This document summarizes key information about estrogens: 1. It describes the main endogenous estrogens - estradiol, estrone, and estriol - and their sources and potencies. 2. It explains the mechanisms of action of estrogens, including their binding to estrogen receptors, dimerization, and gene transcription effects. 3. It outlines the therapeutic uses of estrogens like hormone replacement therapy and the pharmacological actions and regulation of estrogen secretion.

1. ESTROGEN

7.  Estradiol (17-β-estradiol)-most potent –secreted by
ovaries( pre-menopausal)
 Esterone –formed by extra-glandular conversion of
androstenedione in peripheral tissues(after
menopause)
 Estriol is a conjugated metabolite of estrone and
estradiol (pregnancy)
 Natural - Inactive orally, short duration and rapid
metabolism

8. Synthetic oestrogens
• Steroidal:
– SEMI-SYNTHETIC:- Ethinylestradiol,
– SYNTHETIC:- Mestranol and Tibolone
• Non-steroidal: Derivatives of stilbene
– Diethinylstilbestrol, Hexestrol .
– Stilbestrol and chlorotrianisene used to treat patients with
CA prostate.
– Conjugated equine estrogens:-

11. Alpha=N-TERMINAL portion has transcription activation
Beta= repressor domain.

13. Mechanism of Action
• 2 ERs are – ERα and ERß
• ERα - uterus, vagina, breast and blood vessels
• ERß – Prostate and Ovaries
• Work via a steroid hormone mechanism.
• Entering the target cells and binding to specific cytosolic
receptors - dimerization
• The steroid-receptor complex is then translocated to the
nucleus – EREs of target genes= PROTEIN SYNTHESIS.
• Where it alters gene expression - Coactivator proteins
• Antagonist binding- corepressor proteins – inhibits
transcription

14. Regulation of Secretion
• Daily secretion: 10 to 100 mcg (estradiol) per day – starts from
graffian follicle under influence of FSH
• Depends on phase of cycle – increases with FSH in surge –
preovulatory
• Continue to secrete by corpus luteum after ovulation
• During pregnancy – large quantity by placenta – upto 30 mg per
day (estriol)
• Post menopausal: 2 – 10 mcg per day only (estrone)

15. vasodilatationi

16. Actions of Oestrogens
• Brings about pubertal changes in vagina, fallopian tube and
uterus.
Vagina: cornification and thickening of vaginal epithelium
Endometrium: Proliferation of endometrium – preovulatory.
Cervix: Rhythmic contractions of uterus and fallopian tube -
increase of cervical mucous and alkaline watery secretion.
(facilitate sperm penetration)
MAMMARY GLANDS:- proliferation of ducts and stroma (SIZE)
FSH/LH:- feedback control
Chemoreceptor trigger zone:- induces vomiting and nausea
Secondary sexual characters:-breast development
 pigmentation of nipples.
body fat accumulation
femine type hair pattern and voice

18. Other Pharmacological Actions
• Bone: Important for maintaining bone mass – dec bone resorption
– Reduce the maturation and activity of osteoclasts – by
modifying regulatory cytokines from osteoblasts
– Positive Ca++ balance( parathormone)
– Generation of vit.D3 – induction of renal hydroxylase enzyme
• Promote union of epiphysis with metaphysis.
• Vasodilatation of capillaries
• Oedema – salt and water retention
• Decreased LDL and Increased HDL level – HDL:LDL ratio increased
• Increased coagulability: II, VII, IX and X
• INCREASED CHOLESTROL EXCRETION IN BILE( LITHOGENICITY)
• Promotes vasodilatation ( NO,PGI2)
• Causes formation of gall stones.
• LIVER:- Increased hepatic proteins like SHBG(sex hormone binding
globulin), TBG,TRANSCORTIN,CBG

20. Oestrogen - Kinetics
• Natural estrogens are inactive orally due to first
pass metabolism.( EE well absorbed)
• To avoid hepatic s/e prefer other routes like
transdermal/vaginal/IM.
• Estradiol converted into estrone & estriol.
• Bound to plasma protein (SHBG)
• All 3 - Conjugated with glucoronic acid and sulfated
and excreted in urine and bile
• Enterohepatic circulation – undesirable s/e like
THROMBOEMBOLIC DISORDERS, HEPATIC
ADENOMAS on prolonged usage

25. Therapeutic Uses
• Hormone Replacement Therapy to Menopause woman
• Problems of menopause: Physical, psychological and
emotional
– Vasomotor disturbances: Hot flushes ,inappropriate
sweating, aches and pains,vertigo.
– Urogenital atrophy: vaginitis, dysperunia, dryness and
shrinkage,risk of UTI,urgency and urinary incontinence.
– Osteoporosis and fractures
– Psychological and cognitive disturbances: Irritability,
depression, loss of libido etc.
– Dermatological changes-ACNE AND HIRSUTISM
– Risk of cardiovascular diseases: CAD, Stroke MI etc.
– Defeminization:- loss of femine fat,skin aging.
– Sleep disturbances.

26. HRT
• Dosage: START WITH LOW DOSE AVAILABLE
• Conjugated equine estrogens:- 0.625 mg /day in cyclical
manner for( POST-HYSTERECTOMY PT)
• E on day 1-25
• Progestin preparation (medroxyprogesterone/norethisterone)
is used –2.5 mg daily (WITH INTACT UTERUS) E+P(12 DAYS)
• TTS preparations of estradiol may be preferred for osteoporosis
• Topical cream for senile vaginitis.
• Tibolone:
– Developed specifically for HRT
– Estrogenic and progestitional property
– Dose is 2.5 mg daily
– Lesser chance of Breast cancer
– s/e include vaginal spotting, weight gain,growth of facial hair
– c/I in cases of ER+ BREAST or UTERUS CA.

27. What is SERM?
• SERM = SELECTIVE ESTROGEN RECEPTOR MODULATORS
• 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

28. 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

29. 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
• Facilitate ovulation and used to treat infertility.(oligospermia)
• No use in patients with primary ovarian or pituitary failure
 Pharmacokinetics :
• Well absorbed orally
• Long plasma half life - 5 to 7 days
• Highly plasma protein binding, undergoes enterohepatic circulation

30.  Adverse Effects :
• Polycystic Ovarian Disease ( overstimulation causes rupture of ovary
and causes internal haemorrhage)
• Twin pregnancy, Multiple Pregnancy
• Risk of Ovarian Cancer
• Hot flushes ( antagonism of peripheral ER)
 Uses :
• Infertility due to anovulation
• Male infertility due to Oligozoospermia
• In vitro fertilization
• Dosage:
• 50 mg OD from 5th day onwards for 5 days
• Continued for 2-3 cycles
• Conception occurs within 4-6 cycles
• If no, dose increased

32. TAMOXIFEN (SERM)
• Actions:
– Is a competitive antagonist to estrogen receptors in the breast and blood
– Partial agonist at other estrogen receptors (thus minimizing side effects due
to estrogen deprivation) - bone, uterus, liver and pituitary
– 1st CHOICE for breast CA both in pre & post menopausal women.
– Hot flushes – antiestrogenic action
– Stimulation of endometrial proliferation and lowering of Gn and
prolactin levels – agonistic action
– Decrease in LDL level but no change in HDL level
– Agonist action on uterus and blood INC risk of endometrial CA and DVT
– Other benefits: Improvement in bone mass and prevent osteoporosis and
lipid profile improvement and thus lowers CAD risk
• Kinetics: Absorbed orally and has biphasic half life – 10 Hrs
and 7 days – long duration of action
– Excreted in Bile
– Dose is 10 to 20 mg BD

34. Tamoxifen – contd.
• Uses:
BREAST carcinoma of pre and post menopause
–Adjuvant therapy in early cases
–Palliative therapy
• Side effects.
–Hot flushes, nausea, vomiting, rash,
menstrual irregularities and bleeding,
infrequent depression, headache,
hypercalcemia, edema, and blood dyscrasias
–Less toxic than anticancer drugs
–Endometrial carcinoma: thickening of
endometrium
CH2CH3
O(CH3)2N-CH2-CH2
TAMOXIFEN (NOLVADEX)

36. TOREMIFENE
• Triphenylethylene derivative of Tamoxifen
• Chemical structure same as Tamoxifen.
• Similar pharmacological profile.
• Used to treat ER positive breast cancer

37. RALOXIFEN AND ORMELOXIFENE
• Raloxifene: AE on B&E and E on B
– Partial agonist in Bone and CVS – antagonist in Breast and
Endometrium
– Inc osteoblast activity and dec osteoclast activity.
– Decreases LDL cholesterol – no increase in HDL cholesterol
– No stimulation of endometrial proliferation – no risk of
endometrial carcinoma.
– Doesn’t relive hot flushes
– Extensive first pass metabolism so poor bioavailability
– Long t1/2 so given as OD dose of 60mg/day.
– Uses: 1st line of drug in prevention of Osteoporosis in
menopause – Ca++ and Vit. D enhances benefit
– s/e:- hot flushes,leg cramps, inc risk of DVT,PE(estrogenic
effect on blood coagulation)

39. ORMELOXIFENE
• AE IN BREAST AND UTERUS
• Approved for the treatment of DUB
• Used as nonhormonal oral contraceptive as it has
• both AE and AP action
• s/e:- nausea,headache,weight gain,fluid retention.

41. Molecular Action
FULVESTRAN
FULVESTRAN

42. • 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

43. • 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

44. AROMATASE INHIBITORS
• 3rd GEN:- Letrozole, Anastrozole and Exemestane
• MOA: Letrozole
– Non steroidal compound, reversible inhibition of
aromatization all over the body
– Suppression of proliferation of estrogen dependant breast
carcinoma cells(ER+)
– Rapid oral absorption – 100% bioavailability, large Vd,
– t1/2– 40 Hrs
– 2.5 mg BD
– Adjuvant after mastectomy.
• Uses: Early breast carcinoma and Advanced breast
carcinoma which is resistant to TAMOXIFEN.

46. ANASTRAZOLE:- more potent than letrozole
s/e:- hot flushes,headache,fatigue,myalgia,
EXEMESTANE:- more potent
steroidal component
irreversible inhibitor

47. 25

48. Must Know
• Hormone Replacement Therapy
• SERM

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