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Published on March 11, 2014

Author: sohinthaim

Source: slideshare.net

SELECTIVE ESTROGEN RECEPTOR MODULATORS Dr. SOHIN THAIM Date : 11/03/2014 Dept. of Pharmacology JNMC, Sawangi (W)

ESTROGEN • History : • Greek word ‘oistros’ meaning ‘gadfly’ or ‘mad impulse’-sexual passion or desire ‘gens’ meaning ‘producer of’  1900 – Knauer and Halban established that Ovaries control female reproductive function  1923 – Allen and Doisy found that alcoholic extract of Ovaries was capable of producing Estrus  1928 - Zondek reported excretion of estrogen in Urine  1929 – Butendant and Doisy isolated principle Estradiol in pure form

Physiology • Synthesized from Cholestrol in Graffian follicle, Corpus Luteum and Placenta • Natural Estrogens : Estradiol Estrone Estriol • Synthetic Estrogens : Ethinylestradiol, Mestranol, Tibolone Diethylstilbestrol • Regulation : • Estrogen after Ovulation produces negative feedback inhibition of FSH by direct action on Pituitary

• Normally : Daily secretion-10-100 µg in menstruating women Depends on the phase of the cycle. • During pregnancy : Placenta secrets Estrogen Peak up to 30mg/day • Postmenopausal women : Daily production – 2- 10 µg From Extra glandular size

Chemical Structure Phenolic A ring – Principal Structure Hydroxyl Group at Carbon 3 ß – OH or Ketone at Carbon 17

Actions of Estrogen 1. Sex Organs : Pubertal changes in female Growth of - Uterus - Fallopian tubes - Vagina • Estrogen augments rhythmic contractions of fallopian tube and uterus • Induce watery alkaline secretion from cervix making sperm penetration favorable

2. Secondary Sex Characters : - Growth of Breast Proliferation of ducts and stroma Accumulation of fat - Pubic and Axillary Hair - Feminine Body Contour and behaviour

3. Metabolic Effects : Bone : maintains bone mass Inhibits Osteoclast formation Promotes positive calcium balance Fluid Balance : mild salt and water retention Edema and mild rise in BP after prolonged use Lipid Profile : Increase in HDL Increase in Triglycerides Decrease in LDL

Molecular Action

What is SERM ? • SERM is a group of drugs which are - Synthetic - Non Steroidal - Tissue selective Estrogenic and Anti Estrogenic actions • So SERM may have one or combination of - Full agonist such as the natural endogenous estrogen - Mixed agonist /antagonist such as tamoxifen - Full antagonist such as Fulvestrant

Ideal SERM • The ideal SERM is one that - Prevents bone loss - No risk of uterine or breast cancer - + ve effect on lipids & cardiovascular system - Relieves PMS - Maintains cognitive function of the brain

• Examples : Tamoxifen Citrate Tamoxifen Analogue Toremifene Droloxifene Idoxifene Raloxifene Lasofoxifene Arzoxifene

TAMOXIFEN CITRATE • History :  The first true SERM  In use since 1966 for Breast cancer  Developed as an Oral Contraceptive but was found to induce ovulation  Approved for Prophylactic use in Breast cancer since 1997

Chemical Structure l Trans Clomiphene or Enclomiphene Trans conformation –Anti- estrogenic Cis conformation- Estrogenic Tamoxifen is marketed as Trans isomer

Molecular Action

• Potent Estrogen Receptor Antagonist at : - Breast - Blood vessels - Peripheral sites • Potent Estrogen Receptor Agonist at : - Uterus - Bone - Pituitary - Liver

• Mechanism of Action :  Competitive inhibitor of estradiol binding to the ER  Binding of Estradiol and SERM to Estrogen binding sites of ER.  Initiate a change in conformation of ER  Dissociation of ER from Heat Shock Protein  Inhibition of ER Dimiresation

• Pharmacological Actions : • Anti estrogenic effects : Inhibition human breast cancer cells Hot flushes • Estrogenic effects : Endometrial Proliferation Improvement in Bone density Decrease in total and LDL cholesterol No change in HDL and Triglyceride Increase in Thromboembolism

• Pharmacokinetics : - effective orally - biphasic half life – 10hrs and 7days - major metabolite 4 hydroxytamoxifen - long duration of action - excreted in bile and stool • Side effects : - Hot flushes - Vaginal bleeding - Vaginal discharge - Menstrual irregularities

- Increased risk of thromboembolism - Dermatitis - Anorexia - Depression - Mild Leucopenia

• Therapeutic Uses : - Pre and Postmenopausal breast cancer - Primary prophylaxis of Breast cancer in High risk women - Post menopausal Osteoporosis - Male infertility – alternative to Clomiphene • Dose : - 20mg/day in 1 or 2 doses - maximum 40mg/day.

TOREMIFENE • Triphenylethylene derivative of Tamoxifen • Chemical structure same as Tamoxifen with Chlorine substitution as R2 position • Similar pharmacological profile • Used to treat ER positive breast cancer

RALOXIFENE • Developed in 1998 for treatment and prevention of Postmenopausal Osteoporosis. • 1999 approved for prophylaxis of breast cancer • Partial Estrogenic effects : Bone CVS • Antiestrogenic Effects : Breast Endometrium • Has distinct DNA target ‘raloxifene response element’

Chemical Structure Polyhydroxylated nonsteroidal compound

• Pharmacological Actions : - Improves Bone Mineral Density, prevents bone loss - Reduces incidence of Compression vertebral fractures - Decreases LDL, No increase in HDL and Triglycerides - Does not stimulate Endometrial Proliferation • Pharmacokinetics : - Absorbed orally - Has low oral bioavailability – only 2% - Half life 28 hrs - Excreted in faeces

• Side effects : - Hot flushes - Leg cramps - Deep vein thrombosis - Pulmonary embolism • Uses : - Second line drug for Osteoporosis - Secondary prevention and treatment of vertebral fractures - Prevention of Breast cancer - alternative to Hormone replacement therapy

ORMELOXIFENE • Estrogen antagonist at breast and uterus • Has anti estrogenic as well as anti progestogenic action. • Uses :  Dysfunctional Uterine Bleeding  Non Hormonal Oral Contraceptive Under Investigation for USE in :  Osteoporosis  Breast cancer  Endometrial Cancer

• Adverse Effects :  Nausea  Headache  Weight gain  Fluid retention

CLOMIPHENE CITRATE • Competitive antagonist of ER at Hypothalamus • Inhibits negative feedback effects on the release of GnRH • Release of FSH/LH at each secretory pulse is enhanced  Pharmacokinetics : • Well absorbed orally • Long plasma half life - 5 to 7 days • Highly plasma protein binding, undergoes enterohepatic circulation • Excreted in Urine and Faeces

 Adverse Effects : • Polycystic Ovarian Disease • Multiple Pregnancy • Risk of Ovarian Cancer • Hot flushes  Uses : • Infertility due to anovulation • Male infertility due to Oligozoospermia • In vitro fertilization

FULVESTRANT 7 α Alkylamide derivative of Estradiol

Molecular Action

• First member of – SERD ‘ Selective Estrogen Receptor Down-regulators’ • Pure estrogen antagonist • Introduced for treatment of metastatic ER positive breast cancer in postmenopausal women • Inhibits ER Dimerisation-ER interaction with DNA is prevented • Receptor degradation is enhanced

• More complete suppression of ER responsive gene function • Slowly eliminated, half life more than a month • Elimination in faeces  Adverse Effects : • Nausea, Headache, Asthma, Vasodilatation  Dose : 250mg monthly i.m. injections in buttocks  Use : Tamoxifen Resistant Breast Cancer

Recent Advances Lasofoxifene :  Investigated for the treatment of Post menopausal Osteoporosis and Vaginal Atrophy  Not approved by FDA for the treatment of vaginal atrophy Osmepifene :  Similar effects on bone as like Raloxifene- Increase BMD  Does not induce vasomotor symptoms in Post menopausal women  Increases endometrial thickness

 Arzoxifene : • Prevention and treatment of Breast cancer • Reduction in Vertebral Fractures • Failed to meet secondary endpoints of reduction in non vertebral fractures and cardiovascular events and cognitive function  Bazedoxifene : • Prevention and treatment of Post menopausal Osteoporosis • Favorable effects on Lipid profile

THANK YOU….

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