Estrogen and estrogen receptors

1. SEX HORMONES
ESTROGEN

2. INTRODUCTION
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Estrogens are endogenous hormones that produce numerous physiological actions
in the body. It is a category of sex hormone responsible for the development and
regulation of the female reproductive system and development of secondary sexual
characteristics. It is made from cholesterol within the body.
The ovaries, adrenal glands, and fat tissues produce estrogen. Both female and
male bodies have this hormone, but females create more of it.
It stimulates the growth and thickening of the endometrium (the lining of the
uterus).
Estrogens can also induce estrous phase in spayed (ovariectomized) animals.

3. Types of Estrogens :
a.) Natural Estrogens : Estradiol, Estrone, Estriol
 They are secreted by the ovary and are synthesized in the
graffian follicle, corpus luteum and placenta from cholesterol.
b.) Synthetic Estrogens :
Steroidal Ethinylestradiol, Mestranol, Tibolone
Nonsteroidal Diethylstilbestrol, Hexestrol, Dienestrol
 Natural estrogens are inactive orally and have a short duration
of action due to rapid metabolism in liver. To overcome this,
synthetic compounds have been produced.
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4. Structures :
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Estradiol Estrone Estriol
Ethinylestradiol Mestranol Tibolone
Diethylstilbestrol Hexestrol Dienestrol

5. Biosynthesis of Estrogens :
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• Estrogens are synthesized by the ovary and placenta and in
small amounts by the testis and adrenal cortex.
• The starting substance for synthesis of estrogen and other
steroids is cholesterol.
• The immediate precursors to the estrogens are androgenic
substances – androstenedione or testosterone.

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NOTE : Estradiol is rapidly oxidized in liver to estrone, which is hydroxylated to form estriol. All
three are active and circulate in blood, but estradiol is the most potent estrogen.

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How does estrogen (estradiol) change during
the menstrual cycle?

8. Actions of Estrogen :
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1. Sex organs : The estrogens bring about pubertal changes in the female including
growth of uterus, fallopian tubes and vagina. Vaginal epithelium gets thickened,
stratified and cornified. They are responsible for the proliferation of
endometrium in the preovulatory phase.
2. Secondary sexual characters : Estrogens produced at puberty cause growth of
breasts — proliferation of ducts and stroma and accumulation of fat. The pubic
and axillary hair appear, feminine body contours and behavior are influenced.
3. Metabolic effects : They are anabolic, similar to but weaker than testosterone.

9. 9 • Estrogen is important in maintaining bone mass primarily by retarding bone resorption.
The major action of estrogens is to reduce maturation and activity of osteoclasts. The
direct action on osteoclasts is to accelerate their apoptosis.
• It promotes positive calcium balance, partly by inducing renal hydroxylase enzyme
which generates the active form of Vitamin D3.
• Estrogens can cause mild salt and water retention—edema occurs in predisposed patients,
but it can be treated with diuretics.
• Estrogens decrease plasma LDL cholesterol while HDL and triglyceride levels are raised.
The raised HDL : LDL ratio is probably responsible for rarity of atherosclerosis in
premenopausal women.
• Estrogens induce nitric oxide synthase and PGI2 production in vascular endothelium. The
increased availability of NO and PGI2 could promote vasodilatation.

10. Estrogen Receptors :
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Estrogens exert their effect by interaction with receptors that are
members of the superfamily of nuclear receptors. Two distinct ERs
designated as ERα and Erβ have been identified, cloned and
structurally characterized.
The two human ERs are 44% identical in overall amino acid sequence
and share the domain structure common to members of this family.
 ERα is expressed most abundantly in the female reproductive tract
— especially the uterus, vagina, and ovaries — as well as in the
mammary gland, the hypothalamus, endothelial cells and vascular
smooth muscle.
 ERβ is expressed most highly in the prostate and ovaries, with
lower expression in lung, brain, bone and vasculature.

11. Mechanism of Action of Estrogen on ER :
11 • Both ERs are ligand-activated transcription factors that increase or decrease the
transcription of target genes.
• After entering the cell by passive diffusion through the plasma membrane, the
hormone binds to an ER in the nucleus.
• In the nucleus, the ER is present as an inactive monomer bound to HSP90, and on
binding estrogen, a change in ER conformation dissociates the HSPs and causes
receptor dimerization, which increases the affinity and the rate of receptor binding to
DNA.
• The ER dimer binds to EREs, typically located in the promoter region of target genes.
• The ER/DNA complex recruits a cascade of coactivator and other proteins to the
promoter region of target genes and allows the proteins that make up the general
transcription apparatus to assemble and initiate transcription.

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Dimerization
Coactivators
HAT
Promoters
Corepressor
Stabilized
nucleosome

13. Uses of Estrogens :
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Currently, the two most common uses of estrogens are as contraceptives and for hormone
replacement therapy in postmenopausal women.
Hormone replacement therapy (HRT) :
Due to cessation of ovarian function at menopause women suffer a number of physical,
psychological and emotional consequences. The dose of estrogen used in HRT is
substantially lower than that for contraception. Typically conjugated estrogens are used at
0.625 mg/day dose.
The benefits and risks of HRT are considered below:
a. Osteoporosis and fractures : HRT restores Ca2+ balance; further bone loss is prevented
and the excess fracture risk is nullified. Calcium + vitamin D supplements and exercise aid
the beneficial effect of HRT. However, accelerated bone loss starts again on cessation of
HRT.

14. 14 b. Cardiovascular events : Since hypertension and cardiovascular diseases are rare in
premenopausal women and estrogens improve HDL : LDL ratio, it was believed that
estrogen therapy in postmenopausal women will have a protective cardiovascular
influence. But in the past decade, many large scale placebo controlled randomized
interventional trials and cohort studies have yielded opposite results.
c. Cognitive function and dementia : The ‘women’s health initiative memory study’
(WHIMS) conducted among older women (65–79 years) has failed to detect any
protection against cognitive decline by either estrogen alone or combined HRT. There
was in fact a slight global deterioration. Surprisingly, the incidence of dementia
(Alzheimer’s) was doubled.
d. Cancer : That estrogens enhance the growth of breast cancer has been well
recognized. However, it was contended that small replacement doses of estrogens will
not induce new cancer.

15. Drugs Acting on Estrogen Receptors
Selective
Estrogen
Receptor Down
Regulators
(SERDs)
Antiestrogens
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Selective
Estrogen
Receptor
Modulators
(SERMs)

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These are drugs which exert estrogenic as well as antiestrogenic actions. These are compounds
with tissue-selective actions. The pharmacological goal of these drugs is to produce beneficial
estrogenic actions in certain tissues (e.g., bone, brain, and liver) during post-MHT but
antagonist activity in tissues such as breast and endometrium, where estrogenic actions (e.g.,
carcinogenesis) might be deleterious.
Currently approved drugs in the U.S. in this class are tamoxifen citrate, raloxifene
hydrochloride, and toremifene.
1. Tamoxifene
It exhibits antiestrogenic, estrogenic or mixed activity depending on the species and target gene
measured. Tamoxifen inhibits the proliferation of cultured human breast cancer cells and
reduces tumor size and number in women and yet it stimulates proliferation of endometrial
cells and causes endometrial thickening. The drug has an antiresorptive effect on bone and in
humans it decreases total cholesterol and LDL but does not increase HDL and triglycerides.

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2. Raloxifene
Raloxifene is an estrogen agonist in bone, where it exerts an antiresorptive effect. The drug also
acts as an estrogen agonist in reducing total cholesterol and LDL, but it does not increase HDL.
Studies have indicated that it has an antiproliferative effect on ER-positive breast tumors and
significantly reduces the risk of ER-positive but not ER-negative breast cancer.
It does not stimulate endometrial proliferation in postmenopausal women.
3. Toremifene
It is a newer congener of tamoxifen with similar actions, but is a weaker ER agonist. Uses and
adverse effects are also similar.

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1. Fulvestrant
It is antiestrogenic. In clinical trials, it is efficacious in treating tamoxifen-resistant
breast cancers. Fulvestrant binds to ERα and ERβ with high affinity comparable to
estradiol but represses transactivation. It also increases dramatically the intracellular
proteolytic degradation of ERα. This effect on ERα protein levels may explain
fulvestrant’s efficacy in tamoxifen-resistant breast cancer.

19. Antiestrogens
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1. Clomiphene
It binds to both ERα and ERβ and acts as a pure estrogen antagonist in all human tissues. It
induces gonadotropin secretion in women by blocking estrogenic feedback inhibition of
pituitary.
The amount of LH/FSH released at each secretory pulse is increased. In response, the
ovaries enlarge and ovulation occurs if the ovaries are responsive to gonadotropin.
Endometrium and cervical mucus may be modified.
The chief use of clomiphene is for infertility due to failure of ovulation:
50 mg once daily for 5 days starting from 5th day of cycle.
Treatment is given monthly. Conception occurs in many women who previously were
amenorrhoeic or had anovular cycles.

20. Adverse Effects :
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Tamoxifene:
• Hot flushes
• Nausea
• Menstrual irregularities and vaginal bleeding
• Due to its estrogenic activity in the endometrium, hyperplasia and malignancies have
been reported in women maintained on tamoxifene
Raloxifene:
• Hot flashes
• Leg cramps
• Increased risk of DVT, PE, retinal-vein thrombosis
• Women who have a past or active history of venous thromboembolic events should not
take this drug
• Coadministration with cholestyramine can reduce the absorption of raloxifene by 60%
(should not be used together)

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Clomiphene
• Headache
• Nausea
• Vasomotor flushes
• Visual disturbances
• Ovarian enlargement

22. Aromatase Inhibitors
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Aromatization of testosterone and androstenedione is the final and key step in the production
of estrogens (estradiol/ estrone) in the body.
In addition to the circulating hormone, locally produced estrogens appear to play an
important role in the development of breast cancer. Though some aromatase inhibitors (AIs)
were produced in the past, three recent ‘third generation’ AIs – Letrozole, Anastrozole and
Exemestane have demonstrated clinical superiority and are widely used now in the
treatment of breast cancer (approved in US).
Aminoglutethimide inhibits aromatase activity, but its use is limited by its lack of selectivity
and its side effects (sedation). It was discontinued in the U.S. in 2008.

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Letrozole Anastrazole
i. Inhibits aromatization,
resulting in total estrogen
deprivation
ii. Adjuvant therapy after
mastectomy in early breast
cancer
i. More potent than Letrozole
ii. Adjuvant therapy for early
ER +ve breast cancer.

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