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New

Approach in Endometriosis Management

Budi Wiweko
wiwekobudi@yahoo.co.id
budi.wiweko@gmail.com

Academic Health System Universitas Indonesia - Indonesian Medical Education and Research Institute
Faculty of Medicine Universitas Indonesia
Dr. Cipto Mangunkusumo General Hospital

Jakarta
Endometriosis
The presence of endometrial like tissue outside uterine cavity
intramyometrial presence of endometrial mucosa
ADENOMYOSIS (glands and stroma)
QUESTIONS

1. How endometriosis happened ?


2. Endometriosis associated symptoms
3. Management of endometriosis
4. Take home messages
1 1. If the symptom is pain, alleviate the pain
TREAT THE SYMPTOMS
2. If the symptom is infertility, assist fertility

2 PRESERVE FERTILITY

3 PREVENT PROGRESSION TO CHRONIC PAIN

4 KEEP SURGERIES TO A MINIMUM

Identify patients who will really benefit and find the best time for surgery
Importance of post surgical maintenance

Society of Endometriosis and Uterine Disorders 1st Conference. Paris, 2015


How
endometriosis
happened ?
ENDOMETRIOSIS

Symptoms
endometriosis Peritoneum Endometrium
(1927)

Management

menstrual regurgitation
Take home
messages
MOLECULAR PATHWAYS IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS

Soarez. Fertil Steril, 2012


immune system dysfunction

How
endometriosis
happened ?

Endometrial cell

Symptoms
endometriosis

Management

Take home
messages

Yen and Jaffe. Reproductive Endocrinology and Infertility, 2009


How Eutopic endometrium
endometriosis
happened ?

Symptoms
endometriosis

Eutopic endometrium of endometriosis patients is DIFFERENT


Management

They can develop, grow and be implanted out side uterine cavity
Take home
messages

Vinatier et al. Eur J Obstet Gynecol Reprod Biol. 2000


How
endometriosis
happened ?

No CHARACTERISTIC
Symptoms
1 Able to escape from immune system
endometriosis
2 Produce estrogen by themselves
3 Able to develop and infiltrate surrounding tissue
4 Rich of perfusion and vascularization
Management

Take home
messages

Vinatier et al. Eur J Obstet Gynecol Reprod Biol. 2000


ENDOMETRIAL CELLS

How
endometriosis
happened ?

Symptoms
endometriosis

NYERI

Management

Upregulated ER- suppressed ER- and PRB therefore increasing the


activity of COX-2
Take home
messages

Bulun et al. Role of Estrogen Receptor in Endometriosis (2012)


ENDOMETRIAL CELL

PROGESTERONE RESISTANCE
How
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Tariverdian et al. Semin Immunopathol, 2007


ENDOMETRIOSIS SYMPTOMS
How
endometriosis
happened ?

INFERTILITY PAIN
Symptoms
endometriosis

ENDOMETRIOSIS PAIN
The most common pelvic pain:
Management Dysmenorrhea
Dyspareunia
Dischezia
Dysuria
Take home
messages
Effects of endometriosis on human reproduction

How
endometriosis
happened ? 2 3

Symptoms
endometriosis

Management

Take home
messages
1

Ziegler. The Lancet, 2010


PROS AND CONS (1)
How
endometriosis
happened ? ENDOMETRIOSIS ASSOCIATED INFERTILITY

Symptoms
endometriosis

SURGERY NOT SURGERY

Management

Take home
messages
How
endometriosis
happened ?

Endometriomas as a possible cause of reduced ovarian reserve in


women with endometriosis
Symptoms
endometriosis

Objective
To evaluate the adverse effects of endometriomas on ovarian reserve
Management
Laparoscopic cystectomy is recommended for endometriomas larger than
4 cm, but the side effects of this surgery in terms of preservation of
ovarian reserve after surgery have been questioned

Take home
messages

Kitajima et al. Fertil Steril, 2011


< 35 years old
January-October 2010 no history of surgery 22 women
regular menstrual cycle
How
endometriosis
happened ? endometrioma

LAPAROSCOPIC SURGERY cystectomy

Symptoms
endometriosis

BIOPSY

Management
Ovarian cortical tissue was Ovarian cortical tissue from the
excised using scissors contralateral healthy ovary was also
1 cm away biopsied

Take home Follicular density in biopsied cortex was evaluated


messages

Kitajima et al. Fertil Steril, 2011


Kitajima et al. Fertil Steril, 2011
RESULTS
How
endometriosis
happened ? Follicular density in cortex from ovaries with endometriomas less
than 4 cm in size is significantly lower than in cortex from contra-
lateral normal ovaries
Fibrosis was frequently evidenced in cortex derived from
Symptoms
endometriosis endometriomas

Management

surgical interventions, even at an early stage of cyst


development, may be BENEFICIAL TO PROTECT THE
OVARIAN RESERVE in women with endometriomas
Take home
messages

Kitajima et al. Fertil Steril, 2011


How
endometriosis
happened ?

DO ENDOMETRIOMAS INDUCE
AN INFLAMMATORY REACTION
Symptoms
IN NEARBY FOLLICLES ?
endometriosis

this study examined whether intra-ovarian endometriosis is


associated with a local inflammatory reaction and whether
Management
inflammation affects follicular development and oocyte quality

Take home
messages

Opoien et al. Hum Reprod, 2013


How
endometriosis
happened ?
The comparison cytokine concentrations in the follicular
fluid from the two ovaries

Symptoms
endometriosis

Management

The cytokine results did not support inflammation as a cause for


adverse follicular development in endometrioma

Take home
messages

Opoien et al. Hum Reprod, 2013


PROS AND CONS (2)
How
endometriosis
happened ?
ENDOMETRIOSIS ASSOCIATED INFERTILITY

SURGERY NOT SURGERY


Symptoms
endometriosis


NON IVF IVF
Management

COS + Natural conception


Take home
messages COS + IUI
How
endometriosis
happened ?

Symptoms
endometriosis

Management

The objective of the study was to evaluate the pregnancy rate after surgical
treatment and to assess whether a combined approach with laparoscopic
surgery followed by IVFET can improve the overall pregnancy rate
Take home
messages

Pedro N Barri, Buenaventura Coroleu, Rosa Tur, Pedro N Barri Soldevila, Ignacio Rodrguez
How
endometriosis
happened ?
Moderate and severe endometriosis is often associated with anatomic
distortion, tubal obstruction, pelvic adhesions, and ovarian endometriomas

Symptoms
endometriosis
Expectant management has been associated with a low
cumulative conception rate (025%)

Few studies have investigated management options after failed


Management surgery
No randomized trials are available to evaluate the effect of in vitro
fertilization and embryo transfer (IVFET) in addition to surgical
treatment
Take home
messages

Coccia et al. Eur J Obstet Gynecol, 2008


How 107 WOMEN underwent underwent laparoscopic surgery for
endometriosis
happened ?
endometriosis at the Department of Obstetrics and Gynaecology of Florence,
Italy, between March 1995 and December 2003

complete excision of pelvic endometriotic lesions was performed


using scissors and bipolar coagulation
Symptoms stripping technique was used to remove ovarian endometriomas
endometriosis

PREGNANCY OUTCOME

Management

SPONTANEOUS PREGNANCY AFTER IVFET


Take home
messages

Coccia et al. Eur J Obstet Gynecol, 2008


How
endometriosis PREGNANCY RATE AFTER LAPAROSCOPY AND IVF-ET
happened ?

Symptoms
endometriosis

Management
Patients should be advised to start trying to conceive naturally soon after
laparoscopic surgery

If pregnancy does not occur within 912 months, they should move to an
Take home
messages
IVFET program

Coccia et al. Eur J Obstet Gynecol, 2008


How
endometriosis
happened ?
NUMBER OF EMBRYOS FROM ENDOMETRIOSIS PATIENTS

Endometriosis- Male factors-


Total
associated infertility associated infertility
Symptoms
endometriosis Patients (n) 42 43 85

Embryo sample (n) 114 162 276

Female age (years) 34,7 + 4,5 33,0 + 4,9 33,9 + 4,8


Management
No. of embryos 2,7 + 1,8 3,8 + 2,6 3,2 + 2,3

Take home
messages

Wiweko et al. Klinik Yasmin, 2013


Number of embryos from endometriosis-associated
How infertility and male factors-associated infertility
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages
n = 85 patients

Wiweko et al. Klinik Yasmin, 2013


How

SUCCES RATE BASED ON ETIOLOGY


endometriosis
happened ?

Pregnancy
Etiology Success rate (%)
Yes (n=57) No (n=144)
Symptoms Male Factor 7 39 15,2
endometriosis
Tubal factor 5 14 26.3
Endometriosis 6 9 40,0
PCOS 7 7 50,0
Management
Poor responder 14 34 29.1
Unexplained 11 29 27.5
Combined factor 7 12 36.8
Take home
messages

Anggraheni, Wiweko et al. SMART IVF, 2015


How
Management of Endometriosis in the Infertile Patient
endometriosis
happened ?

Symptoms
endometriosis

Management

Decision-making process for infertile women with advanced endometriosis


Take home
messages

Somigliana et al. Seminars Reproductive Medicine, 2015


Expression of mRNA Bcl-2 and BAX on Granulosa Cells
from Endometriosis Patients
How
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Wiweko et al. Ina Repromed, 2016


Expression of mRNA Bcl-2 and BAX on Granulosa Cells
How
from non Endometriosis Patients
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Wiweko et al. Ina Repromed, 2016


How
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages
How
endometriosis
happened ? Second surgery for recurrent endometriomas is more harmful to
healthy ovarian tissue and ovarian reserve than first surgery

Symptoms
endometriosis

Management

Take home
messages

Muzii et al. Fertil Steril, 2015


How
endometriosis
happened ? Second surgery for recurrent endometriomas is more harmful to
healthy ovarian tissue and ovarian reserve than first surgery

Symptoms
endometriosis

Management

Take home
messages

Muzii et al. Fertil Steril, 2015


How
endometriosis
happened ?

Symptoms
endometriosis

Management
Because there is follicular loss during surgery, ultrasonography-
guided transvaginal aspiration has emerged as a surgical option
for the treatment of recurrent ovarian endometrioma.
Take home
messages
Overview of included studies investigating the treatment of recurrent ovarian
endometrioma by ultrasonography-guided aspiration with or without sclerotherapy

Goncalves et al. Int J Obstet Gynecol, article in press


How
endometriosis
happened ?

Symptoms
endometriosis

Management
The first aim of this study was to evaluate the ovarian response to COH for IVF-ET/ICSI
and the outcome of ART in patients with a history of endometriosis that have been
treated once with laparoscopy with or without cystectomy.

Take home The secondary aim was to investigate whether aspiration of recurrent ovarian
messages endometriomas before COH improved the prognosis of IVF-ET/ICSI cycles.
Group of subjects
How
endometriosis
happened ?
q Group A consisted of 176 women with pelvic endometriosis but without
ovarian endometriomas diagnosed by laparoscopy.

q Group B consisted of 125 women who had previously undergone


Symptoms
laparoscopic endometrioma cystectomy; the endometriomas were not
endometriosis recurrent before IVF-ET/ICSI cycles.

q Group C consisted of 38 women with recurrent endometriomas after a


previous cystectomy; the endometriomas were not aspirated
transvaginally before IVF-ET/ICSI cycles.
Management

q Group D consisted of 41 women with recurrent endometriomas after a


previous cystectomy; they underwent aspiration before IVF-ET/ICSI
cycles
Take home
messages

Xing et al. Master Sociomed, 2016


How
endometriosis
happened ? EPIDEMIOLOGIC AND STIMULATION CHARACTERISTICS

Symptoms
endometriosis

Management

Take home
messages

Xing et al. Master Sociomed, 2016


How IVF/ICSI OUTCOMES
endometriosis
happened ?

Symptoms
endometriosis

Management

Long and ultra long protocol

Take home
messages

Xing et al. Master Sociomed, 2016


How Granulosa Cells FSH Receptor Expression and Its Correlation to
endometriosis
happened ? The Total rFSH in Controlled Ovarian Stimulation

This study was done on 27 women (18 endometriosis patients and 5 non-
Symptoms
endometriosis) who underwent IVF in Yasmin Clinic of Dr. Cipto
endometriosis Mangunkusumo General Hospital Jakarta.

No significant correlation between level of FSH-r expression and total dosage


of rFSH (r=0.08, p > 0.05) of 27 women.
Management

Granulosa cells FSH-r expression increased by 27.8 for each IU of total


dosage of recombinant FSH

Take home
messages

Wiweko et al. Ina Repromed, 2016


How
endometriosis
happened ? CLINICAL STUDIES ON THE USE OF FERTILITY PRESERVATION
TECHNIQUES IN WOMEN WITH ENDOMETRIOSIS

Symptoms
endometriosis

Management

Take home
messages

Somigliana et al. Seminars Reproductive Medicine, 2015


Ovarian tissue vitrification as a method for fertility preservation:
A study of follicle number and morphology after vitrification
How
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Wiweko et al. IVF Lite, 2014


How
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Wiweko et al. IVF Lite, 2014


Endometriosis

How
endometriosis
happened ?
Sperm Fallopian tube Ovarian reserve

Abnormal Occluded Poor ovarian reserve


Symptoms
endometriosis Normal

Emergency IVF
Surgery

Management
Minimal - mild Moderate - severe

Insemination
Take home
messages
IVF

Wiweko, 2015
Pharmacologic therapies in endometriosis:
a systematic review
How
endometriosis
happened ?

The ideal pharmacologic agent must fulfill the following criteria:

Symptoms
endometriosis
1. High effectiveness in blocking disease progression and symptoms
2. Ability to inhibit and suppress established lesions
3. High specificity, not interfering with physiologic processes in
which the same molecules that are targeted in the treatment are
Management involved
4. Demonstrated safety for long-term use in humans
5. High lingering effect in the inhibition of endometriotic lesions
Take home
messages

Soarez et al. Fertil Steril, 2012


HYPOMETHYLATION HYPERMETHYLATION
ER- PROGESTERONE RECEPTOR
Over-expression ER-
How
endometriosis
happened ?
Down-regulation PR-B
PROGESTERONE RESISTANCE

Symptoms
endometriosis

CELL PROLIFERATION INFLAMMATION APOPTOSIS NEURO-


INCREASED INCREASED DECREASED ANGIOGENESIS
Management
INCREASED

Take home ENDOMETRIOSIS


messages

Felice Petraglia. Society of Endometriosis and Uterine Disorders 1st Conference. Paris, 2015
PILIHAN PENANGANAN ENDOMETRIOSIS
How
endometriosis
happened ?

Symptoms
endometriosis

Management DIENOGEST

Take home
messages

Crosignani et al. Hum Reprod Update, 2006


How
endometriosis
happened ?

Dienogest inhibits Toll-like receptor 4 expression induced by


costimulation of lipopolysaccharide and high-mobility group box 1
in endometrial epithelial cells
Symptoms
endometriosis

Dienogest inhibits TLR4 mRNA expression and subsequent IL-8 production


induced by TLR4 agonists via an inhibitory effect on NF-kB activation in
Management human endometrial epithelial cells

This pharmacologic effect of dienogest may contribute to its therapeutic


effect on abnormal inflammation of endometrium
Take home
messages

Mita et al. Fertil Steril, 2011


How
endometriosis
happened ?

Dienogest inhibits aromatase and cyclooxygenase-2 expression


and prostaglandin E2 production in human endometriotic
Symptoms
endometriosis stromal cells in spheroid culture

DNG inhibits aromatase and COX-2 expression as well as PGE2 production


Management
in ESCs

Take home
messages

Yamanaka et al. Fertil Steril, 2012


How
endometriosis
happened ?

Symptoms
endometriosis

Management
Dienogest may improve progesterone resistance in endometriotic tissue by
increasing the relative expressions of PR-B and PR-A, and decreasing the
relative expressions of ER and ER.

Take home
messages

Hayashi et al, 2012


How
PENGGUNAAN DIENOGEST PADA ENDOMETRIOSIS
endometriosis
happened ?

menurunkan keluhan dismenorea, dispareunia,


diskezia

Symptoms
endometriosis

Management

Take home
messages
Momoeda M, Harada T, Terakawa N, et al. Long-term use of dienogest for the treatment of
endometriosis. J Obstet Gynaecol Res. 2009
Endometriosis is a chronic, recurrent disease, represents a challenge
How to health-care providers and a burden on the health care system
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Beidawi et al. Fertil Steril, 2017


How
endometriosis
happened ?

Symptoms
endometriosis

Management

Take home
messages

Beidawi et al. Fertil Steril, 2017


SIFAT DIENOGEST BERDASARKAN STRUKTURNYA

Menyerupai turunan
Menyerupai turunan progesteron Sifat khas dienogest
testosteron

Tidak ada akumulasi (waktu Tidak memiliki efek terhadap Tidak mengganggu protein
paruh 10 jam) kardiovaskular dan metabolik pembawa hormon

Memiliki efek transformasi Mempertahankan kadar estradiol antara Kadar hormon bebas berkisar
endometrium yang kuat 30 - 50 pg/ml 10%

Ketersediaan hayati yang tinggi Memiliki aktivitas anti androgen Menekan estradiol secara
(> 90%) Tidak memiliki efek mineralokortikoid langsung (moderate)

Mueck et al. Maturitas, 2012


How How endometriosis management ?
endometriosis
happened ?

Management of endometriosis: moving toward a problem-oriented


and patient-centered approach
Paolo Vercellini
Symptoms
endometriosis

The management of endometriosis is not one size fits all

Management Treatments should not be focused on lesions, but on clinical problems

The physician should be able explain in detail all the available


treatments, and not only those that the physician prefers or is able
Take home to offer
messages

Fertil Steril, 2015


How
endometriosis
happened ?

Symptoms
endometriosis

Some patients may prefer surgery in order to avoid hormonal therapies,


whereas some others may prefer medications with the objective of avoiding
Management surgery.

Some women may chose surgery to increase the chances of natural


conception, some others may prefer IVF in order to limit the periods of time
Take home without medical treatments.
messages

Paolo Vercellini. Fertil Steril, 2015


THE CENTER OF EXCELLENCE IN ENDOMETRIOSIS
IVF
Surgeons Reproductive endocrinologist ICSI
IUI

Immunologists
Nutritionist
Psychologists / counsellors ENDOMETRIOSIS PATIENTS

Pain management
Nurses

Complementary therapies

Patient support groups

Society of Endometriosis and Uterine Disorders 1st Conference. Paris, 2015


Take home messages
How
endometriosis
happened ? 1. Endometriosis occurred because of genetic malfunction on endometrial cell and
peritoneal immune system.

2. Endometrioma reduced ovarian reserve and increased apoptosis of granulosa cells.

Symptoms
3. Treatment of endometriosis is mainly targeted on patients problem (infertility or
endometriosis pain).

4. Surgery, IVF or IUI are the choice of management on endometriosis associated


infertility.

Management
5. Second surgery of recurrent endometrioma is more harmful to ovarian healthy
tissue.

6. Endometriosis medication is developed to suppress endometrial inflammation,


angiogenesis and proliferation through selective progesterone receptor modulator.
Take home
messages
7. Trans-disciplinary and comprehensive approach is essential for developing
endometriosis center of excellent.
ACKNOWLEDGEMENT

Indonesian Reproductive Medicine


Research and Training Center (INA REPROMED)