ESTROGENS and ANTIESTROGENS - Pharmacology

Estrogen - Biosynthesis and metabolism

Estradiol is the major estrogen secreted by ovary

Estradiol is biologically very active whereas estrone and estriol are biologically weak

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

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)

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

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

Uses of Estrogens

1.POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY:

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 :

Antiestrogen- Clomiphene citrate , an ovulation inducing agent

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

1. ESTROGENS AND ANTIESTROGENS Angelin.A

2. Estrogen - Biosynthesis and metabolism Estradiol is the major estrogen secreted by ovary Estradiol is biologically very active whereas estrone and estriol are biologically weak

3. Mechanism of action on 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 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)

7. Estrogens in Pharmacology

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 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 ☆ Feminization in 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 related drugs :

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 : O varian H yper S timulation S yndrome, Multiple pregnancy, hot flashes, ovarian tumor Contraindications : Ovarian cyst ( might enlarge), chronic liver disease

15. Selective Estrogen Receptor Downregulator (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 Receptor Modulators (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: ER positive 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 nonsteroidal reversible (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