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1
Estrogen Receptor and its Modulators
Presenter
Dr C. Handique
PGT, Dept of Pharmacology
INTRODUCTION
 Estrogens are the primary female sex hormones in the body
with numerous physiological functions.
 The word...
3
4
1900
Hormonal nature of ovarian control of female
reproductive system was established by Knauer .
1929
The active princi...
STRUCTURE OF ESTROGEN RECEPTOR
5
6
 ESR1 on chromosome 6
codes for ERα.
 Present in
Uterus, vagina & ovaries
Mammary glad
Hypothalamus
Endothelial cell
V...
MECHANISM OF ACTION
 The estrogen receptor is analogous to other steroid receptors.
 Agonist binding to the ligand bindi...
8
MECHANISM OF ACTION
9
 Upon binding of estrogen (E) to an inactive estrogen
receptor, the receptor is activated.
 Two receptor-ligand monomers...
BIOSYNTHESIS OF ESTROGENS
11
•Steroidal estrogens arise from androstenedione or testosterone
by the aromatization of the A...
12
ACTION OF ESTROGEN
Developmental Action
13
Neuroendocrine Control of Menstrual
Cycle
Metabolic Actions
DEVELOPMENTAL ACTION
In Girls,
 Estrogens are responsible for development of pubertal changes
and secondary sexual charac...
In Males,
 Estrogen plays important developmental role in males
as well.
 In boys estrogen deficiency diminishes puberta...
NEURO ENDOCRINE CONTROL OF MENSTRUAL CYCLE
 Hypothalamus fires at intervals that coincides with the
GnRH release.
 GnRH ...
17
18
METABOLIC EFFECTS
 Estrogens are anabolic in nature
 It promotes fusion of epiphysis both in boys and girls.
 It is imp...
 The drugs which modulate the functions of estrogen
receptor are as follows
The other group of drugs include
20
Estrogen ...
21
Estrogen receptor signaling pathway
ERα ERβ
Ligands
Estradiol SERMS Antiestrogen
Ligand- ER three dimensional conformat...
NATURAL ESTROGENS
 There are 3 major naturally occuring estrogen in the body
 They are estradiol, estrone and estriol
 ...
23
Estradiol
•Most potent
•Predominat estrogen during the
reproductive years
Estriol
•Weakest of the three estrogens
•Pedo...
ESTROGEN PREPRATIONS
 Natural Steroidal Estrogen - Estradiol, Estrone,
Estriol
 Synthetic Steroidal Estrogen – Ethinyl e...
ESTROGEN : THERAPEUTIC USE
 Post menopausal hormonal therapy
 As contraceptives
 Primary ovarian failure
 Dysfunctiona...
HORMONE REPLACEMENT THERAPY
 The 5 common symptoms associated with menopause are
osteoporosis, vasomotor disorders, cardi...
27
28
CVS Events
Improved HDL:LDL
ratio with HRT, but
Increased risk of
venous
Thromoembolism
Increased risk of MI
No sec...
 HRT generally includes the administration of estrogen and
progestin combinations.
 It is given for the shortest possibl...
Primary ovarian failure
 Treatment started with small doses of estrogen in cyclical
pattern.
Dysfunctional uterine bleedi...
As contraceptive
 Estrogen is used in combination of progesterone in combined
pill
 Used as combined pill, phased pill a...
ANTI ESTROGENS – CLOMIPHENE CITRATE
 It acts as a pure antagonist in all the human tissues.
 It binds to both the estrog...
33
34
 Indication
 Infertility due to failure of ovulation
 To aid in invitro fertilization
 Oligozoospermia
Adverse Effects...
ANTIESTROGEN - FULVESTRANT
 It is a 7α alkylamide derivative of estradiol and interacts with
both the estrogen receptor.
...
37
P/K
 Absorption is slow
 Plasma concentration reaches maximal in 7 days an
maintained for a month.
 Numerous metabolite...
SELECTIVE ESTROGEN RECEPTOR MODULATORS
 SERMs are the compounds which exert estrogenic as well as
anti-estrogenic actions...
40
TAMOXIFEN CITRATE
 Tamoxifen is a non steroidal compound.
 It acts as an
 Antagonist – breast carcinoma cells and blood...
 Antiestrogenic action
 Inhibition of human breast cancer cells
 Hot flushes
 P/K
 Effective orally.
 Plasma half li...
43
44
 Indication
 Primary breast carcinoma ( both early and advanced)
 Metastatic breast carcinoma
 Male breast carcinoma
...
Side Effects
Hot flushes
Vaginal bleeding and discharge
Menstrual irregularities
Increased risk of venous thromboembolism
...
RALOXIFENE
 It is a non steroidal compound binding to both the estrogen
receptor with high affinity.
 It acts as an
 Es...
 Raloxifene significantly reduces the risk of ER+ve breast
cancer.
 It doesn’t stimulate uterine proliferation and there...
Side effects
 Hot flushes, leg cramps, vaginal bleeding and
increased risk of deep vein thrombosis.
Use
 It is approved ...
AROMATASE INHIBITORS
 These are the group of drugs which inhibit the estrogen
synthesis.
 Aromatization of the “A” ring ...
 Steroidal or the type 1, agents are substrate analogs that act
as suicide inhibitor to inhibit aromatase enzyme irrevers...
52
53
Letrozole
 Orally active
 100% bioavaialbility
 Slow metabolism
 Large Volume of distibution
 Half life – 40 hours
An...
 One of the first generation aromatase inhibitor is
aminoglutethimide.
However its use is limited by its lack of selectiv...
 They inhibit the production of estrogen in all tissues.
 They are contraindicated in pre-menopausal women.
 They are m...
Advantages
 No endometrial hyperplasia
 No predisposition to uterine cancer
 No effect on lipid profile
 No increase i...
Conclusion
 Estrogens are primary female sex hormones
 The discovery of the estrogen receptors marked an
important step ...
59
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Estrogen receptor and its modulators

estrogen, its receptors, synthesis and actions

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Estrogen receptor and its modulators

  1. 1. 1 Estrogen Receptor and its Modulators Presenter Dr C. Handique PGT, Dept of Pharmacology
  2. 2. INTRODUCTION  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. 2
  3. 3. 3
  4. 4. 4 1900 Hormonal nature of ovarian control of female reproductive system was established by Knauer . 1929 The active principle estradiol was obtained in pure form. 1960 Jensen and his colleagues demonstrated presence of intracellular receptor ERα in target tissues. 1996 The second recepor for estrogen was identified and termed as ERβ . 1923 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.
  5. 5. STRUCTURE OF ESTROGEN RECEPTOR 5
  6. 6. 6  ESR1 on chromosome 6 codes for ERα.  Present in Uterus, vagina & ovaries Mammary glad Hypothalamus Endothelial cell Vascular smooth muscle  ESR2 on chromosome 14 codes for ERβ  Present in Prostrate Ovaries Lung Brain Bone Vasculature ERα ERβ Estrogen receptor are super family of nuclear receptor
  7. 7. 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 Response Element”.  Gene transcription is promoted through certain coactivator proteins.  On binding an estrogen antagonist the receptor assumes a different conformation and interacts with other corepressor proteins inhibiting gene transcription. 7
  8. 8. 8
  9. 9. MECHANISM OF ACTION 9
  10. 10.  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. 10
  11. 11. BIOSYNTHESIS OF ESTROGENS 11 •Steroidal estrogens arise from androstenedione or testosterone by the aromatization of the A ring. •The enzyme catalyzing the reaction is Aromatase (CYP 19) enzyme.
  12. 12. 12
  13. 13. ACTION OF ESTROGEN Developmental Action 13 Neuroendocrine Control of Menstrual Cycle Metabolic Actions
  14. 14. DEVELOPMENTAL ACTION In Girls,  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 epiphyseal closure 14
  15. 15. In Males,  Estrogen plays important developmental role in males as well.  In boys estrogen deficiency diminishes pubertal growth spurt.  Its deficiency delays skeletal maturation and epiphyseal closure so that linear growth continues into adulthood. 15
  16. 16. NEURO ENDOCRINE CONTROL OF MENSTRUAL CYCLE  Hypothalamus fires at intervals that coincides with the GnRH release.  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 pituitary. 16
  17. 17. 17
  18. 18. 18
  19. 19. METABOLIC EFFECTS  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
  20. 20.  The drugs which modulate the functions of estrogen receptor are as follows The other group of drugs include 20 Estrogen preparations Anti estrogens SERMs Aromatase inhbitors
  21. 21. 21 Estrogen receptor signaling pathway ERα ERβ Ligands Estradiol SERMS Antiestrogen Ligand- ER three dimensional conformation Co regulatory factors ( Response element ) ERE Other REs Other REs Transcription AGONISTIC AGONISTIC/ ANTAGONISTIC PURE ANTAGONISTIC
  22. 22. NATURAL ESTROGENS  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. 22
  23. 23. 23 Estradiol •Most potent •Predominat estrogen during the reproductive years Estriol •Weakest of the three estrogens •Pedominant estrogen during pregnancy Estrone •Predominant estrogen during menopause
  24. 24. ESTROGEN PREPRATIONS  Natural Steroidal Estrogen - Estradiol, Estrone, Estriol  Synthetic Steroidal Estrogen – Ethinyl estradiol Mestranol, Tibolone  Synthetic Nonsteroidal Estrogen – Hexesterol, Diethylstilbesterol, Dienesterol  Conjugated Estrogens – mixture of sodium estrone sulfate and sodium equiline sulfate 24
  25. 25. ESTROGEN : THERAPEUTIC USE  Post menopausal hormonal therapy  As contraceptives  Primary ovarian failure  Dysfunctional uterine bleeding  Acne  Carcinoma prostrate  Dysmenorrhea  Delayed puberty in girls  Senile vaginitis 25
  26. 26. HORMONE REPLACEMENT THERAPY  The 5 common symptoms associated with menopause are osteoporosis, vasomotor disorders, cardiovascular problems, urogenital atrophy and psychological disturbances. 26 Osteoporosis HRT restore calcium balance and prevents further bone loss Accelertated bone loss on cessation of HRT Not the best choice, bisphosphonates are DOC Vasomotor symptoms Respond promptly to HRT Most common- hot flushes HRT to be stopped once vasomotor symptoms abate
  27. 27. 27
  28. 28. 28 CVS Events Improved HDL:LDL ratio with HRT, but Increased risk of venous Thromoembolism Increased risk of MI No secondary prophylaxis of CAD Urogenital atrophy Arrest genital atrophic changes Vulval urinary problem resolves Topical application possible
  29. 29.  HRT generally includes the administration of estrogen and progestin combinations.  It is given for the shortest possible duration and smallest effective dose.  It increases the risk of breast cancer, gallstones, migraine and venous thromboembolism. REGIMEN  Conjugated estrogens at a dose of 0.625mg/day is used either  Cyclically(3 weeks treatment & 1 wk gap) OR,  Continuously  A progestin is added for the last 10-12 days each month. 29
  30. 30. Primary ovarian failure  Treatment started with small doses of estrogen in cyclical pattern. Dysfunctional uterine bleeding  Here estrogens have an adjuvant value. Acne  Estrogen benefits by supressing ovarian production of androgen by inhibiting Gn release from pituitary Dysmenorrhea  Estrogen benefit by inhibiting ovulation & decreasing PG synthesis in endometrium. 30
  31. 31. As contraceptive  Estrogen is used in combination of progesterone in combined pill  Used as combined pill, phased pill and emergency (post coital) pill.  Ethinylestradiol (20- 50ug) Senile vaginitis  Topical estrogen therapy preferred  Estrogens change vaginal cytology to premenopausal form Carcinoma prostrate  Estrogens are palliative  They help by suppressing androgen production 31
  32. 32. 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) Enclompiphene (trans)  P/K  Well absorbed orally  Deposited in adipose tissue  Long half life of 6 days  Largely metabolized and excreted in bile 32
  33. 33. 33
  34. 34. 34
  35. 35.  Indication  Infertility due to failure of ovulation  To aid in invitro fertilization  Oligozoospermia Adverse Effects  Polycystic ovaries  Multiple pregnancy  Hot flushes  Gastric upset  Vertigo  Allergic dermatitis 35
  36. 36. 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- regulator”  MOA-  It inhibits the estrogen receptor (ER) dimerization so that ER interaction with the DNA is prevented and thus enhances the receptor degradation  The ER is down regulated and there is complete supression of ER responsive gene action. 36
  37. 37. 37
  38. 38. P/K  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. Indication  Tamoxifen Resistant Breast Cancer  Administered as 250mg monthly i.m injections in the buttock 38
  39. 39. 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. 39
  40. 40. 40
  41. 41. TAMOXIFEN CITRATE  Tamoxifen is a non steroidal compound.  It acts as an  Antagonist – breast carcinoma cells and blood vessels  Agonist – uterus, bone, liver, pituitary Estrogenic actions  Decrease in total and LDL cholesterol  Improvement in bone mass  Stimulation of endometrial proliferation  Increase risk of deep vein thrombosis 41
  42. 42.  Antiestrogenic action  Inhibition of human breast cancer cells  Hot flushes  P/K  Effective orally.  Plasma half life - Biphasic (10 hours and 7 days)  Some of its metabolites are more potent anti estrogens (4- hydroxy tamoxifen)  Excreted - bile 42
  43. 43. 43
  44. 44. 44
  45. 45.  Indication  Primary breast carcinoma ( both early and advanced)  Metastatic breast carcinoma  Male breast carcinoma  Male infertility  Some other uses are  McCune Albright’s Syndrome  Gynnaecomastia 45
  46. 46. Side Effects Hot flushes Vaginal bleeding and discharge Menstrual irregularities 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. 46
  47. 47. RALOXIFENE  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 and TG 47
  48. 48.  Raloxifene significantly reduces the risk of ER+ve breast cancer.  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.  P/K  Well absorbed orally  Extensive first pass metabolism  Half life- 28 hours  Excreted - faeces 48
  49. 49. Side effects  Hot flushes, leg cramps, vaginal bleeding and increased risk of deep vein thrombosis. Use  It is approved as a second line agent for the prevention and treatment of osteoporosis.  Dose is 60mg/day 49
  50. 50. AROMATASE INHIBITORS  These are the group of drugs which inhibit the estrogen synthesis.  Aromatization of the “A” ring of the testosterone and androstenedione is the final step in the production of estrogens.  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. 50
  51. 51.  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 51
  52. 52. 52
  53. 53. 53
  54. 54. Letrozole  Orally active  100% bioavaialbility  Slow metabolism  Large Volume of distibution  Half life – 40 hours Anastrozole  More potent than letrozole  Accumulates in the body  Peak effect after 7-10 days 54
  55. 55.  One of the first generation aromatase inhibitor is aminoglutethimide. However its use is limited by its lack of selectivity and side effects like sedation. Exmestane  Steroidal compound  Type I inhibitor of aromatase  Administered orally  Well tolerated 55
  56. 56.  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 years.  They are effective in tamoxifen failure cases of advanced breast carcinoma. 56
  57. 57. Advantages  No endometrial hyperplasia  No predisposition to uterine cancer  No effect on lipid profile  No increase in thromboembolic risk Adverse effects  Accelerates bone loss  Predisposes to osteoporosis  Predisposes to fracture  Prdisposes the arthritic symptoms  Hot flushes, nausea, dairrhea 57
  58. 58. Conclusion  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 binding.  Further knowledge of such interactions can lead to discovery of other aspects that can be implemented towards human health. 58
  59. 59. 59

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