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Is endometriosis relevant for ART success?
Carlos Calhaz-Jorge
XVI Annual Meeting of the MSRM - Opatija, Set 2019
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None
Conflict of interest
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Is endometriosis relevant for ART success?
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Endometriosis(n=531)
Unexplained infertility(n=737)
Crude OR (95% CI)
P
I – 26.5% / II – 21.5%/ III- 24.9% / IV – 27.1%
LBR 124 (24.1%) 217 (29.4%) 0.76 (0.59-0.98) 0.035
Strong points:- All patients submitted to laparoscopy- 1st cycle- LBR as primary endpoint
Weak points:- Retrospective- No information on previous surgery for endometriosis- Unknown time lag
Is endometriosis relevant for ART success?
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Is endometriosis relevant for ART success?
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Is endometriosis relevant for ART success?
OR 0.85 [0.74,0.98]
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Is endometriosis relevant for ART success?
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Agenda
● Why is this topic so complex?
● How can endometriosis affect ART results?
● Impact of ART on endometriosis
● Obstetric implications of endometriosis
Is endometriosis relevant for ART success?
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● Why is endometriosis such a complex topic?
▪ the definition of the disease
▪ the severity grading
▪ the relationship with infertility
Is endometriosis relevant for ART success?
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ENDOMETRIOSIS
ENDOMETRIOTIC
DISEASE
Subtle
Lesion
Black
Puckered
Lesion
ImplantationMetaplasia
InfiltrationLUF-Immunology
Remodelling
Ovarian
‘Chocolate’
CystAdhesions
Deep
Recto-
Vaginal
Koninckx P, 1994
Endometriosis as a disease
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Why is endometriosis such a complex topic?
● the definition of the disease
● the severity grading
ASRM classification
Endometriosis classification
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Why is endometriosis such a complex topic?
● the definition of the disease
● the severity grading
● the relationship with infertility
Is endometriosis relevant for ART success?
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How can endometriosis affect ART results?
● Lower ovarian response
● Oocyte retrieval difficulties
● Reduced oocyte quality (embryo quality)
● Endometrial receptivity disturbance
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How can endometriosis affect ART results?
● Lower ovarian response
Higher cancellation rate
More medication
Less oocytes
Lower fecundation rate
The ovarian reserve issue
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Prospective cohort study116 patients (58 surgically treated of endometrioma)
No difference in baseline AMH values:
- in patients with at least 1 endometrioma ≥ 5cm vs those with <5 cm.
- In the 19 patients with bilateral endometriomas when compared with the 39 with unilateral endometrioma.
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How can endometriosis affect ART results?
● Lower ovarian response
● Oocyte retrieval difficulties
● Reduced oocyte quality (embryo quality)
● Endometrial receptivity disturbance
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How can endometriosis affect ART results?
• Prospective• Pts with endometrioma (n=56) vs no endometrioma (n=227)• Results:
• Need to transfix the cyst – 8 cases• Contamination of follicular fluid – 9 cases• No. of oocytes not different from the expected• No pelvic infections• No cyst ruptures
• Key message:
The magnitude of the increased difficulties in oocyte retrieval in women with ovarian endometriomas is modest and of doubtful clinical relevance.
RBM Online 2018; 37(1): 77-84.
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How can endometriosis affect ART results?
● Lower ovarian response
● Oocyte retrieval difficulties
● Reduced oocyte quality (embryo quality)
● Endometrial receptivity disturbance
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How can endometriosis affect ART results?
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Pellicer et al, 1994
• Prospective 1-donors and recipients w/out endo (n=44)
2-donors with and recipients w/out endo (n=14)
3-donors w/out and recipients with endo (n=16)
• Group 2: Lower IR and PR/transfer
Sung et al, 1997
• Retrospective
• 239 OD cycles
55 recipients with endo – all stages
184 recipients w/out endo
• No difference in IR and PR
Diaz et al, 2000
• Prospective matched case-control study
25 recipients with endo III-IV
33 recipients w/out endo
a single donor to one recipient with plus one w/out endo
• No difference in IR, PR and LBR
How can endometriosis affect ART results?
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How can endometriosis affect ART results?
Multiple suggested mechanisms:
▪ dysregulation of steroidogenesis
▪ disruption of intrafollicular environment
▪ epigenetic effects on the oocyte
● Oocyte quality (embryo quality)
Sanchez et al, 2017
Conclusion:• No robust evidence• Further investigation are needed
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How can endometriosis affect ART results?
n=305(1880 blastocysts)
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How can endometriosis affect ART results?
7 patients w/ endometriomas (16 oocytes) and 5 healthy donors (16 oocytes)
Fertility preservation (=oocyte cryopreservation) in endometriosis patients
Oocytes from patients showed a different transcriptomic profile compared with those of donors. Patients’ oocytes exhibited similar gene expression patterns independently of whether oocytes came from an affected or unaffected ovary.
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How can endometriosis affect ART results?
● Lower ovarian response
● Oocyte retrieval difficulties
● Reduced oocyte quality (embryo quality)
● Endometrial receptivity
Suggested abnormalities in:
▪ endometrial gene expression
▪ angiogenesis
▪ adhesion molecules
▪ local response to progesterone
▪ immune populations (and their behaviour)
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How can endometriosis affect ART results?
What can we do to offer the best to our patients?
● Different ovarian stimulation protocols?
● Surgery prior to ART?
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Ovarian stimulation in patients with endometriosis
ESHRE Guidelines in endometriosis, 2013
Clinicians can prescribe GnRH agonists for a period of 3 to 6 months
prior to treatment with assisted reproductive technologies to improve
clinical pregnancy rates in infertile women with endometriosis (Sallam, et
al., 2006)
ESHRE Guideline on Management of women with endometriosis, 2013 – Grade B recommendation
Previous surgery
Dicker et al, 1992
• RCT? 35 pts – 6m GnRH ag
32 pts – immediate COS
IVF or ICSI
?? CPR: 25 vs 3.9%/ cycle
Rikes et al, 2002
• RCT 25 pts – 3m GnRH ag
25 pts – immediate COS
IVF
All (<60 months)
No endometriomas
Ongoing PR: 80 vs 55%/ cycle
(ET: 3.28 vs 3.04)
Surrey et al, 2002
• RCT 55 pts – 3m GnRH ag
55 pts – immediate COS
IUI (n=63) or IVF (n=47)
All CPR not different in IVF subgroup
de Ziegler et al. Fertil Steril, 2010Suggested conclusion of a pilot trial:
… 6 to 8 weeks of continuous OC use before ART not only improves outcomes in endometriosis but possibly is as effective as 3 months of GnRH-agonist treatment before ART. However, these findings await confirmation in randomized trials
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Rodriguez-Purata et al, 2013
• Retrospective
• Diagnosis by surgery or US
• “physician preference”
919 cycles Ag (long protoc)
261 Antag
• PR not different
Ovarian stimulation in patients with endometriosis
Drakopoulos et al, 2018
• Retrospective
• 1st cycle (no previous hormonal treatment for 6 months)
• 100 to 450 IU/d – clinician discretion
• IVF or ICSI (or both)
• Primary outcome – LBR
• GnRH antag (fixed dose) vs Agonist (long protocol)
• 386 patients (= 386 cycles):
117 endo I-II (42 ag vs 75 antag),
269 endo III-IV (143 ag vs 126 antag)
• Higher total dose and duration of stimulation with agonist
• No other difference, namely CPR and LR
Cantor et al, 2019
• Retrospective
• Endometrioma and a recent failed IVF cycle
- Depo-leuprolide - 60 days (n=54)
- Depot-leuprolide + Letrozole (5mg/d) - 60 days (n=50)
• CPR – 50% vs 22%
• LBR – 40% vs 17%
(in favour of the Letrozole group)
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• RCT – Antag vs Ag (long protocol)• 246 patients = 246 ICSI cycles
98 endo I-II (no endometrioma), 81 endometriomas surgically treated, 67 endometriomas not operated
Ovarian stimulation in patients with endometriosis
Pabuccu et al, 2007
No difference in duration of stimulation, no. of oocytes, fertilization, implantation or pregnancy rates
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Surgery prior to ART in patients with endometriosis?
Donnez J, 2018
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Prospective cohort study116 patients (58 surgically treated of endometrioma)
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Surgery prior to ART in patients with endometriosis?
Goodman et al, 2016
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Surgery prior to ART in patients with endometriosis?
Wu CQ et al, 2019
Fig.6 Forest plot of random-effects meta-comparing clinical pregnancy rates per cycle in surgically
and expectantly managed infertile patients with endometriomas
Does endometrioma surgery prior to IVF improve its result?
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Fig.2 Forest plot of random-effects meta-comparing live birth rates per cycle in surgically and expectantly
managed infertile patients with endometriomas
Wu CQ et al, 2019
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● Favours surgery as 1st treatment option:
▪ Doubt concerning the endometrioma nature
▪ Intense pelvic pain
● Favours IVF as 1st treatment option:
▪ Older age
▪ Decreased ovarian reserve
▪ Associated infertility factors (male, tubal, … )
▪ Endometrioma recurrence
▪ Previous surgery for endometriosis
There is no scientific argument for systematic endometrioma surgery before IVF (Somigliana, 2015)
Surgery prior to ART in patients with endometriomas
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Somigliana et al, 2015
Surgery prior to ART in patients with endometriosis?
● The particular case of deep endometriosis
At present, evidence is insufficient to definitely
support a causal relationship or to claim a decisive
benefit of surgery.
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Agenda
● Why is this topic so complex?
● How can endometriosis affect ART results?
● Impact of ART on endometriosis
● Obstetric implications of endometriosis
Is endometriosis relevant for ART success?
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● Consequences of COS on endometriosis/omas
Impact of ART on endometriosis
In infertile women with endometriosis, clinicians may offer treatment
with assisted reproductive technologies, since cumulative endometriosis
recurrence rates are not increased after controlled ovarian stimulation
for IVF/ICSI (Benaglia, et al., 2011, Benaglia, et al., 2010, Coccia, et al., 2010,
D'Hooghe, et al., 2006).
ESHRE Guideline on Management of women with endometriosis, 2013 – Grade C recommendation
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Impact of ART on endometriosis
Somigliana et al, 2019
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Agenda
● Why is this topic so complex?
● How can endometriosis affect ART results?
● Impact of ART on endometriosis
● Obstetric implications of endometriosis
Is endometriosis relevant for ART success?
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● Consequences of pregnancy on endometriosis/omas
Obstetric implications of endometriosis
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● Obstetric complications
Horton J et al, 2019
Obstetric implications of endometriosisNNU:OR 1.91 [1.12,3.26]
PTD:OR 1.50 [1.10,2.03]
LSCS:OR 1.73 [1.00,3.00]
PP:OR 3.31 [1.26,8.71]
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Horton J et al, 2019
Obstetric implications of endometriosis
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● Obstetric rare complications
Obstetric implications of endometriosis
▪ Spontaneous hemoperitoneum
▪ Spontaneous bowel perforation
▪ Infection or rupture of endometriomas
▪ Uterine rupture
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Final comments
Is endometriosis relevant for ART success?
A shared and informed decision
with the patient is mandatory
● Some negative obstetric outcomes after ART may be associated
to endometriosis
● Properly designed RCTs addressing many of the raised clinical
points are missing
● No increase in recurrence rate is clear after OS
● Pregnancy has no apparent effect on endometriosis
● Evidence strength depends on a clear definition of populations