FINAL PRESENTATION Latest Modalities in Endometriosis Treatment -3

Latest Modalities For

Endometriosis Treatment

Nusratuddin Abdullah

Therapeutic Basis of Treatment

Related to Pathophysiology

Endometriosis is the disease of:

Estrogen Dependent

Progesterone Resistant

Angiogenic

Inflammatory

LATEST MODALITIES FOR ENDOMETRIOSISTREATMENT

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)


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


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


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 ENDOMETRIOSIS TREATMENT

Evidence of angiogenesis

The peritoneal environment is

highly angiogenic,

quantity and activity of

angiogenic factors :VEGF

INTRODUCTION

TREATMENT

Relieve Pain

Endometrioma

Promote fertility

MEDICAL

Surgical

Combined

Analgesia

Ovulation/ Estrogen

Suppression

Direct Action on

Endometrial Deposit

Immunomodulator


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


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


Aromatase Inhibitor

Selective estrogen receptor modulators (SERMs)

Selective progesterone receptor modulators (SPRMs)

Dienogest

LNG-IUS

Immunomodulator

Anti Angiogenesis

Potential New treatment Modalities:



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

Aromatase Inhibitor


Non Steroid/Reversibel

Selective aromatase

inhibitors 3rd Generation

Anastrozole

&Letrozole

Letrozole , in post

menopause

women may inhibit

aromatase in

peripheral tissue

>99%

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


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


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


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)

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




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)



endometriosis

Consensus

Grading

There is no benefit from raloxifene

on prevention of recurrence of pain

(strong).





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)

THE LATEST MODALITIES TREATMENT FOR ENDOMETRIOSIS

Fer-til Steril2011;96:117589


New class of

progesterone

receptor ligands

Asoprisnil is the

first SPRM to

reached

advances clinical

studies


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

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)




endometriosis

Consensus

Grading

SPRMs might be a reasonable second-

line medical treatment, but more

research is required (weak).





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


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


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

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)


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)



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).





Certain similarities between endometriosis and

auto immune disease

Immunomodulator


- 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

PENTOXIFYLLINE

TUMOR NECROSIS FACTOR-ALPHA

BLOCKERS

PEROXISOME PROLIFERATORACTIVATED

RECEPTOR GAMMA (PPAR-g)

Immunomodulator


Pentoxyfiline


(C Kyama, 2008;Keith et al, 2010)

Pentoxyfiline


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)

Anti TNF


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)

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


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

Increased expression of PPAR and

by peritoneal macrophages

Peroxisome proliferator-activated receptor gamma(PPAR-)

agonist


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)

Peroxisome proliferator-activated receptor gamma(PPAR-)

agonist


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)


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).






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)

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



endometriosis

Consensus

Grading

Anti-angiogenesis agents are at

research level only (strong)





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


THANK YOU

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FINAL PRESENTATION Latest Modalities in Endometriosis Treatment -3