Fertility Preservation for Patients with Endometriosis

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
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

 QUESTIONS

1. Why endometriosis damage ovarian reserve

2. How can we preserve fertility in endometriosis ?
3. Evidence in fertility preservation for
endometriosis
4. Take home messages
Why
endometriosis
damage ovarian Effects of endometriosis on human reproduction
reserve

How can we
preserve fertility
in endometriosis Endometriosis is
responsible of
inflammation related
Evidence in
mechanisms exerted in the
fertility
preservation for pelvic cavity, ovaries,
endometriosis uterus

Take home
messages

Ziegler. The Lancet, 2010

Why
Endometriosis, infertility and ovarian reserve:
endometriosis a complex interaction
damage ovarian
reserve

How can we Ovarian endometriomas are of

preserve fertility
in endometriosis particular concern here since
these cysts contain a plethora
Evidence in of potentially toxic agents such
fertility
preservation for as free iron that may diffuse
endometriosis
through the cyst wall and
damage the ovarian reserve.
Take home
messages
Why
A point of controversy is the impact of endometriosis per se on
endometriosis ovarian reserve, i.e. independently of surgery
damage ovarian
reserve
Assumptions Level Main publications
Endometriosis affects fertility ++ de Ziegler et al. (2010) and Adamson (2013)
How can we
preserve fertility
Endometriosis is a recurrent ++ Guo (2009)
in endometriosis
disease

Ovarian surgery markedly ++ Somigliana et al. (2011) and Raffi et al. (2012)
damages ovarian reserve
Evidence in
Ovarian endometriomas + Sanchez et al. (2014), Ashrafi et al. (2014),
fertility
damage ovarian reserve Filippi et al. (2014) and Coccia et al. (2014)
preservation for
endometriosis
Second surgery for ++ Vercellini et al. (2009a,b)
endometriosis is poorly
effective on infertility

Take home Estro-progestins prevent +++ Vercellini et al. (2010, 2013)

messages endometrioma formation
Why
The causes of follicle loss during
endometriosis
damage ovarian
surgery for endometriosis involve
reserve
injury to blood vessels and stroma
and removal of healthy cortex.
How can we
preserve fertility
in endometriosis 1. Endometrioma.
2. Pseudocapsule of the endometriomal.

Evidence in
3. Healthy cortex containing significant number of follicles stripped with
fertility
preservation for
pseudocapsule.
endometriosis
4. Coagulation of vascular bed.
5. Blood vessels injuries.
Take home 6. Oedema / inflammation.
messages
7. Adhesiolysis and subsequent injuries of the bloody vessels.
Why
endometriosis
damage ovarian
reserve The role of fertility preservation in patients with
endometriosis
How can we L. Carrillo, D. S. Seidman, E. Cittadini, D. Meirow
preserve fertility
in endometriosis

Patients affected with severe endometriosis are at significant risk for

Evidence in ovarian tissue damage.
fertility
preservation for
endometriosis
Enhanced loss of ovarian reserve may also result from the damaging
effect of the pathologic process on follicle reservoir even without
Take home
messages
surgical interventions.
Why
endometriosis
damage ovarian
reserve Endometriomas as a possible cause of reduced ovarian reserve in
women with endometriosis

How can we
preserve fertility
in endometriosis

Objective
Evidence in To evaluate the adverse effects of endometriomas on ovarian reserve
fertility
preservation for
Laparoscopic cystectomy is recommended for endometriomas larger than
endometriosis
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
Why
endometriosis
damage ovarian endometrioma
reserve

LAPAROSCOPIC SURGERY cystectomy

How can we
preserve fertility
in endometriosis

BIOPSY
Evidence in
fertility
preservation for
endometriosis 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
Why
endometriosis
damage ovarian • Follicular density in cortex from ovaries with endometriomas less
reserve
than 4 cm in size is significantly lower than in cortex from contra-
lateral normal ovaries
How can we • Fibrosis was frequently evidenced in cortex derived from
preserve fertility
in endometriosis endometriomas

Evidence in
fertility
preservation for
endometriosis
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

Why
endometriosis
damage ovarian DO ENDOMETRIOMAS INDUCE
reserve
AN INFLAMMATORY REACTION
IN NEARBY FOLLICLES ?
How can we
preserve fertility
in endometriosis
this study examined whether intra-ovarian endometriosis is
associated with a local inflammatory reaction and whether
Evidence in inflammation affects follicular development and oocyte quality
fertility
preservation for
endometriosis

Take home
messages

Opoien et al. Hum Reprod, 2013

Why
endometriosis
damage ovarian
The comparison cytokine concentrations in the follicular
reserve fluid from the two ovaries

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis 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

Why Ovarian reserve in women with and without endometrioma
endometriosis
damage ovarian
reserve
No Variable Authors Endometriosis (n) Controls (n) P value

1 AMH Shebl 2.57 ± 2.0 3.46 ± 2.30 < 0.001

How can we
Hwu 2.34 ± 0.19 3.31 ± 0.08 < 0.001
preserve fertility
in endometriosis Ercan 1.62 ± 1.09 2.06 ± 0.51 NS
Uncu 2.81 4.20 0.02

2 AFC Almog 7.5 ± 0.7 9.3 ± 0.9 P value

Evidence in
Biacchiardi 3.3 ± 3.2 8.4 ± 6.0 < 0.05
fertility
preservation for < 0.0001
endometriosis
3 COH Suzuki 4.40 ± 2.99 5.34 ± 2.99 0.0037
results Kumbak 13.9 (5–33) 16.4 (5–37) 0.03

Take home
Opøien 8±5.3 9.2 ± 5.6 < 0.01
messages
Why
endometriosis
damage ovarian Fertility preservation in women with endometriosis: for
reserve
all, for some, for none ?
Edgardo Somigliana, Paola Vigano, Francesca Filippi, Enrico Papaleo, Laura Benaglia, Massimo
How can we Candiani, and Paolo Vercellini
preserve fertility
in endometriosis

Overall, clinical data on egg and ovarian cortex freezing in women

Evidence in
with endometriosis are very scanty.
fertility
preservation for
endometriosis
On this basis, advocating systematic fertility preservation is utterly
premature.
Take home
messages

Hum Reprod, 2015

Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in In endometriosis, various mechanisms can impair ovarian function

fertility
preservation for and diminish ovarian, particularly bilateral or repeated cystectomy.
endometriosis

Fertility preservation could represent an option for women with

Take home
messages
endometriosis but still remains controversial.
Why Fertility preservation techniques for patients with
endometriosis
damage ovarian
endometriosis
reserve
Embryo cryopreservation
Pros Cons
How can we
preserve fertility • Documented results especially • Risk of infections related to oocyte
in endometriosis when embryos are frozen retrieval and abscess formation
• No risk of procedure-related • Poor quality oocytes, embryos
ovarian reserve depletion (controversial data)
Evidence in • The pick-up may avoid contact of • Need of ovarian stimulation that
fertility the oocyte with the detrimental might cause the progression of the
preservation for
endometriosis
effect of the peritoneal fluid disease (controversial data)
• Patients suffering from • Need of repeated IVF cycles in
endometriosis are frequent order to collect an adequate
costumers of ART procedures number of oocytes that can be
Take home
stored
messages
 Fertility preservation techniques for patients with
Why
endometriosis endometriosis
damage ovarian
reserve Ovarian tissue cryopreservation
Pros Cons
How can we • Highly effective technique for • Laparoscopic procedure in these
preserve fertility fertility preservation patients may be more difficult and
in endometriosis
• Easily performed during the surgical risky
intervention for the disease • Storing tissue surrounding cyst or
• No need of ovarian stimulation pseudo capsule—number and
Evidence in • Frozen tissue is spared from quality of follicles are questionable
fertility
preservation for
potential destruction in cases of • Storing healthy tissue remote from
endometriosis disease recurrence cyst may result in ovarian damage
and reduced ovarian reserve
• No results, so far, have been shown
Take home
in this class of patients
messages
SWOT analysis of cryopreserving oocytes for fertility
preservation in women with endometriosis
Why
endometriosis
damage ovarian In women with endometriosis there are currently no
reserve
published data on the cryo-survival and clinical outcomes
How can we of cryopreserved oocytes.
preserve fertility
in endometriosis

The effect of endometriosis on follicle / oocyte quality is a

Evidence in
fertility debated issue and whether there is a deleterious effect of
preservation for
endometriosis
the disease on vitrification, warming/thawing and
reproductive out-comes remains unknown.
Take home
messages
Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Take home
messages
Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Take home
messages Figure 1. GDF-9 expressions in both the tested groups
 PROS AND CONS (1)
Why

ENDOMETRIOSIS ASSOCIATED INFERTILITY

endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

SURGERY NOT SURGERY

Evidence in
fertility
preservation for
endometriosis

Take home
messages
 PROS AND CONS (2)
Why
endometriosis
damage ovarian
reserve ENDOMETRIOSIS ASSOCIATED INFERTILITY

How can we SURGERY NOT SURGERY

preserve fertility
in endometriosis

Evidence in
√
fertility NON IVF IVF
preservation for
endometriosis

COS + Natural conception

Take home
messages COS + IUI
Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

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

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Take home
messages

Muzii et al. Fertil Steril, 2015

Why
endometriosis
Second surgery for recurrent endometriomas is more
damage ovarian harmful to healthy ovarian tissue and ovarian reserve
reserve
than first surgery

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Take home
messages

Muzii et al. Fertil Steril, 2015

Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis
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

 Group of subjects
Why
endometriosis
damage ovarian 1. Group A consisted of 176 women with pelvic endometriosis but without
reserve
ovarian endometriomas diagnosed by laparoscopy.

2. Group B consisted of 125 women who had previously undergone

How can we laparoscopic endometrioma cystectomy; the endometriomas were not
preserve fertility
in endometriosis
recurrent before IVF-ET/ICSI cycles.

3. Group C consisted of 38 women with recurrent endometriomas after a

previous cystectomy; the endometriomas were not aspirated
Evidence in
transvaginally before IVF-ET/ICSI cycles.
fertility
preservation for
endometriosis 4. 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

Why IVF/ICSI OUTCOMES
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Long and ultra long protocol

Take home
messages

Xing et al. Master Sociomed, 2016

Why
endometriosis
damage ovarian
CLINICAL STUDIES ON THE USE OF FERTILITY PRESERVATION
reserve TECHNIQUES IN WOMEN WITH ENDOMETRIOSIS

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

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
Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Take home
messages

Wiweko et al. IVF Lite, 2014

Why
endometriosis
damage ovarian
reserve

How can we
preserve fertility
in endometriosis

Evidence in
fertility
preservation for
endometriosis

Take home
messages

Wiweko et al. IVF Lite, 2014

Why 1
endometriosis
2
damage ovarian
reserve

4
5
How can we
preserve fertility
in endometriosis
3
6

Evidence in
fertility
preservation for
endometriosis
7

Take home
messages Algorithm for management of infertility associated with endometriosis IVF=in-vitro fertilization. ART=assisted
reproductive technologies. GnRH=gonadotropin-releasing hormone. ICSI=intra cytoplasmic sperm injection

Endometriosis and infertility: pathophysiology and management. de Ziegler, Dominique

Lancet, The, Volume 376, Issue 9742, 730-738
Fertility preservation may be of interest for women with endometriosis, in particular
in women with bilateral unoperated endometriomas and in those who previously had
excision of unilateral endometriomas and require surgery for a contralateral
recurrence.
Why
endometriosis 1. Endometrioma reduced ovarian reserve and increased
damage ovarian
reserve apoptosis of granulosa cells.

2. Second surgery of recurrent endometrioma is more harmful to

How can we ovarian healthy tissue.
preserve fertility
in endometriosis
3. Transvaginal ultrasound guided aspiration should be considered
in recurrent endometrioma.
Evidence in
fertility 4. Long or ultra long protocol is a preferable option in controlled
preservation for ovarian stimulation for patient with endometriosis.
endometriosis

5. Emergency IVF and fertility preservation are management

option in recurrent endometrioma.
Take home
messages
Why
endometriosis FERTILITY PRESERVATION
damage ovarian
reserve

1. Fertility issues are a major concern in the long-term treatment

How can we
preserve fertility
strategy in women with endometriosis.
in endometriosis
2. The refining of stimulation protocols and oocyte vitrification in
the last decade has created new possibilities for women who
Evidence in
fertility wish to preserve their fertility or postpone motherhood.
preservation for
endometriosis 3. Data on fertility preservation in women with endometriosis is
scarce and there is no consensus on the strategy to adopt
Take home
messages
 ACKNOWLEDGEMENT

Indonesian Reproductive Medicine

Research and Training Center (INA – REPROMED)