A PowerPoint presentation on "Estrogens ans antiestrogens" suitable for reading by Undergraduate level Medical students

1. Estrogens and Antiestrogens
Dr. D. K. Brahma
Associate Professor of Pharmacology
NEIGRIHMS, Shillong

2. Introduction
• Substances which can produce estrus in spayed
animals
• Oestrogens include the natural hormones as well
as semi-synthetic and synthetic (stilbene) agents
• Oestrogens are used as hormone:
– replacement therapy (menopause)
– in oncology
– contraceptives
• Most estrogen in the female is produced in the
ovaries by the theca interna and the granulosa
cells of the follicles
• Also in males from testosterone (aromatization)

3. CH3
OH
H
H
H
HO
ESTRADIOL
CH3
H
H
H
HO
O
ESTRONE
CH3
OH
H
H
H
HO
OH
ESTRIOL
Natural Oestrogens
1.
2.
3.

4. Synthetic oestrogens
• Natural - Inactive orally, short duration and
rapid metabolism:
• Steroidal:
– Ethinyl estradiol, Mestranol and Tibolone
• Nonsteroidal:
– Diethinylstilbestrol, Hexestrol and Dienestrol

5. Regulation of Secretion
• Daily secretion: 10 to 100 mcg
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
• Post menopausal: 2 – 10 mcg per
day only

6. Actions of Oestrogens
• On sexual organs (primary and secondary sexual characteristics)
• Brings about pubertal changes in vagina, fallopian tube and uterus – growth
 Vagina: cornification of epithelial cells with thickening and stratification of
epithelium
 Endometrium: Proliferation of endometrium – preovulatory (progeterone)
 Absence of progesterone – anovulatory cycles – withdrawal of estrogen –
menstruation
 Continued estrogen without progesterone – delayed menstruation (but breakthrough bleeding)
 Normal event – progesterone withdrawal – cannot be suppressed by estrogen
 Cervix: Rhythmic contractions of uterus and fallopian tube - increase of cervical
mucous and alkaline watery secretion with a lowered viscosity (favoring sperm
access)
• Secondary Sex Characters: Also acne
• Metabolic effects: Anabolic but weaker than testosterone – pubertal growth
– Continued exposure – fusion of epiphyses

7. Oestrogens Physiology

8. Other Pharmacological Actions
• Bone: Important for maintaining bone mass – increased expression
of bone mass proteins (osteonectin, collagen, osteocalcin, alkaline
phosphatase)
– Reduce the maturation and activity of osteoclasts – by
modifying regulatory cytokines from osteoblasts
– Positive Ca++ balance
– Generation of vit.D3 – induction of renal hydroxylase enzyme
• Oedema – salt and water retention
• Decreased LDL and Increased HDL level – HDL:LDL ration increased
• Increased coagulability: II, VII, IX and X
• Lithogenicity of Bile
• Increased SHBG, TBG and CBG

9. 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
• Where it alters gene expression - Coactivator proteins
• Antagonist binding- corepressor proteins – inhibits
transcription

10. Oestrogen - Kinetics
• Absorbed orally, but quick metabolism –
natural ones except ethinyl estradiol
• All are absorbed transdermally
• Bound to plasma protein (SHBG)
• All 3 - Conjugated with glucoronic acid and
sulfated and excreted in urine
• Enterohepatic circulation – deconjugation in
intestine

11. Oestrogen preparations
• Preferred route is oral, but sometimes parenteral when
large doses are required
• All estrogen preparations are available – tablet and
injections
• Some examples:
– Estradiol – 2.5 mg to 10 mg/ml IM inj.
– EE: 0.01, 0.05, 1 mg tab for menopause
– Conjugated estrogens: 0.625,1.25 mg tab for DUB or injections
25 mg/ml
– Mestranol: 0.1 mg tabs to convert to EE
– Estriol succinate: 1mg/gm cream

12. Transdermal
Patches
• Estradiol-TTS/Estraderm/Estragest - TTS
• Sizes: 5, 10 and 20 sq. cm –
0.025, 0.05 and 1 mg/day
• Menopausal women
• Usual dose: 0.5 mg/day
• Cyclic therapy – 3 weeks on – 1 week off +
Progestin 10-12 days during last days
• ADV: Less hepatic delivery VS Oral – CBG, TBG,
angiotensinogen and clotting factors are not
elevated

13. Estrogen - ADRs
• Suppression of libido, gynaecomastia and
feminization – in Male
• Fusion of epiphyses – reduction of stature
• Stilbestrol – increased incidence of Carcinoma of
cervix in female offspring
• Irregular bleeding – endometrial carcinoma
• Accelerated growth of Breast cancer
• Gall stones and hepatomas
• Migraine, epilepsy and endometriosis - worsens

14. Therapeutic Uses
• Hormone Replacement Therapy to Menopause woman
• Problems of menopause: Physical, psychological and emotional
– Vasomotor disturbances: Hot flash, chilly sensation, inappropriate
sweating, aches and pains etc.
– Urogenital atrophy: vaginitis, dysperunia, dryness and shrinkage etc.
– Osteoporosis and fractures
– Psychological and cognitive disturbances: Irritability, depression, loss of
libido etc.
– Dermatological changes
– Risk of cardiovascular diseases: CAD, Stroke MI etc.
• Dosage: Estrogen equivalent to 0.625 mg of EE/day in cyclical
manner
– Progestin preparation (medroxy progesterone/norethisterone) is used –
2.5 mg daily
– TTS preparations may be preferred

15. HRT Indications
• Benefits: (Indications):
– Vasomotor and other symptoms of perimenopausal period – smallest effective
dose
– Post hysterectomy patients – estrogen only
– Young woman with premature menopause
– Perimenopausal women – cyclical HRT
• Demerits:
– No improvement of cognitive disturbances – risk of dementia
– Does not protect against Cardiovascular diseases: increased venous
thromboembolism, MI and stroke etc. (NO synthase and PGI2 production)
– Not good for Prevention of osteoporosis and fractures
– Combined HRT increases the risk of Breast cancer, gall stones and migraine
– Should be assessed individually
• Tibolone:
– Developed specifically for HRT
– Estrogenic and progestitional property
– Dose is 2.5 mg daily
– Lesser chance of Breast cancer

17. Clomiphene Citrate (Antiestrogen)
• The “Fertility pill” - pure antagonist of ESTROGEN
receptor in all human tissues
• MOA: Induce Gn secretion by blocking estrogenic
feedback inhibition
– Used in women with unexplained infertility or anovulatory
infertility
– Bind to both, ERα and ERß receptors
– Blocks estrogenic feedback inhibition of pituitary and
induces Gn secretion
– Increase in amount of secretion of FSH/LH at each
secretary pulse
– Creates favorable atmosphere (ovarian stimulation) for
ovulation in ovaries
– Hot flashes – antagonism of peripheral actions

18. Clomiphene Citrate – contd.
• 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
– However – antiestrogenic effect may modify developing follicle,
endometrial and cervical secretion
– Luteal phase dysfunction – failure (HCG and Menotropins added)
• ADRs: Polycystic ovaries, multiple pregnancy, gastric upset, hot
flushes and vertigo, allergic dermatitis
• Other Uses:
– Assisted reproduction (to develop multiple eggs)
– Artificial insemination (irregular ovulation)
(Clomiphene Challenge Test)
– Oligospermia (25 mg daily for 6 months – 6 days rest))

19. Tamoxifen (SERM)
• Actions:
– Is a competitive antagonist to estrogen at receptors in the breast.
– Partial agonist at other estrogen receptors (thus minimizing side
effects due to estrogen deprivation) - bone, uterus, liver and pituitary
– 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
– Other benefits: Improvement in bone mass and lipid profile
• 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

20. Tamoxifen – contd.
• Uses:
– Breast carcinoma of pre and post menopause
– Adjuvant therapy in early cases
– Palliative therapy
• Side effects.
– The drug has a low incidence of adverse reactions
– Hot flashes, 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
• Other SERM – Raloxifene, ormeloxifene etc.
– Raloxifene is estrogen antagonist of breast and endometrium while partial
agonist of bone and CVS
CH2CH3
O(CH3)2N-CH2-CH2
TAMOXIFEN (NOLVADEX)

21. Raloxifen and Ormeloxifene
• Raloxifene:
– Partial agonist in Bone and CVS – antagonist in Breast and
Endometrium
– High affinity for both receptors – distinct DNA target – RRE
– Decreases LDL cholesterol – no increase in HDL cholesterol
– No stimulation of endometrial proliferation – risk of cancer
reduced
– Extensive first pass metabolism
– Uses: 1st line of drug in prevention of Osteoporosis in
menopause – Ca++ and Vit. D enhances benefit
• Ormeloxifene: Estrogen antagonist in breast and uterus
– useful in Dysfunctional uterine bleeding

22. Aromatase Inhibitors
• 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
– Rapid oral absorption – 100% bioavailability, large Vd, t1/2
– 40 Hrs
– 2.5 mg BD
• Uses: Early breast carcinoma and Advanced breast
carcinoma

23. Must Know
• Hormone Replacement Therapy
• Clomiphene citrate
• Tamoxiphene

24. Take Home !
 Estrogens have been mainstay of HRT since
long – However, need for HRT to a
menopausal women should be assessed and
individualized……