHARMACOLOGY OF ESTROGEN

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ESTROGEN ANTIESTROGEN HRT : 

ESTROGEN ANTIESTROGEN HRT

INTRODUCTION : 

INTRODUCTION These are substances which can induce estrus in spayed animals. It was established in 1900 that ovaries control female reproductive function through hormonal mechanism. Allen and Doisy (1923) found that an alcoholic extract of ovaries was capable of producing estrus and devised a simple bioassay method. The active principle was obtained in pure form in 1929 and soon its chemical structure was worked out.

NATURAL ESTROGENS : 

NATURAL ESTROGENS Estradiol is the major estrogen secreted by the ovary. It is synthesized in the Graafian follicle, corpus luteum and placenta from cholesterol. Estradiol is rapidly oxidized in liver to Estrone which is hydroxylated to form Estriol. ESTRODIOL is the most potent estrogen. It is derived in human males also from aromatization of testosterone in testes and extra glandular tissues. In mare, large quantity of Equilin is produced which has 1/5 estrogenic potency of Estradiol.

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ESTRODIOL ESTROGEN

ESTROGEN SYNTHESIS : 

ESTROGEN SYNTHESIS

SYNTHETIC ESTROGEN : 

SYNTHETIC ESTROGEN Natural estrogens are inactive orally and have a short duration of action due to rapid metabolism in liver. So, synthetic compounds have been produced: STEROIDAL --- Ethinylestradiol, Mestranol, Tibolone Non steroidal --- Diethylstilbestrol Hexestrol, Dienestrol

ACTIONS: : 

ACTIONS: Sex organs: The estrogen brings about pubertal changes in female including growth of uterus, fallopian tubes etc. Secondary sex characters: Estrogen causes proliferation of ducts and stroma and accumulation of fat. Acne is common in female as it is in male- due to androgens production. Metabolic effect: Estrogen is anabolic. It is important in maintenance bone mass primarily by retarding bone reabsorption. Continued action of it causes the fusion of epiphysis.

MECHANISM OF ACTION: : 

MECHANISM OF ACTION: Estrogen binds to specific nuclear receptors in target cells and to produce effects by regulating protein synthesis. Estrogen receptors (ERs) have been demonstrated in female sex organs, liver, pituatary,bone, blood vessel, heart, CNS, and in certain hormone responsive for the breast carcinoma. The ER is analogous to other steroid receptors: agonist binding to the ligand binding domain brings about receptor dimerization and interaction with ‘estrogen response elements’(ERE’s) of target genes. Gene transcription is promoted trough certain coactivator proteins. On binding an estrogen antagonist the receptor assumes a different conformation and interact with other corepressor proteins inhibiting gene transcription.

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Two ERs designated ER-alpha and ER-beta have been identified: ER-alpha are predominates in uterus, mammary glands, hypothalamus and blood vessels. ER-beta are predominates in prostate glands of male and ovaries of female. ER-alpha and ER-beta may have a different pattern of interaction with coactivators and corepressor.

PREPARATIONS AND DOSES : 

PREPARATIONS AND DOSES All estrogen has similar action and equivalent parenteral doses. They are Estrodiol 0.1mg= ethinylestradiol 0.1mg= Mestranol 0.15mg= conjugated estrogen 10mg= Estriol succinate 16mg= diethylstilbestrol 10mg. Estrodiol is available as Estradiol benzoate, Estradiol cypionate, Estradiol valarate etc. around 5 to 10 mg

MEDICAL USES OF ESTROGEN : 

MEDICAL USES OF ESTROGEN Hormone replacement therapy Oral contraceptives Cardio protective Menopausal hormone therapy Vaginal atrophy Hypoestrogenism Wound healing Experimental treatment of bulimia nervosa

ADVERSE EFFECTS : 

ADVERSE EFFECTS Gynaecomastia cervical and vaginal carcinoma endometrial or uterine cancer enhances the growth of existing breast cancer incidence of gallstone and benign hematomas migraine, epilepsy, endometriosis effect may be enhanced

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ESTRODIOL TABLETS ETHINYLESRADIOL

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ESTRODIAL BENZOATE

TRANSEDERMAL ESTRODIOL: : 

TRANSEDERMAL ESTRODIOL: A transdermal patch has become available in three sizes, 5,10,20 sq.cm delivering 0.025mg, 0.05mg and 0.1mg in 24hrs for 3 days. the systemic side effects are same as oral estrogen but are milder. Oral therapy delivers higher dose of hormone to liver and increases the synthesis of several proteins. The risk thromboembolic phenomenon is less or not seen. Estraderm-MX:25,50,100 microgram per 24hrs Estragest-TTS (Estradiol + norethistrone acetate) Oestragel: 3mg/5gm in 80gm tube

HRT : 

HRT HRT refers to hormone replacement therapy. It is also called as menopausal hormone therapy. It is highly efficacious in suppressing the perimenopausal syndrome of vasomotor instability, psychological disturbances and atrophic changes. MEDICAL PROBLEM RELATED TO MENOPAUSE: Vasomotor disturbances: hot flushes, chilly sensation, inappropriate sweating, faintness, paresthesias, aches and pains Urogenital atrophy

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Osteoporosis: Loss of osteoids as well as calcium leads to thinning and weakening of bone. Dermatological changes: Thinning, drying and loss of elasticity of skin, wrinkles. Psychological/cognitive disturbances: Irritability, depressed mood, loss of libido etc. Increased risk of cardiovascular diseases: Coronary artery disease, myocardial infarction, stroke. The dose of estrogen used in HRT is substantially lower than that for contraception. Typical conjugated estrogens are used 0.625 mg/dl(equivalent to Ethinylestradiol 10mg) and lower doses 0.3-0.45mg/dl

ADR’S OF HRT: : 

ADR’S OF HRT: ESTROGEN Obesity Thromboembolism CVS problems Atherosclerosis Breast cancer uterine cancer or endometrial cancer PROGESTERONE Withdrawal bleeding Nausea and vomiting Mood changes Hisutism

ANTIESTROGENS: : 

ANTIESTROGENS: Two non steroidal compounds clomiphene citrate and tamoxifen citrate previously grouped as estrogen antagonists have been in use since 1970s. CLOMIPHENE CITRATE: It binds to both ER-alpha and ER-beta and acts as a pure estrogen antagonist in all human tissues, but the recemate displays a weak agonistic action in rats. It includes Gn secreation by blocking estrogenic feedback inhibition of pituitary. The use of clomiphene is in sterility due to the failure of ovulation:50mg daily 5days of cycle.

ADRs, PREPARATIONS AND DOSES: : 

ADRs, PREPARATIONS AND DOSES: ADRs : polycystic ovaries, multiple pregnancy, hot flushes, gastric upset, vertigo, allergic dermatitis. Risk of ovarian tumour may be increased. USES: to aid in vitro fertilization clomiphene given with Gns causes synchronous maturation of several ova –improves their harvesting for in vitro fertilization. BRANDs : Clomid, Fertomid-25, 50mg tab. Clofert, clome-25,50mg tab are market available products.

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CLOMIPHENE CITRATE

FULVESTRANT: : 

FULVESTRANT: It is the first member of a distinct class of ER ligands called ‘selective estrogen receptor down regulators’ or ‘pure estrogen antagonists’ that has been introduced for the treatment of metastatic ER positive breast cancer in postmenopausal women which has stopped responding to tamoxifen.

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FULVESTRANT INJECTION

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SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM’s)

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METABOLISM OF TAMOXIFEN

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AROMATASE INHIBITORS

BRAND NAMES: : 

BRAND NAMES: Letrozole ----- Letoval, letroz, femara, oncolet – 2.5 mg tab Anastrozole ----- Altraz, aromatraz- 1 mg tab ADR’s: Hot flushes, nausea, diarrhoea, dyspepsia etc

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