Lecture delivered by Dr Sujoy Dasgupta in IPCON 2823, the Mid term conference of ISOPARB (Indian Society of Perinatology and Reproductive Biology) held at Kolkata on 10 September

1. Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
M Sc, Sexual and Reproductive Medicine (South Wales, UK)
Clinical Director, Genome Fertility Centre, Kolkata
Managing Committee Member, BOGS, 2023-24
Executive Committee Member, ISAR Bengal, 2022-24
Clinical Examiner, MRCOG Part 3 Examination
Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress,
London, 2019
Endometriosis and subfertility…..
what to do?

2. • A chronic, estrogen-
dependent, inflammatory,
painful disorder in which
endometrial tissue grows
outside the uterus.
• Known for recurrence
• No single treatment is ideal
for all patients, management
chosen should be directed to
individual needs of each
patient
• Combination therapy may
be ideal
• Couple’s problem
• About 1/3rd of women
with endometriosis also
suffer from subfertility.
• Endometriosis does not
equal infertility. It just
implies that some women
may have a harder time
becoming pregnant.
• Once the endometriosis is
treated then women often
conceive naturally without
any ART
Endometriosis Subfertility

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

5. Endometriosis-subfertility:
Basic principles of management
• Medical management is not possible
• Medical management does NOT improve the
chance of conception
• Laparoscopy confirms diagnosis and the severity
• Laparoscopy improves pain
• Laparoscopy improves chance of natural
conception
• Laparoscopy does NOT improve the success of
IVF

6. Case Scenario 1
• Mrs AC, 33 yr, trying
for pregnancy for 2
years
• c/o severe and
progressively
increasing
dysmenorrhoea and
dysparaeunia
• TVS-

7. Line of management?
• Laparoscopy
• Fertility preservation then consider laparoscopy
• IVF only
• Hormonal therapy for 3 months, then reevaluate

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

9. Medical therapy
Hormonal therapies
• 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)
Analgesics
• NSAIDs should be avoided
around the time of ovulation

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. 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)

13. 1. 3-10% chances of damaging the
surrounding organs- bladder,
bowel, ureter, nerves
2. Possible decline in ovarian
reserve
3. Risk of oophorectomy
4. Complete excision of
endometriotic tissue not possible.
5. May NOT reverse the
inflammatory and biomolecular
changes shown to influence
fertilisation and implantation.
6. Needs skill
Vercellini et al., 2009; Lebovic, 2016

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

15. After laparoscopy- Attempt of
natural conception or IVF?
• Women should be counselled of their chances of
becoming pregnant after surgery.
• 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)

17. Adamson and Pasta. Fertil Steril. 2010

18. What should be the post-operative
treatment plan?
• Counselling
• Ovarian
suppression after
surgery?
 Chance of recurrence
 After surgery- conception
chance is high
 Women seeking pregnancy
should NOT be prescribed
postoperative hormone
suppression with the sole
purpose to enhance future
pregnancy rates (ESHRE, 2022)

19. 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

20. 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?

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. 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

23. Endometriosis Treatment Italian Club, 2019

24. 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.
• B/L endometrioma (6 cm in right side, 4 cm
left side)
• Minimum dysmenorrhoea
25

25. Options for Mrs FR
1. TESA-ICSI directly?
2. Laparoscopy before
IVF-ICSI?
 Severity of pain
 Scan finding-
1. Cyst location
2. AFC
3. Accessibility of the follicles
4. Hydrosalpinx

26. 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

27. 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)

28. 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

29. 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
31

30. 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 (The lifetime
probability of Ca ovary 1-2%)
32

31. 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)

32. 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.

33. 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

34. 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.

35. Muller V, Kogan I, Yarmolinskaya M, Niauri D, Gzgzyan A, Aylamazyan E.
(2017). Dienogest treatment after ovarian endometrioma removal in infertile
women prior to IVF, Gynecological Endocrinology, 33:sup1, 18-21,

36. Tamura, H., Yoshida, H., Kikuchi, H. et al. The clinical outcome of Dienogest treatment
followed by in vitro fertilization and embryo transfer in infertile women with
endometriosis. J Ovarian Res 12, 123 (2019).
• No significant difference in the implantation and
miscarriage rates between the groups
• The cumulative pregnancy rate and live birth rate were
lower in the DNG group than in the control group.

37. 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.

38. 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
40

39. ESHRE, 2022

40. 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.
• She wanted to defer surgery for 4 months
because of professional commitments

41. 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.

42. 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
44

43. Next step
• GnRH Agonist/ Dineogest post-op
• IVF
• Re-operation by expert
45

44. 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).

45. How does endometriosis affect
oocytes and embryos?
• Ooplasm- “dark cytoplasm,"
"and "diffused cytoplasmic
granularity.“ (Rienzi et al.,
2011).
• Oocytes with degenerative
signs (Ayse et al., 2014).
• Altered oocyte morphology,
abnormal mitochondrial
content (Sanchez et al., 2017).
• Altered follicular fluid
molecules (VEGF, IL-6)
(Garrido et al., 2000).

46. 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).

47. 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)

48. 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?
50

49. 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

51. 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

52. 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

53. 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
• ???

54. Case Scenario 6
• Mrs DH, 27 years, planning for pregnancy
• She underwent left ovarian cystectomy 6
years ago- H/P Endometrioma
• She is having severe dysmenorrhoea
• TVS- 5 cm chocolate cyst in right ovary
• AMH 0.8 ng/ml
58

55. Options
• Laparoscopy and decide
• Fertility preservation?
• In case of extensive
ovarian endometriosis,
clinicians should discuss
the pros and cons of
fertility preservation with
women with
endometriosis.
• The true benefit of
fertility preservation in
women with
endometriosis remains
unknown
ESHRE, 2022
59

56. AMH vs AFC-
and Endometrioma Surgery
Younis JS, Shapso N, Ben-Sira Y, Nelson SM, Izhaki I. Endometrioma surgery-a
systematic review and meta-analysis of the effect on antral follicle count and anti-
Müllerian hormone. Am J Obstet Gynecol. 2022 Jan;226(1):33-51.e7.

57. Endometriosis and ovarian reseve
• In endometriosis, with
and without a history of
ovarian surgery, ovarian
reserve markers were
worse (lower AMH and
higher FSH) compared to
women with male factors
Romanski PA, Brady PC, Farland LV, Thomas AM, Hornstein MD. The effect of
endometriosis on the antimüllerian hormone level in the infertile population. J
Assist Reprod Genet. 2019 Jun;36(6):1179-1184.

58. Endometrioma-related reduction in
ovarian reserve (ERROR)
Kasapoglu I, Ata B, Uyaniklar O, Seyhan A, Orhan A, Yildiz Oguz S, Uncu G.
Endometrioma-related reduction in ovarian reserve (ERROR): a prospective longitudinal
study. Fertil Steril. 2018 Jul 1;110(1):122-127.

59. Endometriosis- surgery or not
Yılmaz Hanege B, Güler Çekıç S, Ata B. Endometrioma and ovarian reserve: effects of
endometriomata per se and its surgical treatment on the ovarian reserve. Facts Views
Vis Obgyn. 2019 Jun;11(2):151-157.

61. 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

62. Take Home
• Take into account overall fertility picture, age,
symptoms, previous surgery
• During Medical therapy pregnancy is NOT possible
• Medical therapy (ovarian suppression) does NOT
improve chance of natural conception
• Surgery improves pain, clarifies diagnosis
• Surgery improves the chance of natural conception
• Immediately after surgery- Best period to conceive
• Surgery does NOT improve the success rate of IVF