Dr Sujoy dasgupta and Dr Arun Madhab Barua were invited to moderate a panel discussion on "Endometriosis and Subfertility, Primium non nocere" in the International Congress on Endometriosis (ICE) on 10 December 2023 at Dhana Dhanya Auditorium, Kolkata

1. Endometriosis with Subfertility:
Primum Non Nocere
Moderators
• Arun Madhab Baruah
• Sujoy Dasgupta
Panelists
• Biman Kumar Ghosh
• Jasmin Banu
• Nargis Fatema
• Ratna Chattopadhyay
• Sehereen Farhad
Siddiqua
• Shovandeb Kalapahar
• Suparna Banerjee

2. Endometriosis and subfertility
• Dysparaeunia
• Distorted Pelvic Anatomy
• Altered Peritoneal Function
• Abnormal Uterotubal Transport
• Hormonal and Ovulatory Abnormalities.
• Impaired Implantation
• Oocyte and Embryo Quality

5. Case Scenario 1
• Mrs AC, 33-yr-old
woman having regular
cycles
• Trying for pregnancy for
3 years
• c/o severe and
progressively increasing
dysmenorrhoea and
dysparaeunia
• TVS-

6. Line of management?
• Laparoscopy
• IVF directly
• IVF, embryo freezing and
then consider laparoscopy
• Hormonal therapy for 3
months, then reevaluate
 Cystectomy
 Cyst aspiration/
drainage
 Dienogest
 GnRH agonists

7. Factors to decide the mode of
treatment?
• Ovarian reserve- Age,
AMH, AFC
• Semen parameters
• Tubal patency
• Severity of symptoms
• Past surgery
• Previous fertility
treatment
• Patient’s wishes
Mrs AC
 Age 33, AMH- 2.5 ng/ml,
AFC- 8+10
 Normozoospermia
 Tubes not yet checked
 Pain not responded to
NSAID
 No previous surgery
 Received 6 cycles of
letrozole for OI
 Relief of pain and wants to
conceive

8. Medical Management
Hormonal Suppression
• Clinicians should NOT
prescribe ovarian
suppression treatment to
improve fertility
• Most of the hormone
therapies will prevent
pregnancy
• Ovarian suppression does
NOT improve subsequent
ovarian response (ESHRE,
2022)
NSAID
• Avoid around the time of
ovulation

9. Surgery for Endometriosis-Subfertility
rASRM stage
I/II
Improves the rate of ongoing pregnancy.
Both ablation and excision (CO2 laser vaporization
> monopolar electrocoagulation)
Endometrioma May increase their chance of natural pregnancy
Cystectomy >> Drainage/coagulation
Deep
endometriosis
 For infertility, severe pain, bowel stenosis
radical excision combined with bowel segmental
resection and anastomosis →improves spontaneous
pregnancy rate
• Operative lap > diagnostic lap
• Still controversial if cumulative pregnancy rate is more after surgery but
time to achieve pregnancy was significantly shorter
• No compelling data from comparative studies exist
(RCOG, 2017; NICE, 2017; ESHRE, 2022)

10. Surgery for Endometriosis-Subfertility
rASRM stage
I/II
Improves the rate of ongoing pregnancy.
Both ablation and excision (CO2 laser vaporization
> monopolar electrocoagulation)
Endometrioma May increase their chance of natural pregnancy
Cystectomy >> Drainage/coagulation
Deep
endometriosis
 For infertility, severe pain, bowel stenosis
radical excision combined with bowel segmental
resection and anastomosis →improves spontaneous
pregnancy rate
• Operative lap > diagnostic lap
• Still controversial if cumulative pregnancy rate is more after surgery but
time to achieve pregnancy was significantly shorter
• No compelling data from comparative studies exist
(RCOG, 2017; NICE, 2017; ESHRE, 2022)

11. Surgery for Endometriosis-Subfertility
rASRM stage
I/II
Improves the rate of ongoing pregnancy.
Both ablation and excision (CO2 laser vaporization
> monopolar electrocoagulation)
Endometrioma May increase their chance of natural pregnancy
Cystectomy >> Drainage/coagulation
Deep
endometriosis
 For infertility, severe pain, bowel stenosis
radical excision combined with bowel segmental
resection and anastomosis →improves spontaneous
pregnancy rate
• Operative lap > diagnostic lap
• Still controversial if cumulative pregnancy rate is more after surgery but
time to achieve pregnancy was significantly shorter
• No compelling data from comparative studies exist
(RCOG, 2017; NICE, 2017; ESHRE, 2022)

12. Before surgery
Planned procedure
• Cystectomy/ Drainage
• Adhesiolysis
• Tubal patency
Other investigations
• Do not systematically request second-level diagnostic
investigations in women with known or suspected non-
subocclusive colorectal endometriosis or with symptoms
responding to medical treatment
• Do NOT check CA 125 routinely (ETIC, 2019)

13. Before surgery
Counselling and consent
• Laparotomy
• Possible decline in ovarian reserve
• Risk of oophorectomy
• 3-10% chances of damaging the surrounding organs- bladder,
bowel, ureter, nerves
• Additional procedure
• Unexpected pathology- hydrosalpinx
• Recurrence
• Complete excision of endometriotic tissue NOT possible.
• May NOT reverse the inflammatory and biomolecular
changes shown to influence fertilisation and implantation.

14. During surgery
• Energy sources
• Minimizing ovarian damage
• Ovarian reconstruction
• Anti-adhesion barrier

15. Mrs AC underwent laparoscopy
• Right Ovarian 5 cm
chocolate cyst
removed
• Severe adhesion in
POD- complete
adhesiolysis was
done
• Dye test B/L positive

16. After laparoscopy-
Attempt of natural conception or
IVF?
• To identify patients that may benefit from ART after
surgery, the Endometriosis Fertility Index (EFI)
should be used as it is validated, reproducible and
cost-effective.
• The results of other fertility investigations such as
their partner’s sperm analysis should be taken into
account (ESHRE, 2022)

18. Adamson and Pasta. 2010

19. Post-operative treatment plan?
• Counselling?
• Ovarian suppression
after surgery?
 Chance of recurrence
 Better not to delay
pregnancy
 Women seeking pregnancy
should NOT be prescribed
postoperative hormone
suppression with the sole
purpose to enhance future
pregnancy rates (ESHRE, 2022)

20. Mrs AC is now pain-free
• Visited 4 doctors over the period of next 2
years.
• Received different brands of letrozole for
ovulation induction- total 12 cycles
• She wants to do IUI

21. ESHRE, 2022
rASRM stage I/II
endometriosis
•May perform IUI with ovarian
stimulation, instead of expectant
management or IUI alone
•IUI+OS increases pregnancy rates.
(better than expectant management or
IUI alone)
rASRM stage III/IV
endometriosis
•The value of IUI in women with tubal
patency is uncertain
•IUI +OS could be considered
Can IUI be done in endometriosis?

22. ESHRE, 2022
rASRM stage I/II
endometriosis
•May perform IUI with ovarian
stimulation, instead of expectant
management or IUI alone
•IUI+OS increases pregnancy rates.
(better than expectant management or
IUI alone)
rASRM stage III/IV
endometriosis
•The value of IUI in women with tubal
patency is uncertain
•IUI +OS could be considered
Can IUI be done in endometriosis?

23. Hughes, 1997 Meta-analysis- IUI success is halved in stage I/II
endometriosis
Gandhi et al., 2014 No difference between expectant management and
IUI
Dmowski et al., 2002 First-cycle chance of pregnancy with IVF is
significantly higher than the cumulative
pregnancy rate after 6 IUI cycles
Van der Houwen et al., 2014;
D’Hooghe et al., 2006
The risk of endometriosis recurrence appears to
be increased by IUI (more than IVF)
IVF, but not IUI, can be expected to overcome the
detrimental effects of a pelvic inflammatory
milieu.
Limitations of IUI in endometriosis

24. Endometriosis Treatment Italian Club, 2019

26. Case Scenario 2
• Mrs FR, 32 yr, has been trying for pregnancy
for last 2 years. AMH, AFC, HSG all
normal.
• Husband is having azoospermia. Donor sperm
is no acceptable.
26

27. Mrs FR has no pelvic pain
• TVS- B/L
endometrioma
(6 cm in right side, 4 cm
left side)
 Anything else to note
in the scan
1. Cyst location
2. AFC
3. Accessibility of the
follicles
4. Hydrosalpinx
 Next plan?
1. TESA-ICSI directly?
2. Laparoscopy before
IVF-ICSI?

28. Can presence of Endometrioma affect
IVF Outcome?
• Endometrioma compared with no endometriosis,
1. ovarian response was lower, with a lower number of oocytes
retrieved (mean difference –0.23; 95% CI 0.37–0.1)
2. a higher cancellation rate (OR 2.83; 95% CI 1.32–6.06)
3. Higher gonadotropin consumption
4. live birth (OR 0.98; 95% CI 0.71–1.36), pregnancy (OR
1.17; 95% CI 0.87–1.58) and miscarriage rates (OR 1.7;
95% CI 0.86–3.35) were similar [Fertil Steril, 2012]
• Endometrioma vs other areas of endometriosis
- IVF outcomes (live birth, pregnancy, miscarriage and cycle
cancellation rates, and mean number of oocytes retrieved) were
similar [Hum Reprod Update 2015]
28

29. Surgery prior to IVF
• Progressive decline in ovarian reserve
• Higher gonadotrophin consumption
• Lower number of oocyte retrieved
Raffi et al., 2012; Somigliana et al., 2012; Sugita et al., 2013; Hamdan et
al., 2015; Polyzos and Sunkara, 2015; Brink Laursen et al., 2017; Tao
et al., 2017; Nickkho-Amiry et al., 2018

30. Operative Lap does NOT improve IVF
outcome
In infertile women with
endometrioma > 3 cm only
consider cystectomy prior to
ART to improve
1. endometriosis-associated
pain or
2. the accessibility of
follicles (ESHRE, 2022)
Concern about
endometrioma puncture
during OPU?
• In women with
endometrioma, clinicians
may use antibiotic
prophylaxis at the time of
oocyte retrieval, although
the risk of ovarian abscess
following follicle
aspiration is low (0-1.9%)
(ESHRE, 2022, RCOG 2017)

31. Complications during and after OPU
• Technical difficulties during oocyte retrieval is low,
• No data to suggest that surgery will prevent adhesion reformation
and facilitate oocyte retrieval effectively.
• Risks of infection from an endometrioma (0–1.9%)
• Follicular fluid contamination (2.8–6.1%)
• Progression of pelvic endometriosis???
• Women with endometriosis can be reassured regarding the safety of
ART since the recurrence rates are not increased compared to
those women not undergoing ART.
ESHRE, 2022; Koch et al., 2012; RCOG, 2017

32. Ultrasound-guided Aspiration
• Transvaginal USG-guided drainage
without surgery does not seem to be
effective.
• a high recurrence rate
• To decrease recurrence rate, aspiration is
combined with in situ injection of
tetracycline/ethanol/methotrexate
• Disadvantages:
 Complications: infection, abscess
formation, and pain
 inability to rule out any malignancy
 risk of pelvic adhesion
32

33. RCOG Scientific Impact Paper (2017)
Directly ART
• Asymptomatic women,
• women of advanced
reproductive age,
• those with reduced
ovarian reserve,
• B/L endometriomas,
• a history of prior ovarian
surgery
Surgery before IVF
• Highly symptomatic
women,
• with an intact ovarian
reserve,
• unilateral and large cysts,
• cysts with suspicious
radiological and clinical
features.
33

34. IVF protocol for Endometriosis
• Any specific IVF
stimulation protocol?
• Pretreatment COC/
Progesterone?
• No specific protocol can be
recommended.
• Both GnRH antagonist and agonist
protocols can be offered based on
patients’ and physicians’ preferences
as no difference in pregnancy or
live birth rate has been
demonstrated
• Insufficient evidence to recommend
prolonged administration of the
COC/progestogens as a pre-treatment
to ART to increase live birth rates
(ESHRE, 2022)

35. Down regulation with GnRH agonist depot?
• The administration of GnRH agonists for a period of
3-6 months prior to IVF or ICSI in women with
endometriosis increases the odds of clinical
pregnancy by 4-fold.

36. Georgiou EX, Melo P, Baker PE, Sallam HN, Arici A, Garcia‐Velasco JA,
Abou‐Setta AM, Becker C, Granne IE. Long‐term GnRH agonist therapy before in
vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.
Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No.: CD013240.
DOI: 10.1002/14651858.CD013240.pub2
• In light of the paucity and very low quality of
existing data, particularly for the primary
outcomes examined, further high‐quality trials
are required to definitively determine the impact
of long‐term GnRH agonist therapy on IVF/ICSI
outcomes, not only compared to no pretreatment,
but also compared to other proposed alternatives
to endometriosis management

37. Paradigm Shift?
ESHRE, 2013 ESHRE, 2022
• Clinicians can prescribe
GnRH agonists for a period
of 3 to 6 months prior to
treatment with ART to
improve clinical pregnancy
rates in infertile women
with endometriosis
• The extended administration
of GnRH agonist prior to
ART treatment to improve
live birth rate in infertile
women with endometriosis
(ultralong protocol) is no
longer recommended due
to unclear benefits.

39. Case Scenario 3
• Mrs PC, 34 yr, trying for pregnancy for 1
year.
• All investigations (Semen, AMH, HSG)
normal.
• 2 cm endometrioma in left ovary.
• No pain.

40. Options?
• Medical management- Dienogest/ GnRH
agonists?
• Laparoscopy
• IVF
• Masterly inactivity

41. Conservative management for spontaneous
conception
Encourage to try natural conception before seeking fertility treatment-
1. Young women,
2. regular menstrual cycles and
3. an incidental finding of an ovarian endometrioma
4. without suspicion of malignancy
•43% spontaneous pregnancy rate during the 6-month follow up period
•Similar ovulation rates in the affected ovary to the healthy ovary
Benaglia et al., 2009; Leone Roberti Maggiore et al., 2015; RCOG, 2017
41

42. ESHRE, 2022

43. Case Scenario 4
• Mrs MS, 28 yr, trying for pregnancy for 3
years. She had severe dysmenorrhoea,
dyschezia and dysuria.
• There was 5 cm unilateral endometrioma and
MRI scan suggested the possibility of
rectosigmoid endometriosis.
• AMH 2.3 ng/ml, tubes not checked, husband’s
semen normal.

44. Options?
• Medical
management-
Dienogest/ GnRH
agonists?
• Laparoscopy
• IVF
• Mrs MS wanted to
defer surgery for 4
months because of
professional
commitments

45. Preoperative hormonal therapies
NICE, 2017
•Consider GnRH agonist x 3
cycles before surgery for deep
infiltrating endometriosis
ESHRE, 2022
•In clinical practice, surgeons prescribe
preoperative medical treatment with
GnRH agonists as this can facilitate
surgery due to reduced inflammation,
vascularisation of endometriosis lesions
and adhesions
•No controlled studies supporting this
•Should be offered before surgery to
women with painful symptoms in the
waiting period before the surgery can
be performed, with the purpose of
reducing pain before, not after, surgery.

46. Mrs MS underwent Laparoscopy
• Grade IV endometriosis
• Tubes and ovaries difficult to identify
• Tubal patency- Right- slow spill, Left- no spill
• Adhesiolysis could not be done
46

47. Next step
• GnRH Agonist/ Dineogest post-op
• IVF
• Re-operation by expert
47

48. Complete excision group
vs
incomplete excision
• significantly higher
complication rate (9.1% VS
0%, P<0.001)
• significant decrease in pain
(VAS score 5.6±3.9 VS
2.9±3.3, P=0.001)
• significantly lower
postoperative recurrence rate
(3.9% VS 35.3%, P=0.000)
• similar pregnancy rate
Complete excision
vs
incomplete excision + post-
operative GnRH agonist
• similar pain score (5.6±3.9
VS 4.5±3.2, P=0.272).
• significantly lower recurrence
rate (3.9% VS 29.4%,
P=0.000).

49. Mrs MS decided for IVF
Does endometriosis affect IVF success?
• Systematic review- stage I and II endometriosis, the
pregnancy rate was similar to that in tubal infertility,
although in stage III and IV endometriosis, the
pregnancy rate was significantly poor (Barnhart, et al.,
2012).
• ESHRE database- No difference in IVF outcome
between endometriosis and other fertility issues
(Dunselman et al., 2014).
• Recent Meta-analysis- Endometriosis does NOT
affect embryo quality or IVF outcome (Dongye et al., 2021.
Qu et al., 2022).

50. Ms MS had IVF-Failure
Role of laparoscopy?
• Normal HSG, repeated IVF failure- 57% cases can have
endometriosis- surgical treatment improves outcome (Yu et
al., 2019)
• In symptomatic women with severe endometriosis-
surgery improves IVF outcome (Soriano et al., 2016)
• Need to do 40 laparoscopy to achieve a pregnancy (ASRM,
2012)
• Down-regulation with GnRH agonist and letrozole may be
useful in RIF patients without surgically proved
endometriosis (Moustafa and Young, 2020)

52. Case Scenario 5
• Mrs JK, 37 years trying
for pregnancy for 4 years
• Tried multiple cycles of
OI with letrozole and CC
• HSG, AMH, Semen all
normal
• No dysmenorrhoea
• “Unexplained
Subfertility”
• Role of laparoscopy to
diagnose endometriosis
and treatment?
52

53. Unexplained Infertility
• Reflects an incomplete fertility evaluation
• 20-40% cases of unexplained infertility may be
because of undiagnosed endometriosis
Hurt, 2003; Fadhlaoui et al., 2014

55. Recent Studies on Endometriosis and
Unexplained Infertility
 RMeta-Analysis
• Success rate of IVF - ∼25% (NNT- 4)
European IVF-Monitoring Consortium (EIM) for ESHRE, 2016
Jacobson et al., 2010 Duffy et al., 2014
OR for ongoing pregnancy (95% CI) 1.64 (1.05– 2.57) 1.94 (1.20–3.16)
The number of infertile women that should
undergo destruction of superficial peritoneal
endometriosis
12 8
The prevalence of grade I/ II endometriosis among
women with unexplained infertility
≤50%
NNT 24 16

56. Laparoscopy to diagnose asymptomatic DIE?
• Uncommon to be asymptomatic
• Uncomplicated- If no symptoms of ureter/ bowel
stenosis- No need of surgery
• 9 out of 10 will not progress
Operate, ONLY when-
1. Occlusive disease (ureter/ bowel)
2. Wishing natural conception, declining IVF
Dunselman et al., 2014; Berlanda et al., 2016; ETIC, 2018

57. Endometriosis Treatment
Italian Club, 2019
• Routine laparoscopy should
NOT be done in women with
infertility without pelvic pain
(Quality of evidence- High)
• Consider surgery for
superficial endometriosis
ONLY in women
1. Having moderate-severe pain
2. Seeking natural conception,
declining ART
Canadian Fertility and
Andrology Society, 2019
• In the absence of evidence for
tubal or other pelvic pathology,
laparoscopy is NOT
warranted in unexplained
infertility (Level II-2B).
ESHRE, 2023
• Routine diagnostic
laparoscopy is NOT
recommended for diagnosis of
unexplained infertility
ASRM, 2020
• ???

59. One size does not fit for all
• Pain
• Age and Ovarian
reserve
• Previous surgery
• Male and tubal factor
• Patient’s wishes
For IVF
• Cost consideration
• Severity of pain
• Accessibility of the
follicles
• Hydrosalpinx

61. Take Home
• During Medical therapy pregnancy is NOT possible
• Medical therapy (ovarian suppression) does NOT
improve chance of natural conception
• Surgery improves pain, clarifies diagnosis (severity
of endometriosis)
• Surgery improves the chance of natural conception
• Immediately after surgery- Best period to conceive
• Surgery does NOT improve the success rate of IVF