Dr Sujoy dasgupta was invited to deliver a lecture in a CME at Pune, India, at August, 2019

1. Endometriosis in IVF
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata
• Managing Committee Member, Bengal Obstetric & Gynaecological Society
(BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology Committee, BOGS-
2019-20
• Member, Quiz Committee, FOGSI, 2018-19, 19-20
• Member, Food and Drug Committee, FOGSI, 2018-19, 19-20
• Convener and Faculty, Spectrum MRCOG Course, Kolkata
• Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress,
London, 2019

2. Patho-physiology of
Reduced Fertility in Endometriosis
 Adhesions, tubal blockage and anatomical
distortion
 Associated with chronic pelvic pain, and therefore
dysparaeunia
 Inflammatory response damaging oocytes, sperms
and fertilization capacities
 Poor embryo quantity and quality
 Poor ovarian reserve
 Inflammation affecting endometrial receptivity
2

3. Diagnosis of Endometriosis
• Clinical examination
• CA-125
• TVS
• MRI
• Laparoscopy

4. NICE, 2017
• Do not exclude the possibility of
endometriosis if the abdominal or pelvic
examination, ultrasound or MRI are
normal. If clinical suspicion remains or
symptoms persist, consider referral for
further assessment and investigation.

5. Gold Standard
•The combination of laparoscopy and the histological verification of
endometrial glands and/or stroma
•In many cases the typical appearances of endometriotic implants in the
abdominal cavity are regarded as proof that endometriosis is present.
•Consider laparoscopy to diagnose endometriosis in women with
suspected endometriosis, even if the ultrasound was normal. (NICE,
2017)
•A negative diagnostic laparoscopy (i.e. a laparoscopy during which no
endometriosis is identified) seems to be highly accurate for excluding
endometriosis and is therefore of use to the clinician in aiding decision-
making. (ESHRE, 2013)

6. Patient's age
Pain symptoms
Extent of disease
Patient's
reproductive
plans
Treatment risks
Side effects
Cost
considerations
CHOICE OF
TREATMENT

7. Presented with Pain only,
fertility is not an immediate concern
NSAIDs
Pain NOT resolved
Hormonal treatment
Pain Not resolved
Ovarian endometrioma ≥3 cm
Laparoscopy
Pain resolved
Follow up
Pain resolved
Follow up

8. Subfertility
• 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 many women can
usually conceive naturally without any ART

9. Unexplained Infertility
• 10-20% of infertile couples
• Reflects an incomplete fertility evaluation
• Many cases represent undiagnosed endometriosis
• Can lead to empiric and costly therapies

10. French Study
63% Endometriosis
Eur J Obstet Gynecol Reprod Biol. 2012
Time to Treat
Undiagnosed Endometriosis
In
Unexplained Infertility
Leads to
Recurrent Implantation Failures
Belgium Study
47% endometriosis
Fertility & Sterility Vol. 92, 1, July 2009

11. Endometriosis and IVF Failure
• Repeated, unexplained IVF failure patients exist in most
practices
• IVF centers may not the inclination or skills to diagnose
endometriosis
• Studies have suggested endometrial receptivity defects
• Meta-analyses suggest IVF is affected by endometriosis
(Barnhart et al., F&S 2002)
• Brosens suggested aromatase expression is a marker of
poor IVF performance (Brosens et al., HR, 2004)

12. Implantation window

13. Case 1
• Mrs AB, P0+0, trying to conceive for one year.
She is having severe dysmenorrhoea not
responding to NSAID.
• Husband’s semen, HSG, AMH all are normal
13

14. Next step
• Laparoscopy
14

15. Hormonal therapies
•Pregnancy is not possible/contraindicated during
hormonal therapy
•hormonal treatment for suppression of ovarian function
does not improve the chance of natural conception
•Only indicated- if wants to delay Laparoscopy/ IVF
and the pain is severe

16. Medical Management
16

17. Surgery for Peritoneal
Endometriosis
• Both ablation and excision improve the chance
of spontaneous conception in ASRM stage I/II
endometriosis (CO2 laser vaporization >
monopolar electrocoagulation)
• Complete surgical removal before ART- ?

18. Surgery for ovarian endometrioma
• Cystectomy improves the chance of spontaneous conception, but NOT the
success of ART
• may not reverse the inflammatory and biomolecular changes shown to
influence fertilisation and implantation.
• controversial if cumulative pregnancy rate is more after surgery but time to
achieve the first pregnancy in infertile patients was significantly shorter
• A small added risk of requiring an oophorectomy
• Management should be individualised
• Should be undertaken by a gynaecologist with specific expertise in
endometriosis and fertility, in order to minimise the impact on the ovarian
reserve
• clinicians counsel regarding the risks of reduced ovarian function after
surgery and the possible loss of the ovary. The decision to proceed with
surgery should be considered carefully if the woman has had previous ovarian
surgery.

19. Which Surgery
(RCOG 2017, NICE 2017)
Compared with drainage and coagulation,
Cystectomy is associated with
• an overall lower recurrence risk
• higher spontaneous postoperative pregnancy rate,
• particularly if the cyst is ≥3 cm in diameter.
• (OR 5.24, 95% CI 1.92–14.27; n = 88; two trials)
[Cochrane Database Syst Rev 2008;(2):CD004992]
19

20. Surgery for deep endometriosis
 In women with infertility and severe pelvic pain who
are resistant to medical treatment or severe bowel
stenosis,
radical excision of endometriosis combined with
bowel segmental resection and anastomosis was
associated with a higher postoperative spontaneous
pregnancy rate
•Role before ART- ?

21. Case 2
• Mrs AB’s laparoscopy suggested grade IV
endometriosis
21

22. Next step
• IVF
22

23. Postoperative hormonal therapies
23
 Do not prescribe adjunctive hormonal
treatment after surgery, in women trying for
pregnancy

24. Case 3
• Mrs AB wants to defer IVF because of
financial reasons. Her pain decreased
significantly after laparoscopy.
• But after 3 months, when she came for IVF,
there is 4 cm chocolate cyst in left ovary
24

25. Next step
• If OPU seems feasible, go for IVF, freeze
embryos, give GnRH agonist depot 3-6, do
FET
25

26. Surgical treatment prior to IVF
• A systematic review (five controlled studies; n = 655) [Hum Reprod
Update 2015]
• surgically-treated endometriomas compared to those with intact
endometriomas, both having IVF
• similar live birth (OR 0.9; 95% CI 0.63–1.28), clinical pregnancy (OR
0.97; 95% CI 0.78–1.2) and miscarriage rates (OR 1.32; 95% CI 0.66–2.65)
• number of oocytes retrieved and the cancellation rates were comparable,
• lower AFC
• required higher doses of gonadotrophins for ovarian stimulation.
• Women who had undergone surgical management for a unilateral
endometrioma had a lower number of oocytes retrieved from the surgically-
treated ovary (mean difference –2.59; 95% CI –4.13 to –1.05) when
compared with the contralateral normal ovary
• The potential physiological compensation by the normal ovary
26

27. ESHRE, 2013
27

28. Complications during and after OPU
(RCOG, 2017)
• Technical difficulties during oocyte retrieval is low,
• No data to suggest that surgery will prevent adhesion reformation and
facilitate oocyte retrieval effectively.
• Progression of pelvic endometriosis and ovarian endometriomas- ?
• Risks of infection from an endometrioma (0–1.9%)
• Follicular fluid contamination (2.8–6.1%)
• The risk of missing an occult malignancy in an endometrioma is
extremely low - The lifetime probability of Ca ovary increasing from 1%
to 2% in the presence of an endometrioma.
• In the context of IVF treatment, delaying surgery for a few months or
years, until the treatment has been completed or following delivery,
would usually be a reasonable course of action unless there are other
immediate concerns.
28

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
29

30. Endometrioma and 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. the total stimulation dosage of gonadotrophin used was
comparable.
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]
30

31. Medical treatment before ART
(ESHRE, 2013)
31

32. Ovarian hyperstimulation by gonadotropins
causes very high estrogen levels
E2 during the pre-implantation period (days
0–6)
Dr. Carlos Simone
ESHRE 1997
Fertility & Sterility
Vol. 70, No. 2, Aug. 1998
Window of uterine receptivity remains open
for an extended period at lower estrogen
levels but rapidly closes at higher levels
High estrogen levels provoke uterine non receptivity

33. Human Reproduction, Volume 27,
Issue 3, 1 March 2012
Systems Biology in Reproductive
Medicine, Volume 60, 2014
Letrozole improves the
marker of Endometrial Receptivity
Letrozole improves
Integrin expression in IVF
Letrozole improves
Integrin, LIF & L- Selectin
expression in natural cycle
Window of uterine receptivity remains open for an extended period
at lower estrogen levels but rapidly closes at higher levels
PNAS March 4, 2003 100 (5) 2963-296

34. New Treatment Protocol
A comparison of pre treatment
with & without GnRH-agonist or Letrozole
in women with 2 failed embryo transfers
undergoing a frozen cycle &
no evidence of endometriosis
New Treatment Protocol
Patient with 2 failed embryo transfers perform
better if pretreated with GnRH-ag - Letrozole,
due to treatment of undiagnosed Endometriosis

35. Case 4
• Mrs DH, 37 years old has been trying for
pregnancy for last 6 months. Husband’s semen
normal, HSG not done. AMH 0.5 ng/ml
• She is having severe dysmenorrhoea, TVS
revealed AFC 2 (right) plus 3 (left) and 5 cm
chocolate cyst in right ovary
35

36. Options
• Laparoscopy and decide
• IVF, freeze all
36

37. RCOG Recommendations (2017)
Directly ART
• Asymptomatic women,
• women of advanced
reproductive age,
• those with reduced
ovarian reserve,
• bilateral 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.
37

38. Case 5
• Mrs FR, 32 years, has been trying for
pregnancy for last 2 years. AMH, AFC, HSG
all normal. Husband is having azoospermia.
Donor sperm is no acceptable.
• 6 cm right ovarian endometrioma, minimum
dysmenorrhoea
38

39. Option
• IVF, freeze all
• Laparoscopy if cyst size increases/ pain/
difficult OPU
39

40. IVF in Endometrioma
(ESHRE, 2013)
40

41. Case 6
• Mrs TM, underwent laparoscopic left ovarian
cystectomy outside, having grade 2
endometriosis. Husband having mild
oligospermia. She has been trying for
pregnancy for last 3 years. AMH, AFC normal,
both tubes patent.
41

42. Next step
• Ovulation induction/ IUI
42

43. IUI in Endometrioma
(ESHRE, 2013)
43

44. 44

45. Predictors of ART Success in
Women with Endometriosis
• Age
• D3 FSH
• AMH
• AFC
45

46. Conclusion
Surgery not only improves symptoms for a
longer period of time, but also increases the
spontaneous pregnancy rate.
In women with previously operated
endometriosis, balance should be made
between repeat surgery and ART
Routine surgery before ART is not justified
Surgery will not improve the outcome of IVF
46