Upload
clarke
View
90
Download
0
Tags:
Embed Size (px)
DESCRIPTION
Estrogen . The Feminine Hormone . That Nourishes & Nurtures womanhood. But Estrogen is an ambivalent steroid hormone, erratic, inconsistent & mercurial in behavior. Tissue. Effect of Estrogen Stimulation. Clinical Effect of Stimulation. Clinical Effect of Absence of Stimulation. Bone. - PowerPoint PPT Presentation
Citation preview
1
That Nourishes & Nurtures
womanhood
The Feminine Hormone
Estrogen
But Estrogen is an ambivalent steroid hormone, erratic,
inconsistent & mercurial in behavior.
2
Effects of Estrogen at Various Sites in the Body
Tissue Effect of Estrogen Stimulation
Clinical Effect of Stimulation
Clinical Effect of Absence of Stimulation
Bone Increased deposits of calcium into bone
Increased bone density Osteoporosis
Brain Blocks the release of ovarian estrogen
None Hot flashes, sleep disorders, mood changes, problems with memory? Alzheimer’s disease??
Breast Stimulates growth of breast tissue
Bigger breasts,? Increased risk of breast cancer, increased sensitivity of the breast,
Smaller breasts
Blood Clotting Increased risk of blood clots No change in clotting
Blood Fats Increased HDL, decreased LDL, decreased Cholesterol,
Decreased HDL, increased LDL, increased Cholesterol
Skin Increased fat deposits in skin Softer skin Thinner skin, liver spots, dry skin
Uterus Increased stimulation of uterine lining and muscle
Heavier cycles, increased risk of uterine cancer
No periods
Vagina Increased thickening of skin, better blood supply to tissue
Vaginal discharge, feelings of pelvic congestion
Dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness
3
Molecular Action of Estrogen
Adopted from George et al
hsp90 – heat shock protein90
4
Molecular Action of Estrogen
Adopted from Stanley J Birge et al
AP I – activator proteinCRP – co regulator proteinER – estrogen receptorERE – estrogen response elementPoly II – polymerase IITATA- adenine-thymine-rich sequence important for gene transcription
5
Estrogen Receptor
Two types have been so far identified : - and
Molecular Action of Estrogen
Illustration by Anne Erickson
6
Estrogen Receptor Distribution
& -CNS, blood vessels, bone, heart, breast, ovary, uterus, testes, prostate
- Liver - Lungs, kidney, bladder,
intestines
Adopted from George GJM Kuiper et al
* Based on the level of ER mRNA levels
* Awaits confirmation till subtype specific monoclonal antibodies are available
Molecular Action of Estrogen
7
Molecular Action of Estrogen
homodimer homodimer & heterodimer• Non-genomic effects
Adopted from George GJM Kuiper et al
Alternating estrogen signaling pathways
8
Molecular Action of EstrogenDifferent response in different
tissues
Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly
9
Estradiol
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.
Molecular Action of
10
SERM(Tamoxifen)
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.
Molecular Action of
11
Estrogen Receptor Down regulator A Promising Area of Research
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.
Molecular Action of
12
Mechanism of Tissue Response - Summary
Oestrogen Receptor Ligand Complex
Oestrogen Receptor
LigandE / SERM / PE/ERD
DNA Oestrogen Response element
Gene Transcriptio
n
Tissue Response
Coregulatory Proteins /
Agonistic & or Antagonistic
AF 1 & 2
Estrogen Signaling in Breast Cancer
In Progress
Tabular Format
Interactive Pathway
14
Selective Ostrogen Receptor Modulators
Estrogens
Anti Estrogens
SERMs
SERMs- designed to act in specific ways at each of the oestrogen receptor sites in different tissuesERDR
Phytoestrogens
15
Designer drugs which exhibit tissue specific desirable Estrogenic & Antiestrogenic
actions in different tissues
“Designer Estrogens”“Fantasy Estrogens”
They have the potential of providing a new paradigm for maintaining the
health of women.
Selective Ostrogen Receptor Modulators
16
• Mer 25 (1958)• Clomiphene1. Tamoxifen
• Toremifene• Droloxifene• Iodoxifene
2. Raloxifene3.Ormeloxifene
As of TodaySelective Ostrogen Receptor
Modulators
17
The Ideal Selective Ostrogen Receptor Modulator
The perfect SERM
The ideal SERM is one that prevents bone loss, has no risk of uterine or breast cancer, a +ve effect on lipids & cardiovascular system, relieves PMS and maintains cognitive function of the brain
The Search goes on
Adopted from – Rita de Cassia M Dardes & V Craig Jordan
18
The Ideal Selective Ostrogen Receptor Modulator
The perfect SERM
TISSUEEndometriumBreastVaginaBoneLiver/CVSCNS
Perfect AEAEEEEEE-Estrogenic, AE-Anti
Estrogenic
Tamo E
AEAEEE
AE
Ralo AEAEAEE
E+E?
Ormelo
AE AE E E E E
The Search goes on
19
Tamoxifen• The first true SERM.• In use for breast cancer treatment since
1968, 10m patient use years.• Approved for prophylactic use in1997.• Beneficial effect on osteoporosis.• Effect on CVS +?
– Lipid profile +.
20
Tamoxifen
• Has many undesirable E / AE actions.– E in uterus – risk of End. Cancer.– Alleged as a carcinogen.– AE in vagina, CNS?
• Unsatisfactory safety/toxicity profile.• Gave boost to the continued research for
SERMs. • Under evaluation-star trial-6/99, 22000
women for 5-10 yrs.
21
Raloxifene
• Originally approved (1998) for use for treatment and prevention of osteoporosis.
• Subsequently (1999) approved for breast cancer prevention after ‘MORE’ study
• Improved safety profile than Tamoxifen• Cardiovascular effects are unequivocal &
under evaluation.
22
Raloxifene Risk of venous thromboembolism• No effect on endometrium. AE on vagina • Effect on CNS?. No improvement in
cognitive function• Does not relieve PM hot flashes • Possible future use as HRT??• Is on evaluation- STAR trial
23
ORMELOXIFENE
The individual elements of the molecular structure give a tissue selectivity- different
DNA transcriptions in different tissues
Estrogen agonist
Estrogen antagonist
Chemical Name- Trans -7-methyl-2-2-dimethyl-3-phenyl-4(4-(2-
pyroldinoethoxy)phenyl(-chroman hydrochloride), related to
centchroman
The perfect SERM
24
The perfect SERMORMELOXIFENE• Enhanced tissue selectivity
– Basic amine side chain – uterine AE action– Pyrolidine base – highest degree of
antagonistic action– Benzopyran group – agonistic action & binding
affinity• Very strong binding affinity to ER
– Quick & potent action• Slow nuclear build up & prolonged retention
of ER– Long half life & prolonged action
25
An optimally designed potent SERM with Varied Tissue ResponseOestrogen Antagonist in UTERUS &
BREASTMild Oestrogenic action on Vagina, Bone mineral density, CNS and Serum LipidsNo action on Hypothalamic Pituitary Ovarian function, Thyroid, Adrenal.
The perfect SERMORMELOXIFENE
No Progestational, Androgenic or Antiandrogenic properties
26
ORMELOXIFENE
Special benefit in perimenopausal women – Relief of PMS
Currently indicated for the treatment of Dysfunctional Uterine Bleeding at ANY AGE.Not suitable for women desiring pregnancy
Approved for inclusion in National Family Welfare Program, for social marketing.
The perfect SERM
27
ORMELOXIFENE• Contraindicated in –
• H/O recent liver dysfunction or clinical jaundice
• PCOD• Cervical Dysplasia & Chronic Cervicitis• Hypersensitivity to the drug• Allergic conditions• Nursing mothers • Chronic illness
The perfect SERM
28
ORMELOXIFENE
Has an excellent safety profile,very well tolerated &
practically without any undesirable side effectsEasy to administer - 60mg tablet
twice a week ( Sunday & Wednesday) for 12 weeks followed
by one tablet of 60mg once weekly
The perfect SERM
29
ORMELOXIFENE Currently being evaluated for
use in the treatment and prevention of: -•Breast Cancer•Osteoporosis Possible future use: -•Menopause management•Fibromyoma•Endometriosis and Adenomyosis•Contraceptive
The perfect SERM
30
ORMELOXIFENE
WARNING: -
Indian contribution Not introduced in the international
arena Not approved by FDA Not yet fully evaluated - extensive
clinical trials needed
The perfect SERM
31
THANK THANK YOUYOU
SERMsWomen have reason to say
SERMs have the potential of providing a new paradigm for
maintaining the health of women.
DNA pol a
Cyclins E,A
B-Myb
Estrogen Receptor
Estrogen Receptors
http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime
Estrogen Receptors• ER-
– Uterus, testis, pituitary, ovary, epididymis, and adrenal gland.
• ER- (Kuiper et al. 1996)– brain, kidney, prostrate, ovary, lung, bladder, intestine, and
epididymis.– 88% identity with rat ER-
identity with human ER-
• Membrane localized ER (Pietras and Szego, 1997)
• ER and differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain.
Regulation of ER activity by coactivators and corepressors
Hall et al. 2001. J. Biol. Chem., 276: 36869-36872
ER effects on different cell types
Estrogens can activate growth factor receptor signaling
Levin ER. Mol.Endocrinol. 2003;17:309-17
Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414.
Estrogen has multiple effects
Phytoestrogens
Aherne and O’Brien, 2002. Nutrition 18:75-81.
Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.
Comparison of binding affinities and transactivation of estrogen and phytoestrogens
Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414
Dietary Sources of Phytoestrogens
Pytoestrogens in humans• Phytoestrogens have weaker estrogenic activity compared
to circulating estrogens (17--estradiol or estrone).• Phytoestrogens can bind sex steroid binding protein (SBP)
and -feroprotein (AFP) and be circulated.• Dietary phytoestrogens are metabolised by intestinal
bacteria, absorbed, conjugated in the liver (by sulfotransferases and UDP-glucoronyosyl transferases), circulated in plasma and excreted in urine.
• Phytoestrogen levels are higher in fluid collected from breast and prostatic ducts compared with serum or plasma.
• Urinary isoflavonoid excretions range from about 0.3-30 M/day.
• Urinary secretions of vegetarians may contain 1000 times higher phytoetsrogens than total urinary steroid estrogens.
• Phytoestrogens demonstrate inhibitory effects at 0.5-50M which are similar to levels in urine.
Soy Phytoestrogens• Genistein, daidzein, coumesterol, and equol bind to and
transactivate both ER and (0.1-10M)• Genistetin has a higher affinity for ER.• Soy PEs effect cell cycle progression, growth, and
differentiation. Have antioxidant and anti‑angiogenic activities.
• Genistein affects cellular function via inhibition of 17 beta-steroid oxidoreductase (an enzyme necessary for conversion of androgens to E2).
• Inhibits aromatase.• Effects cycloxygenase, lipoxygenase, Cholesterol 7
hydroxylase.• Modulates the activity of topoisomerase II.• Modulates enzymes involved in phosphoinositide (PI)
turnover.• Modulates TGF-β signaling cascades• Increases epidermal growth factor (EGF) and EGFR levels.
Genistein
• Both estrogenic and anti-estrogenic effects
• Inhibitor of tyrosine kinases• 20-fold higher binding affinity for ER-
than ER- (Makela et al. 1999)
4',5,7-Trihydroxyisoflavone
Phytoestrogens in Human Health
• Cancer preventive• Post-menopausal supplement• Prevention of osteoporosis• Cardiovascular health• Fertility• Breast enhancement
References: Kurzer, 2003. J. Nutr. 133: 1983S-1986S.
Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.
Cancer preventive• Benefits to human breast and uterine cancer
controversial.• Genistein can be carcinogenic in uterine cancer at
neonatal exposure.• Cancer protective in animal studies, especially when
exposed during breast development.• Isoflavonoids and lignans stimulate proliferation of ER+
breast cancer cells.• Inhibit cell growth at high concentrations and in ER (-)
breast cancer cells. • Therefore, ER may have cancer protective effect.• Anti-angiogenic effects of genistein, daidzein, and
biochanin A may contribute to antitumor activity.• Anti-oxidants in vitro and in vivo.
Post-menopausal therapy
• In 2002, the Women’s Health Initiative (WHI) trial of estrogen/progestin therapy was halted midtrial due to high incidence of breast cancer and cardiovascular disease.
• Consumption of 30mg/d soy isoflavones may reduce hot flashes by 30-50%.
Prevention of osteoporosis
• Isoflavone intake increases bone mineral density.
• Can be useful in preventing post-menopausal osteoporosis.
• Diets rich in phytoestrogens can protect long-term bone loss (Setchell & Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S-609S) .
Cardiovascular health
• Average intake of 47g/day soy protein results in 9% decrease in total cholesterol,13% decrease in LDL cholesterol, and a trend towards HDL cholesterol.
• Flavanoids decrease platelet aggregation.• Genistein-induced inhibition of growth factor
activity can interfere with platelet and thrombin action.
Effects on fertility (premenopausal)
• Interferes with menstrual cycle (delay)Reduced LH and FSH and progesterone.• Male rodents exposed to PEs in early life:
impaired semen quality, congenital malformations, testicular cancer
(coumesterol, delay in mating)
• Antioxidant, anti‑apoptosis, anti‑inflammatory, anti-cancer, and anti‑invasive.• Reduces Cu-induced LDL oxidation by binding to LDL via a glycosidic ether bond. Increases HDL cholesterol. Inhibits platelet activation.• Ameliorates neuronal damage due to ethanol consumption. Probably via antioxidant effect. Minimizes effects of NOS activity by ehtanol. Inhibits ethanol-induced arachidonic acid release and cycloxygenase activity.Anti-ageing role?• inhibitory effects on cancer initiation, growth promotion progression and angiogenesis in model systems. • The anti‑proliferative activity of resveratrol is mediated by p38-MAPKs via p53 mediated inhibition. Resveratrol may inhibit apoptosis induced by oxidized lipoproteins through inhibition of NF-B and AP-1 pathways.• Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER (+) breast cancer cells.
Red wine phytoestrogens:Resveratrol, quercetin, and anthocyanins
The Cell Cycle Control System• The sequential events of the cell cycle are
directed by a distinct cell cycle control system, which is similar to a clock
• The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received
• For many cells, the G1 checkpoint seems to be the most important one
LE 12-14G1 checkpoint
G1
S
M
M checkpointG2 checkpoint
G2
Controlsystem
LE 12-15
G1
G1 checkpoint
G1
G0
If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in the cell cycle.
If a cell does not receive a go-ahead signal at the G1 checkpoint, the cell exits the cell cycle and goes into G0, a nondividing state.
LE 12-16b
Degradedcyclin G2
checkpoint
S
M
G 2G 1
Cdk
Cyclin isdegraded
MPF Cyclin
Cdk
Molecular mechanisms that help regulate the cell cycle
accumulation
Cyclin
Stop and Go Signs: Internal and External Signals at the
Checkpoints• An example of an internal signal is that
kinetochores not attached to spindle microtubules send a molecular signal that delays anaphase
• Some external signals are growth factors, proteins released by certain cells that stimulate other cells to divide
• For example, platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in culture
LE 12-17
Petriplate
Scalpels
Without PDGF
With PDGF
Without PDGF
With PDGF
10 mm
• Another example of external signals is density-dependent inhibition, in which crowded cells stop dividing
• Most animal cells also exhibit anchorage dependence, in which they must be attached to a substratum in order to divide
LE 12-18aCells anchor to dish surface anddivide (anchorage dependence).
When cells have formed a completesingle layer, they stop dividing(density-dependent inhibition).
If some cells are scraped away, theremaining cells divide to fill the gap andthen stop (density-dependent inhibition).
25 µmNormal mammalian cells
• Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence
LE 12-18b
Cancer cells do not exhibitanchorage dependenceor density-dependent inhibition.
Cancer cells25 µm
Loss of Cell Cycle Controls in Cancer Cells• Cancer cells do not respond normally to the
body’s control mechanisms• Cancer cells form tumors, masses of
abnormal cells within otherwise normal tissue• If abnormal cells remain at the original site,
the lump is called a benign tumor• Malignant tumors invade surrounding tissues
and can metastasize, exporting cancer cells to other parts of the body, where they may form secondary tumors