ART and endometriosis

1. NARENDRA MALHOTRA
M.D., F.I.C.O.G., F.I.C.M.C.H
• Prof .DIU, Croatia
• President FOGSI (2008)
• Dean of I.C.M.U. (2008)
• Director Ian Donald School of Ultrasound
• National Tech. Advisor for FOGSI-G.O.I.—Mc Arthur Foundation EOC Course
• Hon Prof Ob Gyn at DMIMS,Sawangi,Advisor ART unit at MAMC & SMS Jaipur
• Practicing Obstetrician Gynecologist at Agra. Special Interest in High Risk Obs.,
Ultrasound, Laparoscopy and Infertility, ART & Genetics
• Member and Fellow of many Indian and international organisations
• FOGSI Imaging Science Chairman (1996-2000)
• Awarded best paper and best poster at FOGSI : 5 times, Ethicon fellowship, AOFOG young
gyn. award, Corion award, Man of the year award, Best Citizens of India award
• Over 30 published and 100 presented papers
• Over 50 guest lectures given in India & Abroad.Presented 15 orations.
• Organised many workshops, training programmes, travel seminars and conferences
• Editor 8 books, many chapters, on editorial board of many journals
• Editor SAFOG journal
• Editor of series of STEP by STEP books
• Revising editor for Jeatcoate’s Textbook of Gynaecology (2007)
• Very active Sports man, Rotarian and Social worker
MALHOTRA HOSPITALS
84, M.G. Road, Agra-282 010
Phone : (O) 0562-2260275/2260276/2260277, (R) 0562-2260279, (M) 98370-33335; Fax : 0562-2265194
E-mail : mnmhagra10@dataone.in / mnmhagra3@gmail.com
Website : www.malhotrahospitals.com
Apollo Pankaj Hospitals, Agra
Consultant for IVF at jalandhar,ludhiana,ambala,bhiwani,gwalior,allahabad,gorakhpur,udaipur,bariely,jaipur,delhi
Neapal & Bangladesh

2. ENDOMETRIOSIS AND ASSISTED
REPRODUCTION
OUR EXPERIENCE
jaideep malhotra
narendra malhotra
neharika malhotra
www.malhotrahospitals.com

3. ENDOMETRIOSIS
• Endometriosis is a challenging disease
observed in 20-40% subfertile women
• Alteration of immunologic milieu in the
peritoneal cavity creates an “hostile
enviornment” for gamete interaction and early
embryo development.
• Treatments available are:
medical,surgical,expectant and COH with ART

4. ENDOMETRIOSIS
Presence of tissue outside the uterus
which is similar to endometrium.
invasive but non neoplastic growth
pattern.

5. WHERE ALL CAN ECTOPIC
ENDOMETRIUM BE ?
• COULD BE PRESENT :
• REPRODUCTIVE TRACT
• URINARY TRACT
• GIT
• SURGICAL SCAR/UMBILICUS
• LUNG
• RARELY PERICARDIUM,PLEURA,CNS,NOSE,EYE
• Ectopic endometrium responds to changes in
ovarian hormones
• Cyclical bleeding within & from deposits leads to
inflammation ,then fibrosis, peritoneal damage &
adhesions

6. “ He who knows Endometriosis,
knows Gynecology ”
Sir William Osler
Endometriosis is a Benign ,
Estrogen dependant
Progressive Gynecological
Disease in women of
Reproductive Age ,
which is extremely common
Yet however , there is much that is still not
understood and the condition still arouses
Interest and Controversies
Robert W. Shaw

7. DIAGNOSIS & TREATMENT
• Laparoscopy is the
gold standard, as far
as diagnosis and
therapy.

8. In our practice ,on diagnostic laparoscopy, even small implants seen
are fulgurated, and case is managed aggressively.

9. Generally we try to do laparoscopy for endometriomas of more than
3cm in size ,with H/O infertility, however ,small endometriomas with
short period of infertility, medical management with ovarian stimulation
and IUI is tried for 3-4 cycles ,before taking the patient up for
laparoscopy

10. For endometriotic cysts ,most preferred is cystectomy, but whenever
this is not possible then removal of the cyst lining as much as possible
is done, along with fulguration of the rest .

11. Larger endometriomas, with long standing infertility, laparoscopic cystectomy is
the first choice and immediately the patient is put on GnRH analogues and
taken up for IVF. This has proved to be very successful .

12. ASSISTED REPRODUCTION
• Definitely referred for ART
little earlier
• IUI improves fertility in
minimal –mild endometriosis
• IUI with ovarian stimulation is
more effective
• IVF appropriate where IUI fails
or tubal function
compromised.

13. Indications for IVF - ICSI
 Tubal Infertility 30 %
 Male Infertility 20 %
 Endometriosis 10 %
 PCOS 5 %
 Unexplained Infertility 15 %
 3rd Party Reproduction 20 %
Egg Donation
Sperm Donation
Embryo Donation
Surrogacy

14. Endometriosis Fertility Index
The New Validated Endometriosis
Staging System

15. Endometriosis Fertility Index
The New Validated Endometriosis Staging System
• Objective: To develop a clinical tool that predicts pregnancy rates
(PRs) in patients with surgically documented endometriosis who
attempt non-IVF conception
• Design: Prospective data collection on 579 patients and
comprehensive statistical analysis to derive a new staging system—
the endometriosis fertility index (EFI)—from data rather than a priori
assumptions, followed by testing the EFI prospectively on 222
additional patients for correlation of predicted and actual outcomes
• Setting: Private reproductive endocrinology practice
• Patient(s): A total of 801 consecutively diagnosed and treated
infertile patients with endometriosis.

16. Descriptions of Least Function Terms

17. Endometriosis Fertility Index (EFI) Surgery Form
Least Function (LF) Score at Conclusion of Surgery

18. Endometriosis Fertility Index (EFI)

19. Estimated Percent Pregnant by EFI Score

20. MINIMAL & MILD ENDOMETRIOSIS ( Stage I & II )
Pregnancy Rate
Super Ovulation + IUI 10 - 15 % Per Cycle
Clomiphene
FSH / HMG + HCG 3-4 Cycles
Treatment with Intrauterine Insemination ( IUI )
Improves Fertility in MINIMAL & MILD ENDOMETRIOSIS .
IUI with Super Ovulation is effective but the
Role of Unstimulated IUI is Uncertain.
Tummon et. al, 1997
ESHRE Guideline
Recommendation Grade A , Evidence Level 1b

21. MINIMAL & MILD ENDOMETRIOSIS ( Stage I & II )
SUPEROVULATION ( HMG / FSH ) + IUI
To be considered for 3 – 4 Cycles
Super Ovulation & Intrauterine Insemination in Endometriosis
ENDOMETRIOSIS No. of PREGNANCIES / CYCLE FECUNDITY (%)
STAGE No. of CYCLES
MINIMAL 45/280 16
MILD 14/143 10
MODERATE 9/51 18
SEVERE 0/14 0
TOTAL 68/488 14
Data from Haney et al , 1997
‘ Endometriosis ’ has Decreased per Cycle Conception Rate
in Comparison with Male Factor & Unexplained Infertility
Hughes et al , 1997
Repetitive Super Ovulation + IUI Cycles have a Plateau effect
After 3 – 4 Cycles Deaton et al , 1990

22. MODERATE ( Stage III ) &
SEVERE ENDOMETRIOSIS ( Stage IV )
ENDOMETRIOMA
Cyst Wall Excision
Deep Infiltrating
Recto - Vaginal
ENDOMETRIOSIS

23. AFTER LAPAROSCOPIC SURGERY WHAT NEXT ?
Aggressive Treatment of ENDOMETRIOMAS is associated with
CUMULATIVE PREGNANCY RATE of 60 % over 12 Months
Koninck PR & Martin D ( 1994 ), Treatment of deeply infiltrating endometriosis ,
( review ) Curr Opin Obstet Gynecol , 6 : 231 - 241
No RCTs or Meta - analyses are available to answer the
question whether Surgical Excision of Moderate to Severe
Endometriosis Enhances Pregnancy Rate.
Based upon 3 studies (Adamson et al., 1993; Guzick et al., 1997;
Osuga et al., 2002) there seems to be a Negative Correlation between
the Stage of Endometriosis and the
Spontaneous Cumulative Pregnancy Rate after Surgical
Removal of Endometriosis, but statistical significance was
only reached in one study ( Osuga et al., 2002 )
ESHRE Guideline
Recommendation Grade B , Evidence Level 3

24. When is IVF - ICSI
Indicated in Endometriosis ?
 Failed Super Ovulation + IUI in Minimal - Mild
Endometriosis
 Failed Super Ovulation + IUI in Moderate - Severe
Endometriosis in Women < 35 years
 Moderate to Severe Endometriosis
in Women > 35 years
 Associated Tubal Factor
 Associated Male Factor
ESHRE 2005 Guidelines for
Diagnosis & Treatment of Endometriosis

25. ART: IVF-ICSI
IVF may improve the conception
rates
Several studies say that preg
rates are lower
Some studies have reported
equal preg rates
Lower fertilization rates
Decreased no of oocytes
retrieved
Oocyte development
Negative effect on
embryogenesis
Negative effect on implantation

26. Indications of IVF in
endometriosis
• stage III/IV
• Tubal block secondary to
endometriosis
• Associated male factor

27. ART procedures in
endometriosis
• COH + IUI in stage I/II when atleast one
tube is patent(live birth rate 11% vs.
2%)
• IVF in stage III/IV

28. Issues to be considered
• GnRH analogs requirement?
• Prolonged downregulation with depo or
daily injection long protocol?
• Cyst aspiration pre IVF
• Effect of stage of disease
• Agonist vs. Antagonist

29. Our experiences

30. Table1: Characteristics of patients
No. of patients 1258
Age year (mean ± ) 31.2 ±4.6
Infertile 1006 (80%)
Stage I 201 (20%)
Stage II 231 (23%)
Stage III 322 (32%)
Stage IV 252 (25%)

31. Table2: Pregnancy outcome after one year of
surgery without IVF
Laparoscopy 1006 (100%)
Pregnancy in I&II stage 402 (40%)
Pregnancy in III stage 41(4%)
Pregnancy in IV stage 10 (1%)

32. Table 3 : IVF outcome
Characteristic n (%)
No. of patients starting IVF 115
No. of patients retrieved oocytes 110 (95.65%)
No. of patients performed ET 107 (93.04%)
No. of patients achieved pregnancy 37 (32.17%)
No. of patients with live birth 29(25%)

33. Table 4: Recurrence of endometriosis after
one year stage III-IV
n =572
Recurrence 178 (31.1%)

34. ISSUES WITH ART
ENDOMETRIOSIS

35. Issues to be considered
• GnRH analogs requirement?
• Prolonged downregulation with depo or
daily injection long protocol?
• Cyst aspiration pre IVF
• Effect of stage of disease
• Agonist vs. Antagonist

36. Cochrane database 2006
• Three randomised controlled trials (with 165
women) were included.
• The live birth rate per woman was significantly
higher in women receiving the GnRH agonist
compared to the control group (OR 9.19, 95% CI
1.08 to 78.22).
• The clinical pregnancy rate per woman was also
significantly higher (three studies: OR 4.28, 95% CI
2.00 to 9.15).

37. Cochrane database 2006
• AUTHORS' CONCLUSIONS: The
administration of GnRH agonists for a
period of three to six months prior to
IVF or ICSI in women with
endometriosis increases the odds of
clinical pregnancy by fourfold.
(khurd/malhotra/ISAR/others)

38. Cochrane database 2007,issue 4
• Six studies, with a total of 552 women
• No statistically significant difference between the
use of depot GnRHa or daily GnRHa in clinical
pregnancy rates per woman (OR 0.94, 95% CI 0.65 to
1.37).
• However, the use of depot GnRHa for pituitary
desensitization in IVF cycles increased the number
of gonadotrophins ampoules (WMD 3.30, 95% CI 1.27
to 5.34) and the duration of the ovarian stimulation
(WMD 0.56, 95% CI 0.31 to 0.81), as compared with
daily GnRHa.

39. Cochrane database 2007,issue 4
• Long-acting GnRHa instead of a daily
dose in IVF cycles increases costs,
without improving pregnancy rates or
other outcomes

40. Stage of disease
• No difference in the IVF outcome was found
between patients with AFS stage I-II or AFS stage
III-IV disease.
• No evidence of an increased incidence of
miscarriage.
Human Reproduction, Vol. 10, No. 6, pp. 1507-1511,
1995
ESHRE

41. Ovarian Endometrioma
• Ovarian response was reduced during IVF-ET
cycles in patients with history of severe
endometriosis and laparoscopic excision of
endometriomas compared to women with mild or
minimal endometriosis without ovarian surgery.
Gynecol Obstet Fertil. 2006 Sep;34(9):808-12

42. Agonist vs.Antagonist
• Considering the implantation and clinical
pregnancy rates, COH with both GnRH antagonist
and GnRH-a protocols may be equally effective in
patients with mild-to-moderate endometriosis and
endometrioma who did and did not undergo
ovarian surgery.
Fertil Steril. 2007 Oct;88(4):832-9

43. U/L vs. B/L endometrioma
• A higher amount of FSH is needed to achieve an
acceptable IVF outcome after unilateral
endometrioma surgery. Indications for surgical
treatment of patients having larger and bilateral
cysts with an expectation for future fertility should
be cautiously reviewed
J Reprod Med. 2007 Sep;52(9):805-9

44. Does Surgery
Prior to IVF
Improve
IVF Success

45. Retrospective Matched Case - Control Study
Endometrioma <3 Cms
Laparoscopic No Surgery
Ovarian Cystectomy
Gonadotropins More Requirement
E 2 Peak Levels Lower Levels
Implantation Rate Same Same
Clinical Pregnancy Rate Same Same
Miscarriage Rate Same Same
Conclusion :
In Asymptomatic Patients with Endometriomas,
Not Larger than 4
Cms , offer IVF treatment directly,
because
- Shorter ‘ Time to Pregnancy ’
- Avoidance of Risk
- Decreased Cost
Garcia – Velasco JA et al
Removal of Endometriomas before IVF does not improve fertility outcomes :
a matched case - control study
Fertil Steril 2004 ; 81 :1194-97

46. Large Randomized Trials are needed to solve the issue of
Surgical Removal of Endometriomas ,
Prior to or After IVF Cycle
Considerations – Pregnancy Success
Endometriomas > 4 Cms
# Difficulties in Oocyte Retrieval
# Added Risk of Cyst Puncture during Ovum Pickup
• Risk of Rupture
• Infection
• Follicular Fluid Contamination
Somigliana E, Vercellini P, Vigano P, Ragni G, Corsignani P
Should Endometriomas be Treated before IVF – ICSI Cycles ?
Hum Reprod 2006;12:57-64

47. Endometrioma Excision
 Large Endometrioma > 4 cms
Oocyte Retrieval may be Difficult with possibility of Infection
and Follicular Fluid Contamination
 Symptomatic Women should undergo Excision
 Possibility of Occult Malignancy to be kept in mind
POST – SURGERY COUNSELING
• Chances of Successful IVF Outcome - Not
Decreased
• No Difference in Implantation Rate, Pregnancy Rate &
Miscarriage Rate ASRM Guidelines
• 20 – 30 % Recurrence Rate
• < 3 % Chances of Premature Ovarian Failure

48. SHOULD ENDOMETRIOMAS
BE EXCISED BEFORE ART
CYCLES
ALTHOUGH SURGICAL TT GIVES
A SATISFACTORY PREGNANCY RATE
THE CONCERN ABOUT REMOVAL
AND OVARIAN RESERVE.
LAP CYSTECTOMY BEFORE COH IVF
DOES NOT APPEAR TO IMPROVE
FERTILITY VIS A VIS DIRECT IVF
ASYMPTOMATIC ENDOMETRIOMAS
MAY BE BETTER DIRECTLY TAKEN FOR
IVF/ICSI
TVS ASPIRATION OF ENDOMETRIOMAS
BEFORE IVF/ICSI OFFERS A NONSURGICAL
APPROACH

49. ENDOMETRIOMA
PRE - IVF SURGICAL TREATMENT
LARGE ENDOMETRIOMA > 4 cms
LAPAROSCOPIC ? Aspiration Only
SURGERY ? Incision - Drainage &
Vaporize Implants
Lining The Cyst Wall
+
* Incision - Drainage &
Excision Of Cyst Wall
RCOG Guidelines , 2006
MEDICAL TREATMENT GnRH Agonist
3 – 6 Months
IMMEDIATELY AFTER MEDICAL TREATMENT
IVF - ICSI to be Done

50. ROLE OF USG GUIDED CYST
ASPIRATION

51. CYST ASPIRATION BEFORE
STIMULATION
• NO STATISTICALLY DIFFERENT RESPONSE SEEN,WITH OR
WITHOUT CYST ASPIRATION,SO WE DO NOT ASPIRATE
SMALL CYSTS BEFORE STIMULATION
• IF MORE THAN 4 CM THEN ASPIRATION IS MAY BE BETTER
THAN SURGERY (SPECIALLY RECURRENT CASES)

52. Stimulation protocols for
endometriosis
• Stimulation response for
patients with endometriosis/
endometriomas, generally
does not seem to be
compromised, however, after
the surgery, we do get smaller
number of follicles, though
pregnancy rates are
comparable.
INDIVIDUALISED IVF PROTOCOLS ACCORDING TO VARIOUS STAGES ON
ENDOMETRIOMAS
NO PROSPECTIVE STUDY COMAPRING AGONIST/ANTAGONIST PROTOCOL

53. Endometriosis & IVF - ICSI
GnRH Agonist
3 RCTs of 165 patients
OR 4.28 95 % CI 2.00 – 9.15
 3 – 6 Cycles of GnRH Agonist before IVF - ICSI
 Improves the Outcome of Pregnancy and
 Reduces Miscarriage
 GnRH Agonist Modulates NK Cells of Uterus
 Normalises the Endometrial Aromatase expression
Sallam et al, 2006

54. Endometrioma & IVF - ICSI
Controlled Ovarian Stimulation
Post - Surgical Patients Need More Gonadotropins
Reduced E 2 Levels
Oocyte Retrieval
 Decreased Oocyte yield due to Poor Folliculogenesis
 Decreased Ovarian Reserve in
Post - Surgical Cases
 Technical Difficulty

55. Agonist vs Antagonist protocol
• We prefer to do long agonist protocol, for all our
endometriosis patients, however of late, we have
done quite a few cycles with antagonist protocol
and have got comparable results in mild to
moderate endometriosis.
AGONIST PROTOCOLS IN GRD 1 AND 2 DISEASE GIVES SAME RESULTS
AS IN TUBAL FACTOR
ANTAGONIST MAY BE USED AS A REASONABLE CHOICE FOR
POOR RESPONDERS
THE RESULTS OF IVF IN ADVANCED ENDOMETRIOSIS IS 36% REDUCED AS
COMPARED TO OTHER INDICATIONS
(IMPAIRED FERTILIZATION AND IMPLANTATION)

56. Deeply Infiltrating Endometriosis & ART
Prospective study of 169 Patients, < 38 years of AGE
with
Symptomatic Deeply Infiltrating Endometriosis
Pregnancy Rate achieved with IVF was
Significantly Higher in Women who chose
Preliminary Surgical Treatment
Bianchi PH, Pareira RM, Zanatta A, Alegretti JR, Motta EL, Serafini PC,
Extensive excision of deep infiltrating endometriosis before in vitro fertilization
significantly improves pregnancy rates
J Minim Invasive Gynecol 16:174, 2009,

57. Endometrioma & IVF - ICSI
Controlled Ovarian Stimulation
Post - Surgical Patients Need More Gonadotropins
Reduced E 2 Levels
Oocyte Retrieval
 Decreased Oocyte yield due to Poor Folliculogenesis
 Decreased Ovarian Reserve in
Post - Surgical Cases
 Technical Difficulty

58. Endometriosis Management
IVF or ICSI
Which is better ?
Barnhart et al 2002 , reported Less Fertilization in IVF in Women
with Endometriosis
 Improved Ovarian Stimulation and
TVS Oocyte Reterival Techniques have
Increased Oocyte yield which
Compensates for Reduced Fertilization Rate in IVF
 ICSI is always Better than IVF
Endometriosis - “ ICSI for ALL ”

59. Our strategy
• Laparoscopy for all unexplained infertility
• Any endometriotic implant visualised during laparoscopy is
taken care of.
• Short history of infertilty ,with endometriomas , <3cms,ovarian
stimulation and IUI if required.
• Endometriomas >3cms,laparoscopy, followed by, ovarian
stimulation and IUI
• If longstanding infertility with endometriomas,surgery followed
by IVF immediately.Bigger and recurrent cysts are drained
before stimulation cycle.
• Recurrence is quite common, so proper couselling is required.

60. Problem with refferal for ART
• Infertile women with endometriosis do
not systamatically undego early ART
• Attitude of women towards ART
• Possible benefits of second line
surgery
• IVF as an emotional and physical
burden
• Gynaecs not involved in ART are still
hesitant for early refferal even with grd
3-4 disease(lack of awareness)

61. ENDOMETRIOSIS SUMMARY
 ENDOMETRIOSIS at ALL STAGES has a
NEGATIVE IMPACT on FERTILITY
Causes SUBFERTILITY
 More Severe the Disease Lesser is the Fecundity
 H / O PAIN, Clinical Exam, USG, Doppler, MRI & CA 125
help in Provisional Diagnosis
 LAPAROSCOPY is the GOLD STANDARD to make a
Correct & Confirmed Diagnosis
 TREATMENT – INDIVIDUALIZED
 LAPAROSCOPIC SURGERY is the GOLD STANDARD
for Management of ENDOMETRIOSIS
1st Line of Treatment for ALL STAGES
EXCISE or DESTROY LESIONS
Surgery Enhances Pregnancy Success & brings Pain Relief

62. ENDOMETRIOSIS SUMMARY
ENDOMETRIOMA Considerations
LOSS of OVARIAN RESERVE Vs RECURRENCE
Aspiration & Drainage
Incision & Drainage & Vaporization
 Incision & Drainage & Excision
CUMULATIVE PREGNANCY RATE 43 % - 60 %
following Laparoscopic Surgery
ASSISTED REPRODUCTIVE TECHNOLOGY
SUPER – OVULATION + IUI 4 – 6 Cycles
Enhances Lowered Fecundity
IVF – ICSI
30 - 40 % per Cycle Live Birth
• Reduced with Severity of Endometriosis
• Reduced in Comparison with
Tubal Infertility, Ovulatory Dysfunction,
Male Factor, Unexplained Infertility

63. PRE IVF – ICSI TREATMENTS
 Laparoscopic Surgery
 Endometrioma > 4 Cms
 Endometrioma with Symptoms
 Symptomatic Deeply Infiltrating Endometriosis
 Inj. GnRH (lupride)
3 – 6 Months before IVF – ICSI
ICSI Preferred over IVF to
Improve Reduced Fertilization Rate in
ENDOMETRIOSIS

64. conclusion
• ART-IUI/IVF/ICSI is currently an
effective treatment in women with
endometriosis.
• There is a general consensus that IVF
should be recommended in infertile
women who fail to get pregnant after
surgical treatment.
• In grd d 3-4 disease early reference to
IVF/ICSI

65. CONCLUSION
• Endometriosis is an example – the more
treatments there are for a disease ,the
more likely it is that none is ideal
• Albert Yuzpe

66. endometriosis remains an
enigma shrouded in mystery
is this
chronic,enigmatic and incurable ??
Chronic ..YES,potentially curable and preventable with surgery,but the surgery
must Be complete and performed by a qualified gynaec surgeon with
experience in Dealing with endometriosis

67. HE WHO KNOWS
ENDOMETRIOSIS,KNOWS
GYNAECOLOGY- Sir William Osler
Thank you

68. THANKYOU