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Estrogen Receptor and its Modulators
Dr C. Handique
PGT, Dept of Pharmacology
Estrogens are the primary female sex hormones in the body
with numerous physiological functions.
The word estrogen is derived from Greek word “oistrus”
literally meaning “verve or inspiration” and the suffix “-
gen” meaning “producer of”.
The therapeutic uses of estrogen largely represents the
extension of their physiological activities.
Hormonal nature of ovarian control of female
reproductive system was established by Knauer .
The active principle estradiol was obtained in pure
Jensen and his colleagues demonstrated presence of
intracellular receptor ERα in target tissues.
The second recepor for estrogen was identified
and termed as ERβ .
Allen & Doisy devised an bioassay for alcoholic
ovarian extract base on vaginal smear of rat.
1926 Loewe & Lange found that a sex hormone varied
in urine of women throughout the menstrual cycle.
ESR1 on chromosome 6
codes for ERα.
Uterus, vagina & ovaries
Vascular smooth muscle
ESR2 on chromosome 14
codes for ERβ
Estrogen receptor are super family of nuclear receptor
MECHANISM OF ACTION
The estrogen receptor is analogous to other steroid receptors.
Agonist binding to the ligand binding domain brings about
receptor dimerization and its interaction with “ Estrogen
Gene transcription is promoted through certain coactivator
On binding an estrogen antagonist the receptor assumes a
different conformation and interacts with other corepressor
proteins inhibiting gene transcription. 7
Upon binding of estrogen (E) to an inactive estrogen
receptor, the receptor is activated.
Two receptor-ligand monomers dimerize and bind to the
estrogen response element (ERE).
Once bound to the ERE, the ER uses AF-1 and AF-2 to
stimulate transcription from the promoter.
Coactivators such as RIP140, CBP and SRC-1 bind to and
link the hormone receptor with the general transcription
factors (GTFs) and RNA polymerase of the transcription
machinery to alter gene transcription.
BIOSYNTHESIS OF ESTROGENS
•Steroidal estrogens arise from androstenedione or testosterone
by the aromatization of the A ring.
•The enzyme catalyzing the reaction is Aromatase (CYP 19)
ACTION OF ESTROGEN
Neuroendocrine Control of Menstrual
Estrogens are responsible for development of pubertal changes
and secondary sexual characteristics.
They cause the growth and development of uterus, vagina and
fallopian tubes as well as also contribute to breast enlargement.
They contribute to the molding of the body contours and are
responsible for the pubertal growth spurt of the long bones and
Estrogen plays important developmental role in males
In boys estrogen deficiency diminishes pubertal growth
Its deficiency delays skeletal maturation and epiphyseal
closure so that linear growth continues into adulthood.
NEURO ENDOCRINE CONTROL OF MENSTRUAL CYCLE
Hypothalamus fires at intervals that coincides with the
GnRH interacts with its receptor on pituitary gonadotropes
to cause release of LH and FSH.
FSH and LH regulates the growth and maturation of graafian
follicle in the ovary.
The ovarian production of estrogen and progesterone which
exerts negative feedback regulation on hypothalamus and
Estrogens are anabolic in nature
It promotes fusion of epiphysis both in boys and girls.
It is important in maintaining the bone mass
It promotes positive calcium balance
It increases the HDL:LDL ratio.
The blood coagulability is also increased. 19
The drugs which modulate the functions of estrogen
receptor are as follows
The other group of drugs include
Estrogen receptor signaling pathway
Estradiol SERMS Antiestrogen
Ligand- ER three dimensional conformation
Co regulatory factors ( Response element )
ERE Other REs Other REs
There are 3 major naturally occuring estrogen in the body
They are estradiol, estrone and estriol
Estradiol is synthesized in the graafian follicle, corpus
luteum and placenta
All the three forms are active and circulate in blood.
•Predominat estrogen during the
•Weakest of the three estrogens
•Pedominant estrogen during pregnancy
ESTROGEN : THERAPEUTIC USE
Post menopausal hormonal therapy
Primary ovarian failure
Dysfunctional uterine bleeding
Delayed puberty in girls
HORMONE REPLACEMENT THERAPY
The 5 common symptoms associated with menopause are
osteoporosis, vasomotor disorders, cardiovascular problems,
urogenital atrophy and psychological disturbances.
HRT restore calcium
balance and prevents
further bone loss
Accelertated bone loss
on cessation of HRT
Not the best choice,
bisphosphonates are DOC
Respond promptly to
Most common- hot
HRT to be stopped once
ratio with HRT, but
Increased risk of
Increased risk of MI
prophylaxis of CAD
HRT generally includes the administration of estrogen and
It is given for the shortest possible duration and smallest
It increases the risk of breast cancer, gallstones, migraine and
Conjugated estrogens at a dose of 0.625mg/day is used either
Cyclically(3 weeks treatment & 1 wk gap) OR,
A progestin is added for the last 10-12 days each month.
Primary ovarian failure
Treatment started with small doses of estrogen in cyclical
Dysfunctional uterine bleeding
Here estrogens have an adjuvant value.
Estrogen benefits by supressing ovarian production of
androgen by inhibiting Gn release from pituitary
Estrogen benefit by inhibiting ovulation & decreasing PG
synthesis in endometrium.
Estrogen is used in combination of progesterone in combined
Used as combined pill, phased pill and emergency (post
Ethinylestradiol (20- 50ug)
Topical estrogen therapy preferred
Estrogens change vaginal cytology to premenopausal form
Estrogens are palliative
They help by suppressing androgen production
ANTI ESTROGENS – CLOMIPHENE CITRATE
It acts as a pure antagonist in all the human tissues.
It binds to both the estrogen receptors .
It has got two isomers- Zuclomiphene (cis)
Well absorbed orally
Deposited in adipose tissue
Long half life of 6 days
Largely metabolized and excreted in bile
Infertility due to failure of ovulation
To aid in invitro fertilization
Allergic dermatitis 35
ANTIESTROGEN - FULVESTRANT
It is a 7α alkylamide derivative of estradiol and interacts with
both the estrogen receptor.
It is also known as “Selective Estrogen Receptor Down-
It inhibits the estrogen receptor (ER) dimerization so that ER
interaction with the DNA is prevented and thus enhances the
The ER is down regulated and there is complete supression
of ER responsive gene action.
Absorption is slow
Plasma concentration reaches maximal in 7 days an
maintained for a month.
Numerous metabolites are formed invivo
Mainly eliminated (90%) in faeces.
Tamoxifen Resistant Breast Cancer
Administered as 250mg monthly i.m injections in the
SELECTIVE ESTROGEN RECEPTOR MODULATORS
SERMs are the compounds which exert estrogenic as well as
anti-estrogenic actions in a tissue selective manner.
The pharmacological goal of these drugs is to
produce beneficial estrogenic effect in certain tissues ( like
bone, brain and liver)
while producing antagonistic activity in tissues such as
breast and endometrium where estrogenic action ( e.g
carcinogenesis) may be harmful.
Tamoxifen is a non steroidal compound.
It acts as an
Antagonist – breast carcinoma cells and blood vessels
Agonist – uterus, bone, liver, pituitary
Decrease in total and LDL cholesterol
Improvement in bone mass
Stimulation of endometrial proliferation
Increase risk of deep vein thrombosis
Inhibition of human breast cancer cells
Plasma half life - Biphasic (10 hours and 7 days)
Some of its metabolites are more potent anti estrogens (4-
Excreted - bile
Primary breast carcinoma ( both early and advanced)
Metastatic breast carcinoma
Male breast carcinoma
Some other uses are
McCune Albright’s Syndrome
Vaginal bleeding and discharge
Increased risk of venous thromboembolism
Increased risk of uterine cancer
DOLOXIFEN and TOREMIFENE are other SERMs in
clinical use with the similar pharmacological indications ,
property and toxicity.
It is a non steroidal compound binding to both the estrogen
receptor with high affinity.
It acts as an
Estrogen agonist – Bone & Cardiovascular system
Estrogen antagonist – Endometrium & Breast
In Post Menopausal women
Prevents bone loss
Reduces LDL cholesterol but there is no increase in HDL
Raloxifene significantly reduces the risk of ER+ve breast
It doesn’t stimulate uterine proliferation and there is no
increase in risk of endometrial carcinoma.
However, it doesn’t alleviate the post menopausal vasomotor
symptoms: rather hot flushes may be induced in some women.
Well absorbed orally
Extensive first pass metabolism
Half life- 28 hours
Excreted - faeces 48
Hot flushes, leg cramps, vaginal bleeding and
increased risk of deep vein thrombosis.
It is approved as a second line agent for the prevention
and treatment of osteoporosis.
Dose is 60mg/day
These are the group of drugs which inhibit the estrogen
Aromatization of the “A” ring of the testosterone and
androstenedione is the final step in the production of
This group of drugs come into play as locally produced
estrogens appear to play an important role in the
development of breast cancer.
Both steroidal and non steroidal agents are available.
Steroidal or the type 1, agents are substrate analogs that act
as suicide inhibitor to inhibit aromatase enzyme irreversibly.
Example- formestane, exmestane
Non steroidal or the type II agents interact reversibly with
the heme group of CYPs
Example – anastrozole, letrozole, vorozole
Large Volume of distibution
Half life – 40 hours
More potent than letrozole
Accumulates in the body
Peak effect after 7-10 days
One of the first generation aromatase inhibitor is
However its use is limited by its lack of selectivity and
side effects like sedation.
Type I inhibitor of aromatase
They inhibit the production of estrogen in all tissues.
They are contraindicated in pre-menopausal women.
They are more effective in delaying recurrence of early stage
breast cancer and continue to exert prophylactic effect beyond 5
They are effective in tamoxifen failure cases of advanced breast
No endometrial hyperplasia
No predisposition to uterine cancer
No effect on lipid profile
No increase in thromboembolic risk
Accelerates bone loss
Predisposes to osteoporosis
Predisposes to fracture
Prdisposes the arthritic symptoms
Hot flushes, nausea, dairrhea
Estrogens are primary female sex hormones
The discovery of the estrogen receptors marked an
important step towards the development of various drugs.
These drugs exert different effects depending upon the three
dimensional conformation the receptor acquires after ligand
Further knowledge of such interactions can lead to discovery
of other aspects that can be implemented towards human