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ESTROGENS and ANTIESTROGENS - Pharmacology
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- 2. Estrogen - Biosynthesisand metabolism Estradiol is the major estrogen secreted by ovary Estradiol is biologically very active whereas estrone and estriol are biologically weak
- 3. Mechanism of actionon receptors Estrogen diffuses through plasma membrane ↓ Binds to ER in cytosol ⊙ ER α in uterus,vagina, breast,bone,blood vessels ⊙ ER β in male prostate gland and ovaries ↓ Receptor dimerization ↓ Dimer interacts with Estrogen response elements in promoter of target genes ↓ Recruits coactivators to promoter ↓ Gene transcription → various effects
- 4. Effects of Estrogen 1.SEX ORGANS : ● Proliferation of endometrium in preovulatory phase ● Thickening and cornification of vagina 2. SECONDARY SEXUAL CHARACTERS : ● Pubertal Growth and development ● Proliferation of ducts and stroma of breast ● Appearance of public and axillary hair and feminine body contour ● Regression of acne (decreases androgen by suppressing gonadotropin release) 3. BONE : ● Fusion of epiphysis ● Maintains bone mass (increases expression of bone matrix proteins) ● Retards bone resorption (antagonizes osteoclastogenic activity of PTH and IL 6)
- 5. Effects of Estrogen 4.METABOLISM : ● Impairs glucose tolerance at higher doses ● Decreases LDL and increases HDL - atherosclerosis is rare in premenopausal women ● Increases cholesterol excretion in bile 5. BLOOD : ● Decreases antithrombin III and increases levels of coagulation factors - Blood coagulability is increased ● Sodium and water retention - since angiotensinogen synthesis in liver is increased
- 6. Hypothalamic - pituitary-ovarian axis : Feedback inhibition of estrogen on GnRH and Gonadotropins (LH,FSH)
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- 8. Pharmacokinetics NATURAL ESTROGENS : -not given orally (rapid metabolism in liver) - Bound to SHBG and albumin in circulation - Glucuronate and sulfate conjugated - Enterohepatic circulation - excreted in urine SYNTHETIC ESTROGENS : ● Ethinyl estradiol and diethylstilbestrol- orally active ● Mestranol - prodrug of ethinyl estradiol ● Dienesterol - only topical use as vaginal creams ● Tibolone - is converted to three metabolites having estrogen, progesterone and weak androgen effects ROUTES : # Parenteral (i.m., i.v.) # Oral # Transdermal # Topical (vaginal creams)
- 9. Uses of Estrogens 1.POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY: Deficiency of estrogen in postmenopausal women lead to the following symptoms : × hot flashes, night sweats- short term therapy(3 to 6 months) , smaller dose × atrophy of uterus and vagina, vaginal dryness, senile vaginitis - local estrogen creams LATE CONSEQUENCES: × increased risk of osteoporosis - to prevent further bone loss and reduce fracture risk × increased incidence of cardiovascular diseases × risk of Alzheimer ‘s disease Can estrogen be used alone ? No. Estrogens induce endometrial hyperplasia which predisposes to endometrial carcinoma. So progesterone is added with Estrogen (progesterone halts endometrial growth)
- 10. Uses of Estrogens(cont.) 2. PRIMARY HYPOGONADISM - to stimulate secondary sexual characters, mensus, optimal growth Initiated at low dose, continued till menopause, a progestin is added after first uterine bleeding 3. DYSMENNORHOEA: cyclic estrogen + progestin = anovulatory cycles which are painless 4. ACNE : cyclic treatment with progestin 5. AS A COMPONENT OF ORAL CONTRACEPTIVE PILLS :
- 11. Adverse effects ☆ Feminizationin males ☆ Premature Fusion of epiphysis - reduced adult stature in children ☆ Accelerate the growth of existing breast cancer ☆ Endometrial carcinoma (Endometrial hyperplasia) ☆ Increased incidence of Gall stones (Cholesterol excretion is increased) ☆ increased risk of venous thromboembolism (Hypercoagulability) ☆ Edema (Retention of water)
- 12. Other estrogen relateddrugs :
- 13. Antiestrogen- Clomiphene citrate, an ovulation inducing agent Competitively binds to estrogen receptors in hypothalamus ↓ Blocks negative feedback of circulating estrogen ↓ Hypothalamus perceives hypoestrogenic state ↓ GnRH is released ↓ Increased FSH,LH release (in both males and females) ↓ OVULATION occurs due to LH surge Note : Clomiphene citrate has antiestrogenic effect on endometrium and cervix
- 14. Clomiphene citrate (cont.) PK: absorbed orally, deposited in adipose tissue, metabolized in liver and excreted in faecus and urine ( t 1/2 : 6 days) Undergoes Enterohepatic circulation Uses : ● Female Infertility - 50 mg OD for 5 days starting from 5th day of cycle each month ● Harvesting eggs in invitro fertilization ● Oligozoospermia - 25 mg daily for 24 days of a month for 6 months Adverse effects : Ovarian HyperStimulation Syndrome, Multiple pregnancy, hot flashes, ovarian tumor Contraindications : Ovarian cyst ( might enlarge), chronic liver disease
- 15. Selective Estrogen ReceptorDownregulator (SERD)- Fulvestrant Inhibits receptor dimerization and Increases proteasomal degradation of estrogen receptor Preferred route : intramuscular PK : slow absorption, long Elimination t1/2 Use : Tamoxifen resistant ER positive breast cancer - 250 to 500 mg monthly i.m. injection in gluteal region Adverse effect : hot flashes
- 16. Selective Estrogen ReceptorModulators (SERM) 1. Tamoxifen citrate : ER positive breast cancer ■ ESTROGEN ANTAGONIST in breast carcinoma cells and some peripheral tissues - Inhibits breast cancer cells but causes hot flashes ■ PARTIAL AGONIST in - Uterus : Results in endometrial hyperplasia - Bone : improves bone density - Liver : improves lipid profile - cardioprotective - increased clotting factor synthesis - deep vein thrombosis Uses : Primary and metastatic ER positive breast cancer - Prophylaxis and treatment Adverse effects : hot flashes, increased risk of venous thromboembolism, endometrial hyperplasia Dose : 20 mg/day in 1 or 2 doses ….. ineffective after 5 years 2. Toremifene- newer congener of tamoxifen
- 17. 3. Raloxifene :second line drug for osteoporosis ■ ESTROGEN ANTAGONIST in breast and endometrium - Reduces the risk of ER positive breast cancer and No risk of endometrial carcinoma ■ PARTIAL AGONIST in - bone : increases bone mineral density - Lipid metabolism : reduces LDL Uses : osteoporosis, endometriosis Adverse effects : deep vein thrombosis (3 fold increased risk), hot flashes Dose : 60 mg/day
- 18. Aromatase inhibitors: ERpositive breast cancer LETROZOLE, ANASTROZOLE, EXEMESTANE Since Estrogen synthesis is reduced, there is ● No growth of breast cancer cells ● No endometrial hyperplasia ● No increased risk of thromboembolism ● No effect on lipid profile ● Accelerated bone loss Adverse effects : hot flashes, bone loss, vaginal dryness
- 19. Letrozole, Anastrozole - nonsteroidalreversible (type 2) aromatase inhibitors - nearly total estrogen deprivation (small amount secreted from ovaries - so not used in premenopausal women) PK : ◇ Letrozole has 100% oral bioavailability, large volume of distribution, t1/2 of 40 hours - dose : 2.5 mg OD ◇ Anastrazole accumulates in body and produces peak effect after 7-10 days - dose : 1 mg OD Uses : ▪︎adjuvant therapy in early and advanced ER positive breast cancer in postmenopausal women ▪︎Second line drug in tamoxifen resistant breast cancer
- 20. Exemestane - steroidal irreversible(type 1) aromatase inhibitor - > 90% suppression of estradiol production Use : adjuvant therapy in early breast cancer Dose : 25 mg OD after meals