Invited lecture delivered by Dr Sujoy Dasgupta in a webinar organized by Bharat Serum and Vaccines Limited held in December, 2020

1. Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata
Managing Committee Member, Bengal Obstetric & Gynaecological Society (BOGS)
Secretary, Subfertility and Reproductive Endocrinology Committee, BOGS
Executive Committee Member, Indian Fertility Society (IFS)- West Bengal Chapter
Executive Committee Member, Indian Society for Assisted Reproduction (ISAR)- Bengal
Member, Endocrinology Committee, Federation of Obstetric and Gynaecological Societies of
India (FOGSI)
Convener and Faculty, Spectrum MRCOG Course
Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London, 2019
Management of Infertility in
Endometriosis

2. ENDOMETRIOSIS is a
chronic, estrogen-
dependent, inflammatory,
painful disorder in which
endometrial tissue grows
outside the uterus.

3. Types of Endometriosis
• Peritoneal endometriosis
They are endometriotic implants on the surface of the surface of pelvic
peritoneum and ovaries.
• Endometriomas
They are ovarian cysts lined by endometrioid mucosa.
• Rectovaginal endometriotic nodules
It is a complex solid mass comprised of endometriotic tissue blended
with adipose and fibromuscular tissue, residing between the rectum and
the vagina.
•Adenomyosis (Endometriosis Interna)
Endometriosis in the myometrium (Musculature of the uterus)
•Extragenital endometriosis
Scar tissue, pleura, omentum, lungs, limbs

4. • Occurs in 6–10% of women of reproductive
age
• with a prevalence of 38% in infertile women,
and
• in 71–87% of women with chronic pelvic pain
• The Endometriosis Society of India estimates
that 25 million i.e about 35% Indian women
suffer from this condition.

5. 1. Endometriosis may be a diagnosis of
exclusion
2. A significant number of women with
endometriosis remain asymptomatic
Therefore, DIAGNOSIS of endometriosis in a
woman with pelvic pain is often delayed &
stretches over several years!

7. Diagnosis Of Endometriosis
Clinicians should consider the
diagnosis of endometriosis
in the presence of gynecological
symptoms-
 Dysmenorrhea
 non-cyclical pelvic pain
 deep dyspareunia
 Infertility
 fatigue
in women of reproductive age with
non-gynecological cyclical symptoms
 Dyschezia
 rectal bleeding
 Dysuria
 Hematuria
 shoulder pain

8. Visceral Hypersensitivity
• Thresholds for
pain in
endometriosis
groups were
found to be
similar to those
in the IBS group

9. Diagnosis of Endometriosis
• Clinical examination
• CA-125
• TVS
• MRI
• Laparoscopy
• 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. (NICE,
2017)

10. Advanced Imaging
• Do not systematically
request second-level
diagnostic investigations
in women with known or
suspected non-occlusive
colorectal endometriosis
or with symptoms
responding to medical
treatment (quality of the
evidence, low; weak
suggestion)

11. 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.
•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)

12. Standard procedure
A good quality laparoscopy should include systematic checking of
•1) the uterus and adnexa,
•2) the peritoneum of ovarian fossae, vesico-uterine fold, Douglas and
pararectal spaces,
•3) the rectum and sigmoid (isolated sigmoid nodules),
•4) the appendix and caecum and
•5) the diaphragm.
•6) speculum examination and palpation of the vagina and cervix under
laparoscopic control, to check for 'buried' nodules.
•A good quality laparoscopy can only be performed by using at least
one secondary port for a suitable grasper to clear the pelvis of obstruction
from bowel loops, or fluid suction to ensure the whole pouch of Douglas
is inspected.
•By a gynaecologist with training and skills in laparoscopic surgery for
endometriosis

13. Biopsy
to confirm the diagnosis of endometriosis
(be aware that a negative histological result
does not exclude endometriosis)
to exclude malignancy
1. if an endometrioma is treated but not excised
2. deep infiltrating disease

14. Stage 1: Lesions are
minimal & isolated
Stage 2: Lesions are mild -
may be several; adhesions
are possible.
Stage 3: Lesions are
moderate, deep or
superficial with clear
adhesions
Stage 4: Lesions are
multiple & severe, both
superficial & deep, with
prominent adhesions.
ASRM
classification of
endometriosis

15. Staging of Endometriosis
• Does not correlate well with the symptoms of
pain or fertility.
• Offer endometriosis treatment according to the
woman's symptoms, preferences and priorities,
rather than the stage of the endometriosis.
*NICE, 2017

16. Management of endometriosis
• Surgical management
1. Conservative surgery (preferably laproscopy)
2. Hysterectomy (laparoscopy/ laparotomy)
• Medical management
1. NSAIDS
2. GnRh analogs
3. Continuous combined oral contraceptives (COC)
4. Progestins- oral, injectable, Mirena (IUD)
5. Antiprogestins- Danazol

17. There is NO permanent cure for
endometriosis
• No single treatment is ideal for all patients, management
chosen should be directed to individual needs of each patient
• Combination therapy may be ideal; as it is a chronic disease,
we should consider not only efficacy but also long-term safety
and tolerability of treatment options.
• Long-term treatment / repeated courses owing to frequent
recurrence of pain within 6-12 months of completing
treatment course (within 5 years in about half of women)

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

19. Subfertility is “Couple’s” problem
Unexplained
10%
Endometriosis
25%
Tubal Factor
15%
Ovulation
20%
Male Factor
30%
Diagnosis

20. Endometriosis and Infertility
• Dysparaeunia
• Distorted Pelvic Anatomy.
• Altered Peritoneal Function.
• Hormonal and Ovulatory Abnormalities.
• Impaired Implantation (challenged based on b-3
integrin research)
• Oocyte and Embryo Quality.
• Abnormal Uterotubal Transport.

21. 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 women can usually
conceive naturally without any assisted reproductive
techniques.

22. Endometriosis-Infertility:
Basic principles of management
• Medical management is not possible
• Medical management does NOT improve the
chance of conception (except: GnRH Ago in IVF)
• Laparoscopy confirms the severity of
endometriosis
• Laparoscopy improves pain
• Laparoscopy improves chance of natural
conception
• Laparoscopy does NOT improve the success of
IVF

23. 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
24

24. Medical therapy
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
Analgesics
• NSAIDs should be avoided
around the time of
ovulation

25. Next step in Mrs AB
• Laparoscopy
26

26. 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- ?

27. Surgery for ovarian endometrioma
• Cystectomy improves the chance of spontaneous
conception, but NOT the success of ART
• A small added risk of requiring an oophorectomy
• 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.
• Preoperative assessment of ovarian reserve
• Management should be individualised

28. Which Surgery
(ESHRE 2013, RCOG 2017, NICE 2017)
Compared with drainage and coagulation,
Cystectomy is associated with
• an overall lower recurrence risk
• decreased pain
• 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]
29

29. 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

30. 1. 3-10% chances of damaging
the surrounding organs-
bladder, bowel, ureter, nerves
2. Risk of oophorectomy.
3. Complete excision of
endometriotic tissue not
possible.
4. May not reverse the
inflammatory and
biomolecular changes shown
to influence fertilisation and
implantation.
5. Needs skill
*Vercellini et al., 2009; Lebovic, 2016

31. Case 1 (Contd.)
• Mrs AB underwent laparoscopy
• ovarian cystectomy (4 cm), adhesiolysis and
ablation of superficial peritoneal endometriosis
were done.
• Tubal patency was confirmed B/L.
32

32. Next Step
• GnRh Agonist/ Dienogest- Post op?
• Do not prescribe adjunctive hormonal
treatment after surgery, in women trying for
pregnancy (ESHRE, 2013)

33. Case 2
• Mrs PC, 32, trying for pregnancy for 1 year.
• All investigations (Semen, AMH, HSG)
normal.
• 2 cm endometrioma in left ovary.
• No pain.

34. 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
35

35. Case 2 (Contd)
• Mrs PC returns after 6 months after trying 5
cycles of ovulation induction.
• She is interested in IUI

36. IUI in Endometriosis
(ESHRE, 2013)
37

38. Limitations of IUI in endometriosis
• 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
• IVF, but not IUI, can be expected to overcome the
detrimental effects of a pelvic inflammatory milieu.
• 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)

39. Case 3
• Mrs PS, 28, 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, husband’s semen normal, tubes
not checked
• She wanted to defer surgery for 4 months because
of professional commitments

40. Preoperative hormonal therapies
 Furness S, Yap C, Farquhar C and Cheong YC. Pre and post-operative medical therapy
for endometriosis surgery. Cochrane Database Syst Rev 2004:CD003678. [New search
for studies, and content updated (no change to conclusions), published in Issue 1, 2011.]
 Clinicians should not prescribe preoperative hormonal treatment to improve the
outcome of surgery for pain in women with endometriosis
•In clinical practice, surgeons prescribe preoperative medical treatment with GnRH
analogues as this can facilitate surgery due to reduced inflammation, vascularisation of
endometriosis lesions and adhesions. However, there are no controlled studies supporting
this (ESHRE, 2013)
•Consider GnRH agonist x 3 cycles before surgery for deep infiltrating endometriosis
(NICE, 2017)
• From a patient perspective, medical treatment 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.

41. Case 2 (Contd)
• Mrs PS’s laparoscopy suggested grade IV
endometriosis
• Adhesiolysis could not be done
• Tubes and ovaries difficult to identify
• Tubal patency- Right- slow spill, Left- no spill
42

42. Next step
• IVF
• Re-operation by expert
43

43. IVF in Endometriosis
44

44. Medical treatment before ART
(ESHRE, 2013)
45

45. Surrey ES. "Endometriosis-Related Infertility: The Role of the Assisted
Reproductive Technologies", BioMed Research International, 2015

46. 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

47. 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,

48. 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.

49. GnRH Ago in IVF for endometriosis
1. Ultra-long protocol
2. Antagonist protocol → OPU → Freeze all →
GnRH Ago (3-6) → FET
Antagonist protocol may not be inferior to
agonist protocol (ESHRE, 2013)

50. Case 3 (Contd)
• Mrs PS was referred for IVF.
• She received 2 doses of injection (Leuprolide
acetate depot 3.75) IM before referral to the
IVF clinic

51. She does not want to defer IVF
anymore
• Start stimulation, utilizing the long agonist
protocol

52. Case 4
• 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
53

53. Option
• TESA-ICSI
• Laparoscopy if cyst size
increases/ pain/ difficult
OPU
• Evaluate
1. Cyst location
2. Accessibility of the
follicles
3. AFC
54

54. 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. 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]
55

55. Surgery prior to IVF
• Lowers serum AMH levels further
• 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

57. ESHRE, 2013
58

58. 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 and ovarian
endometriomas- ?
*Koch et al., 2012; RCOG, 2017

59. Risk of missing malignancy
• Extremely low in endometrioma
• The lifetime probability of Ca ovary 1-2% 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.
*RCOG, 2017

60. 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
61

61. Case 5
• 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 underwent left ovarian cystectomy 6 years
ago, no documents are available for that.
• She is having severe dysmenorrhoea, TVS
revealed AFC 2 (right) plus 3 (left) and 5 cm
chocolate cyst in right ovary
62

62. Options
• Laparoscopy and decide
• IVF, freeze all
63

63. 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.
64

64. Case 5 (Contd)
• Mrs DH underwent IVF-ICSI. 2 good quality
of embryos (grade A) on day3 were transferred
after GnRH-Ago down regulation.
• Beta hCG negative !!!
65

66. Molecular expression - Implantation
• Aromatase present in Endometrium of women with
endometriosis. (Noble et al 1995)
• B-3 integrin expression is aberrant in endometrium
of women with endometriosis (Lessey et al 1996)
Implantation Requires Synchrony
• Delayed implantation - leads to miscarriage
• Miscarriage goes up with each day of delay
• Clinical evidence for the window of implantation

67. 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

68. 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

69. Role of laparoscopy in IVF-Failure
and endoemtriosis
• 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)

70. Case 6
• Mrs JK, 29 years with “unexplained infertility”
of 2 years duration.
• Tried multiple cycles of OI and IUI
• HSG, AMH, Semen all normal
• No dysmenorrhoea
• Role of laparoscopy to diagnose
endometriosis and treatment?
71

71. 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

73. Recent Studies on Endometriosis and
Unexplained Infertility
• RCTs- Parazzini, 1999; Gad and Badroui, 2012
• Meta-Analysis
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

74. Recent Studies on Endometriosis and
Unexplained Infertility
• RCTs- Parazzini, 1999; Gad and Badroui, 2012
• Meta-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

75. • 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

76. • In the absence of evidence for tubal or other pelvic
pathology, laparoscopy is NOT warranted in
unexplained infertility (Level II-2B).

77. Deep endometriosis - asymptomatic
• Uncommon to be asymptomatic
• Uncomplicated- If no symptoms of ureter/ bowel
stenosis- No need of surgery
• 9 out of 10 will not progress
• Improper resection will worsen bowel/ bladder
symptoms
Operate, ONLY when-
1. Occlusive disease (ureter/ bowel)
2. Wishing natural conception, declining IVF
*Dunselman et al., 2014; Berlanda et al., 2016; ETIC, 2018

78. Before final decision
• Pain
• Age and Ovarian reserve
• Previous surgery
• Male and tubal factor
• Patient’s wishes

79. After the woman with endometriosis
conceives

80. Miscarriage Preterm birth
Small for gestational age Caesarean delivery

81. 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
• Medical therapy will NOT compensate for
inadequate surgery
• Surgery does NOT improve the success rate of IVF