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Endometriosisrelated infertility:

A global approach in 2014 ?

Université Paris Descartes,

Sorbonne Paris Cité

Faculté de Médecine, AP-HP,

GHU Ouest, CHU Cochin, Paris, France

Professor Charles Chapron, M.D

Head of Department,

GynecologySurgical unit:

C Chapron, B Borghese, P Santulli, H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, A Bititi, P Marzouk, L Marcellin

Medical unit: A Gompel, G Plu-Bureau, L Maitrot

Reproductive Endocrinology unit:D de Ziegler, P Santulli, V Gayet, I Streuli, FX Aubriot

Intestinal surgeryB Dousset, M Leconte

RadiologyAE Millischer

Laboratory: GeneticD Vaiman, F Mondon, S Barbaux

Laboratory: ImunulogyB Weill, F Batteux, C Nicco, C Chéreau

Laboratory: Reproductive biologyJP Wolf, V Lange, K Pocate,JM Kuntzman, C Chalas

Statistical unitF Goffinet, PY Ancel

D. de Ziegler, Professor and Head, Reproductive Endocrinology and Infertility unit,A. Gompel, Professor and Head, Medical Gynecological unit,

C. Chapron, Professor and Chair, Dpt Gynecology Obstetrics II and Reproductive Medicine

Endometriosis and infertility: PathogenesisPelvic cavity:

Inflammation-related process interfereswith sperm-oocyte intercations:

Reduced chances of IN VIVO fertilization

Uterus: Alterations of eutopic endometrium:

- Activation CYP-19- Resistance to P4 (PR-D)

Ovaries: Decreased ovarian response to COH:

- More FSH / hMG needeed- Less oocytes obtained

Receptivity

de Ziegler, Borghese and Chapron The Lancet (2010)

Endometriosis related infertility

- Specifications and pathogenesis

- What are the therapeutic options ?

- How to choose between the therapeutic options?

- Proposition for a strategy

Endometriosis - related infertilityManagement options

Endometriosisrelated infertility

Expectant

Ovarian suppression

Surgery

Controlled ovarian

hyperstimulation

Intracervicaland intrauterine

insemination

Assisted Reproductive Technologies:

FIV, ICSI Association of medical and surgical Ttt

(per and/or post op)

Endometriosis related infertilityManagement options

- Medical treatment

- Surgery

- Assisted Reproductive Technologies

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Endometriosis related infertilityManagement options

- Medical treatment

- Surgery

- Assisted Reproductive Technologies

Hughes et al., Cochrane Database (2007)

Endometriosis related infertilityOvarian Suppression versus Placebo

All options are contraceptive

Endometriosis related infertilityManagement options

- Medical treatment

- Surgery

- Assisted Reproductive Technologies

Vercellini et al., Human Reprod 2009;24:254-69.

ConsiderSx + 6-18 Mo

in vivoCumulative PR

50%

Time (months)6 18

Endometriosis - related infertility

≥ 12 months

< 12 months

Pregnancy: 0.79 (95% CI: 0.46–1.35)

Vercellini et al., RBMO (2010)

Endometriosis - related infertility :Postoperative delayed initiation of attempted conception

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Endometriosisis - related infertility

Marcoux et al.,NEJM (1997)

Deep infiltrating endometriosis (DIE) N # IUP % IUP

Coronado et al., 1990 33 13 39.4 Nehzat et al., 1994 8 1 12.5 Bailey et al., 1994 49 24 48.9 Jerby et al., 1999 7 3 42.8 Chapron et al., 1999 30 15 50.0 Possover et al., 2000 15 8 53.3 Redwine and Wright, 2001 23 7 30.4 Kavallaris et al., 2003 38 18 47.4 Fedele et al., 2004 50 17 34.0 Thomassin et al., 2004 15 4 26.7 Chopin et al., 2005 78 42 53.8 Daraï et al., 2005 22 10 45.5 Fleisch et al., 2005 17 4 23.5 Keckstein et al., 2005 95 47 49.5 Mohr et al., 2005 58 23 39.6 Lyons et al., 2006 3 3 100.0 Vercellini et al., 2006 44 15 34.1 Ferrero et al., 2009 46 22 47.8 Meuleman et al., 2009 33 16 48.5 Stepniewska et al., 2009 30 12 40.0 Total 694 304 43.8

43.8%

Laparoscopic excision of endometrioma (OMA) N # IUP % IUP

Daniell et al., 1991 32 12 37.5 Marrs et al., 1991 23 7 30.4 Bateman et al., 1994 21 9 42.8 Crosignani et al., 1996 22 6 27.3 Montanino et al., 1996 11 5 45.5 Donnez et al., 1996 814 414 50.8 Sutton et al., 1997 66 30 45.5 Beretta et al., 1998 9 6 66.7 Milingos et al., 1998 32 17 53.1 Busacca et al., 1999 67 39 58.2 Jones and Sutton, 2002 39 15 38.5 Alborzi et al., 2004 32 19 59.4 Fedele et al., 2006 90 29 32.2 Vercellini et al., 2006 237 128 54.0 Total 1495 736 49.2

49.2%

De Ziegler, Borghese and Chapron Lancet (2010)

OMA

DIE

Stages I and II

Meuleman et al., Ann Surg (2013)

Deep endometriosis related infertility :Laparoscopic surgery in women

with moderate to severe endometriosisPatientsoperated

Wishing to conceive

Pregnant

127 94 (74%) 48 (51%)

76 54 (71%) 27 (50%)

44%

58%

1 Y

ear

2 Y

ears

3 Y

ears

73%

Meuleman et al., Ann Surg (2013)

Deep endometriosis related infertility :Laparoscopic surgery in women

with moderate to severe endometriosis

Only 41% conceived spontaneously

Bowel resection p

Yes No

Recurrence 2/76 (3 %) 6/127 (5%) < 0.05

Intestinal DIE: Surgical techniques

Spontaneousconception

IVFtreatment

Expectation of pregnancy

Time after surgery (days)

Stepniewska et al., Hum Reprod (2009)Bowel resection Residuel bowelendometriosis

Bowelresection

Residuel bowelendometriosis

Conception No Conception

1 year

No bowelendometriosis

2 years

4 years

Pre opAMH levels≥ 3.1ng/ml

Raffi et al., JCEM (2012)

Laparoscopic excision of OMAs

Muzii et al., Fertil Steril (2002)

Oma cyst wall: no follicule

Oma cyst wall: Scanty primordial follicule

Oma cyst wall: Two primordial follicule

Ovarian cysts Recognizable ovariantissue adjacent to OC wall

N n %

OMAs 26 14 54

Serous 7 0 0

Dermoid 6 1 17

Mucinous 3 0 0

Total 42 15 36

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Deep endometriosis: Complications

....................................................................................

Complicat ion Observed incidence(%)

Neurogenic bladder dysfunction 4–10

Rectovaginal fistula formation 2–10

Blood transfusion 2–6

Inadvertent rectal perforation 1–3

Anastomotic leakage 1–2

Pelvic abscess 1–2

Temporary diverting loop ileostomy/colostomy

0.5–1.5

Intraoperative ureteral lesion 0.5–1

Post-operative ureteral fistula formation 0.5–1

Post-anastomotic rectal stenosis 0.5–1

Post-anastomotic ureteral stenosis 0.5–1

Vercellini et al., Hum Reprod (2009)

Surgery for endometriosis (n = 790 patients)

No (n = 471; 60%) Yes (n = 309; 40%)

SUP 109 (23.1%) 22 (7.1%)

OMA 152 (32.3%) 45 (14.6%)

DIE 210 (44.6%) 242 (78.3%) 4.5 (3.2 - 6.2)

- DIE isolated 144 (68.6%) 138 (57.0%)

- DIE associated OMA 66 (31.4%) 104 (43.0%)

Endometriotic lesions Previous surgery for Osis OR 95% CI

Worst DIE lesion Previous surgery for Osis OR 95% CI

No (n = 471; 60%) Yes (n = 309; 40%)

USL 71 (34.0%) 32 (13.3)

Vagina 21 (10.0%) 16 (6.7%)

Bladder 18 (8.6%) 17 (7.0%)

Intestine 77 (36.8%) 159 (66.0%) 3.2 (2.1 - 4.8)

Ureter 22 (10.5%) 17 (7.0%) (Sibude and Chapron, Obstet Gynecol (in press)

Coef = 0.62, 95% CI 0.47-0.77, p<0.0001

Nu

mb

er

of

DIE

le

sio

ns

Determinants for existence of DIE: Results with multiple logistic regression analysis

AOR (95% CI) p

Previous surgery (yes vs no) 2.7 (1.7-4.3) <0.001

Previous surgery for endometriosis (n = 790 patients)

(Sibiude and Chapron, Obstet Gynecol (in press)

Endometriosis:Surgical management

Disease Surgery

Progression

Recurrence

Unnecessary

Inappropriate

?

Endometriosis:and pain

SUP

OMAs

DIE

DIE

The Lancet (2010)

Vercellini et al., Am J Obstet Gynecol (2006)Vercellini et al., Hum Reprod Update (2009)

Reduce rate of:

- Recurrence DM OR : 0.15 ; CI 0.06 - 0.06

- Recurrence DP OR : 0.08 ; CI 0.01 - 0.51

- Recurrence NCPP OR : 0.10 ; CI 0.02 - 0.5656

Hart (2005)

Sutton (1994)

Surgery

Endometriosis related infertilityManagement options

- Medical treatment

- Surgery

- Assisted Reproductive Technologies

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Canada 2004

Australia 2009

France2001-2005

USA2009

IVF ICSI IVF + ICSI IVF + ICSI IVF + ICSI

Primary diagnosis Pregnancies(% per retrieval)

Pregnancies(% per retrieval)

Pregnancies (% per initiated cycle)

Pregnancies(% per initiated cycle)

Live births(% per aspiration)

Male factor 31.0% 37.7% 24.9% 20.1% 37.6%

Tubal factor 33.5% 29.4% 23.5% 21.0% 32.2%

Idiopathic 36.4% 34.7% 23.7% 21.6% 33.7%

Endometriosis 37.8% 41.4% 25.7% 23.7% 35.3%

Ovulatory disorder 35.6% 36.3% 23.2% 22.6% 40.4%

Other 37.6% 27.9% 18.5%% 27.7%

Gunby J et al. Fertil Steril (2008)Yueping A et al. Assisted Reproductive technology in Australia and New Zeland (2009)

FIVNAT (2001-2005)USA, 2009 aspirations: National Center for Chronic Disease Prevention and Health Promotion Division of Reproductive Health

Endometriosis: ART outcome

Harb et al., BJOG (2013)

Singleton pregnancies resulting from IVF/ICSI: Obstetric and perinatal outcomes

Outcome OR 95% CI

Ante-partum haemorrhage 2.49 (2.30 - 2.69)

Congenital anomalies 1.67 (1.33 - 2.09)

Hypertensive disorders of pregnancy 1.49 (1.39 - 1.59)

Preterm rupture of membrane 1.16 (1.07 - 1.26)

Caesaren section 1.56 (1.51 - 1.60)

Low birth weight 1.65 (1.56 - 1.75)

Perinatal mortality 1.87 (1.48 - 2.37)

Preterm delivery 1.54 (1.47 - 1.62)

Gestational diabetes 1.48 (1.33 - 1.66)

Induction of labor 1.18 (1.10 - 1.28)

Small for gestational age 1.39 (1.27 - 1.53)

Pandey et al., Hum Reprod (2012)

ART: Reasons for and predictors of discontinuation

Gameiro et al., HR Update (2012)

Infertiles patients with Omas:

Garcia-Velasco et al., Fertil Steril (2004)

Unoperated Bilateral OMAs: ART outcome

Benaglia et al., Fertil Steril, (2013)

Characteristics Case n = 39 Control n = 78 p

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OMAs and oocytes quality: IVF cycles

Filippi et al., Fertil Steril, (2014)

Surgery versus ARTSurgery ART

Fertility results

Limits Specific complicationsUnnecessary surgeriesOvarian reserve damage

Specific complicationsPost ponction infections No efficient for pain

Advantages Pelvic pain treatmentAvoid risk of ovariancancer

OMA surgery not necessary

Endometriosis related infertility

- Specifications and pathogenesis

- What are the therapeutic options ?

- How to choose between the therapeutic options?

- Proposition for a strategy

Endometriosis: n = 870 patients

Pelvic pain Infertility

Asymptomatic

202 23.2%

SUP 21 10.4%OMA 36 17.8%DIE 145 71.8%

* Oma + 76 52.4%* Oma - 69 47.6%

453 52.1%

SUP 52 11.5%OMA 105 23.2%DIE 296 65.3%

110 12.6%

SUP 25 22.7%OMA 59 53.6%DIE 26 23.6%

Chapron and Santulli, (2013)

105 120%

SUP 49 46.7%OMA 29 27.6%DIE 27 25.7%

* Oma + 9 33.3%* Oma - 18 66.7%

p < 0.001

≠

OMAs and Pelvic Pain: Relationship

Hum Reprod (2012)

OMA

DIE

OMAs and Pelvic Pain: Relationship

Hum Reprod(2012)

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OMA: Factors associated with DIE in the multiple logistic regression analysis

Lafay – Pillet and Chapron Hum Reprod (2014)

Parameters Ad OR 95% CI AUC

0.84

Duration of pain > 24 months 3.8 1.9 - 7.7

VAS DP > 5 or GI symptoms > 5 6.0 2.9 - 12.1

Severe dysmenorrhea 3.8 1.9 - 7.6

Infertility (primary or secondary) 2.5 1.2 - 4.9

Number of DIE score points contributedby each factor and clinical prediction rule.

Lafay – Pillet and Chapron Hum Reprod (2014)

OMA:

Total Score PointsSum

Predicted risk(95% CI)

< 13: Low risk 10% (7 - 15)

≥ 35: High risk 88% (83 - 92)

OMA: Performance of clinical scoringsystem to predict associated DIE

Lafay – Pillet and Chapron Hum Reprod (2014)

Training sample

Validation sample

Deep endometriosis:Frequency of associatedovarian endometriomas

(n = 636 patients)

Main lesion Associated OMAs

N n %

Bladder 51 8 15.7

USL 279 49 17.6

Vagina 93 19 20.4

Ureter 29 13 44.8

Intestine 184 86 46.7

Total 636 175 27.5

Chapron et al., Fertil Steril (2010)

Deeply infiltrating endometriosis (n = 500 patients).Results according to the presence of OMA

OMA - OMA + p - value

Mean number of DIE lesions 1.64 ± 1.0 2.51 ± 1.72 < 0.0001

rAFS scores

Implants 6.7 ± 4.9 28.1 ± 10.1 < 0.0001

Adhesions 16.5 ± 23.7 36.2 ± 28.7 < 0.0001

Total 23.6 ± 25.7 65.6 ± 33.1 < 0.0001

Chapron et al., Fertil Steril (2009)

Adenomyosis and intestinal DIEAssociated OMA

Intestinal DIE Ad Ose post + Ad Ose post - p OR (95% CI)

N % N %

OMAs + 37 53.6 9 30.0 0.025 2.7 (1.1 - 6.7)

OMAs - 32 46.4 21 70.0

Chapron, (in preparation)

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Painful OMAsModern management

OMAs DIEVAS

≥ 7« Severe » OMAs

IntestineUreter

USLVaginaBladder

« Isolated » OMAs

Preoperative work-up imaging:Referral center

Chapron – Santulli et al., Hum Reprod (2012)

< 7

Painful ovarian endometrioma

Painful ovarian endometrioma Painful ovarian endometrioma

DIE: Excisional surgeryDeep infiltrating endometriosis (DIE) N # IUP % IUP

Coronado et al., 1990 33 13 39.4 Nehzat et al., 1994 8 1 12.5 Bailey et al., 1994 49 24 48.9 Jerby et al., 1999 7 3 42.8 Chapron et al., 1999 30 15 50.0 Possover et al., 2000 15 8 53.3 Redwine and Wright, 2001 23 7 30.4 Kavallaris et al., 2003 38 18 47.4 Fedele et al., 2004 50 17 34.0 Thomassin et al., 2004 15 4 26.7 Chopin et al., 2005 78 42 53.8 Daraï et al., 2005 22 10 45.5 Fleisch et al., 2005 17 4 23.5 Keckstein et al., 2005 95 47 49.5 Mohr et al., 2005 58 23 39.6 Lyons et al., 2006 3 3 100.0 Vercellini et al., 2006 44 15 34.1 Ferrero et al., 2009 46 22 47.8 Meuleman et al., 2009 33 16 48.5 Stepniewska et al., 2009 30 12 40.0 Total 694 304 43.8

The Lancet (2010)

43.8%

Intestinal DIE and infertility: ICSI - IVF

Ballester et al., Hum Reprod (2012)

CMR after ICSI - IVF

Mathieu d’Argent et al., Fertil Steril (2011)

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Intestinal DIE and infertility: ICSI - IVF

Ballester et al., Hum Reprod (2012)

Adenomyosis

Age

AMH

Endometriosis: AMH levels according to the type of Osis lesions and prior OMA surgery

Streuli, de Ziegler and Chapron, Hum Reprod (2012)

Endometriosis: AMH levels according to the presence of OMAs and prior OMA surgery

Streuli, de Ziegler and Chapron, Hum Reprod (2012)

Endometriosis: Logistic regression analysisof factors preidcting AMH levels < 1 ng/ml

Streuli, de Ziegler and Chapron, Hum Reprod (2012)

Fertilitypreservation:

Oocyte vitrification

Rienzi et al., Hum Reprod (2012)

Effect of patients and cycle characteristics on delivery obtained with vitrified oocytes.

(logistic regression)

*

* *Endometriosis related infertility

- Specifications and pathogenesis

- What are the therapeutic options ?

- How to choose between the therapeutic options?

- Proposition for a strategy

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Take home messages

Pelvic pain

Infertility

Take home messages

Strategy

- Multidisciplinary management

Endometriosis

and

Patients

- Global approach

Surgery

Medical Ttt

ART

SUP OMAs DIE

Adenomyosis

Pelvic pain

Infertility

1

1

de Ziegler, Borghese and ChapronThe Lancet (2010)

In principleNO surgery

Ovarian suppression(3 months)

IVF / ICSI

« EmergencyART »

Infertilitywork-up

Ovarian reserveTime available for In Vivo

Ovarian endometriomais the « KEY lesion »

Risk factor for DIE severity

Ovariandamage

Risk factor for associated

Adosis to DIE

Take home message

Deep infiltrating endometriosis

Painful OMA

Ovarian endometrioma:Modern management

Infertility Pelvic painA

Referral center

VAS < 7: Isolated Omas

VAS ≥ 7: Omas associated

with severe DIE

Classical center

CB

?

New concept:« Emergency ART »

Surgery

SurgeryART withoutsurgery

Previous ART ?- Medical Ttt ?

- Fertilitypreservation ?

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Take home messages

Best indication for surgery

in cases of endometriosis

related infertility is

pelvic pain

Take home messages

Necessity to reconsider the strategy:

Surgery ART? ? ?

Take home messages

Surgery:

* Avoid unnecessary procedures

* Precise the best moment

* New concept: Once onlyin « the endometriosis life »