final presentation latest modalities in endometriosis treatment -3
DESCRIPTION
modalitiesTRANSCRIPT
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Latest Modalities For
Endometriosis Treatment
Nusratuddin Abdullah
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Therapeutic Basis of Treatment
Related to Pathophysiology
Endometriosis is the disease of:
Estrogen Dependent
Progesterone Resistant
Angiogenic
Inflammatory
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Evidence That Endometriosis is
Estrogen Dependent
Unusual before menarche (has been reported in the larche)
Prolonged E2 exposure
early menarche
nulliparity (more menses)
xenoestrogen exposure (Messmer, 2004)
Animal models
trophic effects of E2 in mice implants (Osteen, 2007)
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Endometriosis & Progesterone
Lesions are P4 resistant
Progestins are commonly used (counter-intuitive)
Because they
have anti-angiogenic effects
are immunomodulatory
are anti-inflammatory
oppose E2 action
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Progesterone Resistance
17Hydrosteroid
Dehydrogenase(17HSD)
Estrone EstradiolType I
Type II
In normal condition
Expression 17HSD type I > 17HSD type II
Progesterone induces 17HSD type II in normal epithelium
In Endometriotic implant progesterone receptor expression
is abnormal no induction 17HSD type II
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Evidence of Inflammation
Observe high levels of inflammatory cytokines (IL-8, IL-1, TNF-) in peritoneal fluid (PF) in women with osis
PF activated macrophages secrete inflammatory cytokines
PF activated macrophages cannot phagocytose endometrial cells
In systemic circulation, higher levels of TNF- and IL-8
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Evidence of angiogenesis
The peritoneal environment is
highly angiogenic,
quantity and activity of
angiogenic factors :VEGF
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INTRODUCTION
TREATMENT
Relieve Pain
Endometrioma
Promote fertility
MEDICAL
Surgical
Combined
Analgesia
Ovulation/ Estrogen
Suppression
Direct Action on
Endometrial Deposit
Immunomodulator
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Why newer medical treatments:
No medical or surgical treatments have been proven
to improve fertility rates substantially in women with
endometriosis in its early stages.
The focus of treatment is on the relief of pain
symptoms
The chronic nature of this disease need long-term or
repeated therapy to control the symptoms
Evidence suggests that surgery does not provide any
greater relief of pain symptoms than does medical
therapy
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Chief medical approaches
Analgesics
Suppression of ovulation / oestrogen
production
Direct action on endometrial deposits
Modulation of the Immune/inflamatory
response
Newer therapies aim to target endometriotic
deposits more specifically to avoid systemic side
effects of cycle suppression
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Aromatase Inhibitor
Selective estrogen receptor modulators (SERMs)
Selective progesterone receptor modulators (SPRMs)
Dienogest
LNG-IUS
Immunomodulator
Anti Angiogenesis
Potential New treatment Modalities:
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Aromatase is a cytochrome P450 (CYP) enzyme
catalyzes the conversion of androgens, androstenediones
and testosterone to estrogens, estrone and estradiol.
Have pathogenic role in endometriosis because it is abberantly
expressed in endometriotic implant & in eutopic endometrium of
women with endometriosis.
Inhibition of aromatase activity may represent a new
therapeutic option for endometriosis. (Simeno Ferrero, 2009)
,
Aromatase Inhibitor
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Aromatase Inhibitor
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Non Steroid/Reversibel
Selective aromatase
inhibitors 3rd Generation
Anastrozole
&Letrozole
Letrozole , in post
menopause
women may inhibit
aromatase in
peripheral tissue
>99%
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Anastrazole1mg or letrozole 2.5mg daily could be
effective in pain relief associated with endometriosis
(Nothnick, 2011; Shippen&West, 2004).
Because of stimulatory action of aromataseinhibitors
in FSH secretion, in premenopausal women they
could cause ovarian cysts
AIs administer with GnRH agonist or OCPs or
progestins to reduce their disadvantage in prolong
usage: bone loss (Ferrero etal,2009).
Aromatase Inhibitor
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Anastrazole1mg or letrozole 2.5mg daily could be
effective in pain relief associated with endometriosis
(Nothnick, 2011; Shippen&West, 2004).
Because of stimulatory action of aromataseinhibitors
in FSH secretion, in premenopausal women they
could cause ovarian cysts
AIs administer with GnRH agonist or OCPs or
progestins to reduce their disadvantage in prolong
usage: bone loss (Ferrero etal,2009).
Aromatase Inhibitor
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Aromatase inhibitors most beneficial in the
treatment women with recurrent endometriosis who
have not had success with more conventional
treatment regimes
However, one must keep in mind that aromatase
inhibitors exhibit suboptimal tolerability and greater
costs compared to some of the more conventional
therapies.
Aromatase Inhibitor
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Emerging medical therapies for SYMPTOMATIC
endometriosis
Consensus
Grading
Aromatase inhibitors might be
reasonable as a second-line
medical treatment, but more
research is required (weak).
, unanimous or near-unanimous (>80% agreed without caveat and fewer than 5% disagreed)
, majority (5080% agreed)
CONSENSUS ON CURRENT MANAGEMENT
OF ENDOMETRIOSIS 2013World Endometriosis Society Montpellier Consortium
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LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
J.H. Pickar et al.,(2010)
(SERMS):
nonsteroidal agents
that bind to the
estrogen receptor with
agonistic or
antagonistic effects
depending on the
tissue and endocrine
milieu.
Selective estrogen reseptor modulators (SERMs)
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SERMs
The ideal SERM would be has antagonistic ctivity in
the endometrium and agonistic activity for bone and
lipids.
Raloxifene, has been investigated inthe treatment of
endometriosis
Raloxifene can increase estrogen production in
reproductive-age females, potentially limiting their
usefulness for treating endometriosis to
postmenopausal women
Selective estrogen reseptor modulators (SERMs)
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Selective estrogen reseptor modulators (SERMs)
Developed agent is TZE-5323, which is thought to
exert its anti-estrogenic effects by inhibiting binding of
E2 to er and er, as well as suppressing E2ER
transcriptional activation
Tze-5323 dose dependently reduced the volume of
Endometriosis implants without affecting serum
estradiol concentrations or decreasing BMD in the
intact rats
(Saito et al, 2003)
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Emerging medical therapies for SYMPTOMATIC
endometriosis
Consensus
Grading
There is no benefit from raloxifene
on prevention of recurrence of pain
(strong).
, unanimous or near-unanimous (>80% agreed without caveat and fewer than 5% disagreed)
, majority (5080% agreed)
CONSENSUS ON CURRENT MANAGEMENT
OF ENDOMETRIOSIS 2013World Endometriosis Society Montpellier Consortium
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LATEST MODALITIES TREATMENT FOR ENDOMETRIOSIS
Progesterone receptors (PR): isoforms (A & B) and differ
funtionally
Progesterone action on target genes is conferred
primarily by PR B homodimer
Progesterone induced the expression of 17 hydrosteroid
dehydrogenase 2, which catalyzes the conversion of
biologically potent estradiol to the less estrogenic estrone
PRA repress the function of the B iso form
Selective progesteron reseptor modulators (SPRMs)
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THE LATEST MODALITIES TREATMENT FOR ENDOMETRIOSIS
Fer-til Steril2011;96:117589
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Selective progesteron reseptor modulators (SPRMs)
New class of
progesterone
receptor ligands
Asoprisnil is the
first SPRM to
reached
advances clinical
studies
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Anti-proliferative effects
Inhibition of estrogen receptor gene
transcription by the PRA isoform
Atrophy of spiral arteries
Blockade of progesterone-dependent
growth factors
Inhibition of angiogenesis
Blockade cell cycle or modulation of
apoptosis via growth factors
Suppress endometrial prostaglandin
production
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Mifepristone (RU-486)
25-100 mg daily for 3 mo
Induces amenorhea and
reduced pelvic pain
Problem with erratic
bleeding
Onapristone (ZK98299)and
ZK 136799,ZK230211
Direct inhibitory Effect on
human endometrial cells
Anti prgesterone effect
Block Progesterone receptors in
endometrium
Loss of functional integrity
/shedding
Early work showed
improvement in pain
(Cochrane,2000)
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Selective progesteron reseptor modulators (SPRMs)
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Emerging medical therapies for SYMPTOMATIC
endometriosis
Consensus
Grading
SPRMs might be a reasonable second-
line medical treatment, but more
research is required (weak).
, unanimous or near-unanimous (>80% agreed without caveat and fewer than 5% disagreed)
, majority (5080% agreed)
CONSENSUS ON CURRENT MANAGEMENT
OF ENDOMETRIOSIS 2013World Endometriosis Society Montpellier Consortium
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Dienogest
Hybrid of both categories, 17 hydroxyprogesteron&19
Nortestosterone
A novel 19-noretestosterone derivate, highly selective
binding to the progesterone receptors
(Paul McCormack, 2010)
Exerts anti-proliferative, anti-inflammatory and anti-
angiogenic properties in experimental
endometriosis
Strong progestational effects and moderate antigonadotropic
effect, but no androgenic, glucocorticoid or mineralocorticoid
activity
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Growth of endometrial lesions inhibited via:
Central effects: Inhibition of gonadotropin secretion Hypoestrogenic, hypergestagenic endocrine environment, causing
decidualization of endometrial tissue followed by atrophy of lesions1,2
Local effects (preclinical findings): Direct inhibitory effect on proliferation of endometrium-like tissue (in
addition to classical progestational effects)1
Impact on endometriosis-related inflammation3
Modulation of metalloproteinases, which regulate the response of
endometrium-like tissue to estrogen at the paracrine level2
Significant suppression of angiogenesis of endometrial autografts41. Shimizu Y et al. Mol Hum Reprod 2009;
2. Vercellini P et al. Hum Reprod Update 2003;
3. Katsuki Y et al. Eur J Endocrinol 1998.
4. Katayama H et al 2010
Dienogest
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Reduced Pelvic pain in women woth endometriosis: efficacy of
Long term Dienogest Treatment
Felice et al. Arch Gnecol Obstet (2012)285:167-173
Significant decrease
in pelvic pain,
frequency and
intensity of bleeding
progressively
decreased
Long term treatment
show efficacy and
safety profile,
decreased pelvic
pain presisted for 24
wks after cessation
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LNG: derived from 19-nortestosterone, has androgenic and
anti-estrogenic effects on the endometrium. (Mirena)
LNG-IUS has local and systemic effects.
Local activity for endometriotic lesions in the peritoneum
LNG level in the peritoneal fluid during LNG-IUS use.
The mechanism of action in endometriosis: controversial
Vigano et al, 2007)
Levonorgestrel-releasing intrauterine system
(LNG-IUS)
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Gomes et al. 2009:
LNG-IUS cell proliferation and PRA, ER- and Fas
expression in the eutopic and ectopic endometrium of
patients with endometriosis.
Some of these actions were not observed with GnRHa.
Bayogyu et al. 2010:
LNG-IUS (Mirena) vs GnRH analogue (Zoladex)
in patients with severe endometriosis during 12 months
comparable effectiveness for chronic pelvic pain
Levonorgestrel-releasing intrauterine system
(LNG-IUS)
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Emerging medical therapies for SYMPTOMATIC
endometriosis
Consensus
Grading
Second-line medical treatments could include
gonadotrophin-releasing hormone agonists (GnRH-a,
which should be used with add-back HRT, routinely),
the LNG-IUS and depot progestins (weak).
Y
The LNG-IUS may be considered for use as empirical
medical treatment for women who are not optimally
treated with first-line
empirical therapy prior to surgical diagnosis and
treatment,whilst awaiting laparoscopic surgery
(weak).
, unanimous or near-unanimous (>80% agreed without caveat and fewer than 5% disagreed)
, majority (5080% agreed)
CONSENSUS ON CURRENT MANAGEMENT
OF ENDOMETRIOSIS 2013World Endometriosis Society Montpellier Consortium
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Certain similarities between endometriosis and
auto immune disease
Immunomodulator
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
- cytokines and growth factors in peritoneal fluid
- peritoneal macrophages number, concentration and activity
- alterations in B-cell activity
- incidence of autoantibodies in endometriosis
(Warren NB, 2011)
TNF binding protein inhibits development of endometriosis
inrodent and baboon model no human studies
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PENTOXIFYLLINE
TUMOR NECROSIS FACTOR-ALPHA
BLOCKERS
PEROXISOME PROLIFERATORACTIVATED
RECEPTOR GAMMA (PPAR-g)
Immunomodulator
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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Pentoxyfiline
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
(C Kyama, 2008;Keith et al, 2010)
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Pentoxyfiline
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Synthetic Dimethylxanthine derivate, Leukotrine Receptor
Antagonist increasing cAMP inhibit TNF and IL1
RCT the postoperative use of pentoxifylline improved pain
scores at 2 and 3 months after conservative surgery
A Cochrane systematic review, no evidence to support the
use of pentoxifylline for the treatment of endometriosis-
associated pain
(Kamenric, 2008)
(Song, 2009)
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Anti TNF
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Recent trial, 21 women with severe pain and a rectovaginal
nodule were randomly assigned to receive infliximab or placebo
for 3months after surgery.
Pain decreased in both the groups by 30% before surgery and to
20% of the original value after surgery.
(Koninckx, 2008)
Activation TNF- : Tumor Necrosis Factor 1 (TNFR1/p55)
and Tumor Necrosis Factor2 (TNFR2/p75)
TNFR1 will activated caspaseapoptosis and inflamation(Ketih, et al ,2010)
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Inhibit direct endometrial deposit, prevent the
establishment of endometriosis related adhesions even
improve subfertility conditions
May be used for long term course, no menstrual cycle
inteference
AntiTNF
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
ADVANTAGES
The most important adverse side effect of r-hTBP-1 and
other anti TNF therapies is sepsis
Other side effect, respiratory infections, injection site
reactions, headache, rhinitis ,exacerbate CHF, increase
lymphoproliferative diseases, reactivation of latent
tuberculosis, GI effects, abnormal LFT& fatigue
DISADVANTAGES
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Increased expression of PPAR and
by peritoneal macrophages
Peroxisome proliferator-activated receptor gamma(PPAR-)
agonist
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Endometriosis
Sythetic artificial
PPAR ligands
inhibit
endometrial VEGF
expression
Thiazolidinediones
(Rosiglitazone)
BENEFIT
DISADVANTAGES
Increasing Cardiovascular Risk
No menstrual cycle inteference
(McKinnon, 2010;Ketih, et al ,2010)
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Peroxisome proliferator-activated receptor gamma(PPAR-)
agonist
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Sythetic artificial PPAR receptor ligands
inhibit endometrial VEGF expression
Thiazolidinediones
(Rosiglitazone) (McKinnon, 2010;Ketih, et al ,2010)
PPAR- on baboon had decreased development of new lesions
In a case series, 3 subjects with endometriosis-associated pain
were treated with rosiglitazone for 6months. Two subjects
experienced improvement in their pain
Blackbox warning by the FDA for an increased risk of
cardiovascular effects in patients with heart failure
(Lebovic, 2007)
(Moravek, 2009)
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Emerging medical therapies for SYMPTOMATIC
endometriosis
Consensus
Grading
There is no evidence of a benefit of pentoxifylline on
the reduction of pain (strong).
There is no evidence of a benefit of anti-TNFa(anti
tumour necrosis factor alpha) on the reduction of pain
(weak).
There is insufficient evidence of a benefit of
rosiglitazone on the reduction of pain (weak).
, unanimous or near-unanimous (>80% agreed without caveat and fewer than 5% disagreed)
, majority (5080% agreed)
CONSENSUS ON CURRENT MANAGEMENT
OF ENDOMETRIOSIS 2013World Endometriosis Society Montpellier Consortium
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LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
Anti angiogenesis
Anti-angiogenic agents inhibited the growth of endometriotic
implants by disrupting the vascular supply ,mouse model
Angiostatic compounds significantly decreased microvessel
density and the number of endometriotic lesions suggesting
that inhibitors of angio-genesis interfere with the maintenance
and growth of ectopic endometrial tissue
(Warrren, 2009)
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The expression of VEGF by endometriotic implants
neovascularization particularly in hemorrhagic implants
VEGF-A in peritoneal fluid (Donez, 1998, Becker ZM, 2007)
the highest levels: proliferative phase of the cycle
A positive correlation: (Donnez, 1998, Becker ZM, 2007)
severity of endometriosis VEGF-level in peritoneal fluid
Anti-angiogenic drugs: (Kyama et al, 2008)
VEGF inhibitors & angiostatic agents (GM1470 , endostatin,
sirolimus) establishment & progression of endometriotic
lesions.
Anti angiogenesis
LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT
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Emerging medical therapies for SYMPTOMATIC
endometriosis
Consensus
Grading
Anti-angiogenesis agents are at
research level only (strong)
, unanimous or near-unanimous (>80% agreed without caveat and fewer than 5% disagreed)
, majority (5080% agreed)
CONSENSUS ON CURRENT MANAGEMENT
OF ENDOMETRIOSIS 2013World Endometriosis Society Montpellier Consortium
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Fewer medications to treat endometriosis have
been tested in humans than in experimental models
The molecular mechanisms of implantation,
migrationinvasion angiogenesis,and growth
apoptosis are the aim of designing new more
specific targets
LATEST MODALITIES FOR ENDOMETRIOSIS TREATMENT
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