Evidence-based management of endometriosis-associated infertility

1
Evidence-based management of endometriosis-associa
ted infertility

• Hassan N. Sallam,
• MD, FRCOG, PhD (London)
• Professor in Obstetrics and Gynaecology
• The University of Alexandria, and
• Clinical and Scientific Director, Alexandria
  Fertility Center, Alexandria, Egypt

3rd Congress of Society of Reproductive Medicine,
5 9
October 2011, Antalya / Turkey
2
The old Alexandria medical school
3
The uterus (after Soranos of Ephesus)
4
Karl, baron von Rokitansky (1804-1878)
5
Does endometriosis affect infertility?
YES 1. More commonly found in infertility
patients (Mahmoud and Templeton, 1991) 2.
Pregnancy rates are higher in treated patients
(Marcoux et al, 1997) 3. Pregnancy with AID is
lower with endometriosis (Jansen, 1986) 4.
Pregnancy with IVF is lower with endometriosis
(Barnhart et al, 2002)
6
Prevalence of endometriosis (Mahmoud and
Templeton, 1991) (OS)
25
21
15
6
Mahmoud and Templeton, Hum Reprod 6(4) 544-9,
1991
7
Laparoscopic surgery v/s no surgery (RCT)
(Canadian Collaborative Group, Marcoux et al,
1997)
P value No surgery (n 169) Surgery (n172)
0.006 17.7 30.7 CPR
lt0.05 2.4 4.7 Fecundity
Marcoux et al, N Engl J Med 337(4)217-22, 1997
8
AID in minimal endometriosis(Fecundity rates per
month of exposure)
Jansen RP, Fertil Steril 46 (1) 141-3, 1986
9
IVF in endometriosis versus tubal infertility
(CPR)
Barnhart et al, Fertil Steril 77(6) 1148-55, 2002
10
How does endometriosis affect infertility?

• 1. Tubal adhesions
• 2. Impaired gamete interaction
• 3. Impaired implantation

11
i.e. Endometrial receptivity does not play a role
in diminished pregnancy rates in endometriosis
Cross-over oocyte donation study (Pellicer et al,
2001)
Oocytes from normal controls to endometriosis
patients
Oocytes from endometriosis patients to normal
controls
Reduced implantation rates
Similar implantation rates
12
Causes of diminished pregnancy and implantation
rates in IVF for endometriosis
Poor quality of oocytes
(Hull et al, 1998 Norenstedt et al, 2001)
Lower quality embryos with a reduced ability to
implant (Simon
et al, 1994 Arici et al, 1996)
13
The poor quality of the oocytes is probably due
to the altered follicular environment

• Increased progesterone concentration in FF
  (Pellicer et al, 1998)
• Increased concentration of IL-6 in FF
  (Pellicer et al, 1998)
• Lower levels of cortisol in FF
  (Smith et al, 2002)
• Lower concentrations of IGFBP-1 in FF
  (Cunha-Filho et al, 2003)

14
The poor quality of the oocytes is probably due
to the altered follicular environment (cont)

• Increased expression of the TNF-a in the
  cultured granulosa cells (Carlberg et al, 2000)
• Increased rate of apoptosis (cell death) in the
  granulosa cells mediated by elevated
  concentrations of soluble Fas ligand in serum and
  peritoneal fluid (Garcia-Velasco et al, 2002)

15
Effect of GnRHa on the endometrium in
endometriosis (CCT)
P value Fresh cycles Frozen cycles
lt0.05 11.9 16.9 LBR
lt0.05 12.7 18.2 CPR
Mohamed et al, Eur J Obstet Gynecol Reprod Biol
156(2)177-80 , 2011
16
Management of endometriosis-associated infertility

• 1. Surgical treatment
• 2. Medical treatment
• 3. Combined medical and surgical therapy
• 4. Controlled ovarian hyperstimulation /- IUI
• 5. Assisted reproductive techniques

17
Evidence-based medicine

• Level A The recommendation based on good and
  consistent scientific evidence (RCT)
• Level B The recommendation is based on limited
  or inconsistent scientific evidence (CT, cohort,
  case control)
• Level C The recommendation is based primarily
  on consensus and expert opinion

18
Problems in the evaluation of management options

• 1. Any management option should be compared to
  expectant management
• 2. The monthly fecundity rate (MFR) is more
  meaningful than the pregnancy rate (PR)

19
Expectant management in endometriosis
(Prospective cohort study PCS)
Monthly fecundity rate (MFR) Cumulative pregnancy rate (CPR) Degree of endometriosis
5.7 52.9 Mild
3.2 25 Moderate
0 0 Severe
3.1 24.4 All cases
Olive et al, Fertil Steril 44(1)35-41, 1985
20
Expectant management of stage I and II
endometriosis (CCT)
Miscarriage rate Cumulative pregnancy rate
14.3 55 No treatment
6.3 71 MPA
11 46 Danazol
NS NS P value
Hull et al, Fertil Steril 47(1)40-4, 1987
21
Management of endometriosis-associated infertility

• 1. Surgical treatment
• 2. Medical treatment
• 3. Combined medical and surgical therapy
• 4. Controlled ovarian hyperstimulation /- IUI
• 5. Assisted reproductive techniques

22
Problems in evaluating surgical management of
endometriosis

• 1. Few studies are controlled
• 2. Few studies report the fecundity rate
• 3. Techniques/skills differ
• 4. Recognition of atypical lesions
• 5. Use of adhesion prevention agents

23
White endometriosis, clear endometriosis, red
endometriosis and powder burn lesions.
24
Powder burns on the right uterosacral ligament
causing painful intercourse
25
Surgical treatment of endometriosis

• 1. Ablation and/or resection of laparoscopic
  lesions
• 2. Drainage /- excision/ablation of
  endometriomas

26
Surgical treatment of endometriosis

• 1. Ablation and/or resection of laparoscopic
  lesions
• 2. Drainage /- excision/ablation of
  endometriomas

27
Power sources in endoscopic surgery (Sutton, 1995)

• 1. Electrocautery (mono or bipolar)
• 2. CO2 Laser
• 3. Fibre lasers (KTP, argon, contact NdYAG,
  tunable dye or diode laser)
• 4. Harmonic scalpel
• 5. Helica thermal coagulator

28
Resection or ablation for minimal or mild
endometriosis - Canadian Collaborative Group (RCT)
P value Diagnostic laparoscopy (n 169) Resection or ablation (n 172)
lt0.01 17.7 30.7 Clinical pregnancy rate
lt0.05 2.4 4.7 Fecundity rate
0.91 21.6 20.6 Miscarriage rate
Marcoux et al, N Engl J Med 337(4)217-22, 1997
29
Resection or ablation for minimal or mild
endometriosis (RCT)
P value Diagnostic laparoscopy (n 47) Resection or ablation (n 54)
NS 29 24 Clinical pregnancy rate
NS 22.2 19.6 Birth rate
NS 23.1 16.7 Miscarriage rate
Parazzini et al, Hum Reprod 141332-4, 1999
30
Resection or ablation versus no surgery for
minimal or mild endometriosis (MA)

• Clinical pregnancy rate
• OR 1.613 (95 CI 1.04 2.50)
• P 0.042

Sallam et al, submitted for publication
31
Resection or ablation for moderate and severe
endometriosis (stages III and IV)
Fecundity rate Cumulative pregnancy rate
6.7 70 Luciano et al, 1992 (OS)
2.4 57.5 Busacca et al, 1999 (OS)
32
Surgical treatment of endometriosis

• 1. Ablation and/or resection of laparoscopic
  lesions
• 2. Drainage /- excision/ablation of
  endometriomas.

33
leads torecurrence in 50-100 of
cases(Nezhat et al, 1988 Vercillini et al,
1992 Olive, 1989)
Simple drainage of endometriomas
34
Excision of endometriomas
35
Drainage resection/ablation of cyst wall
CPR Technique n Study
38 Laser stripping 32 Daniell et al, 1991
30.4 KTP laser ablation 23 Marrs et al, 1991
50 Cyst stripping 52 Wood et al, 1992
42.8 Cyst stripping 21 Bateman et al, 1994
45 Stripping GnRHa 11 Montanino et al, 1996
51 CO2Laser GnRHa 814 Donnez et al, 1996
36
Drainage resection/ablation of cyst wall (cont)
CPR Technique n Study
45 CO2 Laser KTP 66 Sutton et al, 1997
50 Cyst stripping 84 Hemings et al, 1998
66.7 Cyst stripping 64 Beretta et al, 1998
57.5 Cyst stripping 57 Busacca et al, 1999
53 Cyst stripping 32 Milingos et al, 1999
39.5 KTP laser/diathermy 39 Jones Sutton, 2002
37
Surgical versus non-surgical therapy
Adamson and Pasta, Am J Obstet Gynecol
1711488-504, 1994
38
Laparoscopic excision versus electro-coagulation
in mild endometriosis (CCT)
P value Excision (n 53) Electro-coagulation (n 48)
NS 53.5 57.1 Pregnacy rate
NS 17.4 12.5 Miscarriage rate
13.3 months 10.7 months Duration to pregnancy
Tulandi and Al-Took, Fertil Steril 69(2)229-31,
1998
39
Laparoscopy versus laparotomy(Cumulative
pregnancy rates CCT)
P value Laparotomy Laparoscopy
NS 74.3 67.4 Stage I II
lt0.05 44.4 62.2 Stage III IV
Adamson et al, Fertil Steril 59(1) 35-44, 1993
40
Laparoscopy versus laparotomy in severe
endometriosis (CCT)
P value Laparotomy (n 149) Laparoscopy (n 67)
NS 62.7 44.9 CPR
NS 20.3 16.4 Recurrence of dysmenorrhoa
NS 15.4 33.3 Recurrence of dyspareunia
Crosignani et al, Fertil Steril 66(5) 706-11,
1996
41
Management of endometriosis-associated infertility

• 1. Surgical treatment
• 2. Medical treatment
• 3. Combined medical and surgical therapy
• 4. Controlled ovarian hyperstimulation /- IUI
• 5. Assisted reproductive techniques

42
Medical treatment of endometriosis

• (A) Ovarian suppression
• - Medroxyprogesterone (MPA)
• - Gestrinone
• - GnRH agonists
• - Danazol
• (B) Aromatase inhibitors
• - Letrozole
• (C) Novel approaches

43
Ovarian suppression for endometriosis (CPR)
P value Ovarian suppression No therapy
NS 25 24 Thomas et al, 1987 (RCT) (Gestrinone)
NS 37.2 57.4 Bayer et al, 1988 (RCT) (Danazol)
NS 33 46 Telimaa et al, 1988 (RCT) (Danazol)
NS 42 46 Telimaa et al, 1988 (RCT) (MPA)
NS 37 61 Fedele et al, 1992 (RCT) (Buserelin)
44
Ovarian suppression for endometriosis(Hughes et
al, 2007) (Odds ratio for pregnancy)

• Ovarian suppression v/s no treatment or placebo
• OR 0.79 (95 CI 0.54 1.14)
• Ovarian suppression v/s danazol
• OR 1.37 (95 CI 0.94 1.99)

Hughes et al, Cochrane Database Syst Rev. 2007
Jul 18(3)CD000155
45
Effect of letrozole on the ASRM score (OS)
Ailawadi et al, Fertil Steril 81(2) 290-6, 2004
46
Letrozole for the treatment of endometriosis (RCT)
P value Controls (n 57) Triptorelin (n 40) Letrozole (n 47)
NS 28.1 27.5 23.4 CPR after 12 months
NS 5.3 5 6.4 Recur-rence
Alborzi et al, Arch Gynecol Obstet 284 105-10,
2011
47
Novel medical therapies

• 1. Antiangiogenic agents (Dabrosin et al, 2002)
• 2. SPRMs (e.g. J867) (Chwalisz et al, 2002)
• 3. GnRH antagonists (e.g. ganirelix and
  cetrorelix) (Kupker et al, 2002)
• 4. Mifepristone (Murphy et al, 2002)
• 5. Local therapy (e.g. methotrexate) (Mesogitsis
  et al, 2000)

48
Management of endometriosis-associated infertility

• 1. Surgical treatment
• 2. Medical treatment
• 3. Combined medical and surgical therapy
• 4. Controlled ovarian hyperstimulation /- IUI
• 5. Assisted reproductive techniques

49
Pre-operative medical treatment for endometriosis
(CCT)
Buserelin Gestrinone Danazol
73 34 30 Regression of endometriosis
58 47 45 Cumulative pregnancy rate
Donnez et al, Int J Fertil 35(5) 297-301, 1990
50
Post-operative GnRHa for endometriosis
(Cumulative pregnancy rates - CPR)
P value Surgery without GnRHa Surgery with GnRHa
NS 18 19 Parazzini et al, 1994 (RCT)
NS 18.4 11.6 Vercellini et al, 1999 (RCT)
51
Pre and post operative medical therapy for
endometriosis surgery (Cochrane review)

• Pre-surgical medical therapy showed a
  significant improvement in AFS scores
• Post-surgical hormonal suppression showed no
  benefit for the outcomes of pain or pregnancy
  rates but a significant improvement in disease
  recurrence

Yap et al, Cochrane Database Syst
2004(3)CD003678
52
Management of endometriosis-associated infertility

• 1. Surgical treatment
• 2. Medical treatment
• 3. Combined medical and surgical therapy
• 4. Controlled ovarian hyperstimulation /- IUI
• 5. Assisted reproductive techniques

53
COH in stages I II endometriosis
P value COH No therapy Intervention
lt0.05 22 9 Clomiphene citrate Simpson et al, 1992 (CCT)
NS 37.4 24 HMG Fedele et al, 1992 (RCT)
54
COH IUI in stages I II endometriosis
P value COH IUI No therapy
lt0.05 9.5 3.3 Deaton et al, 1990 (RCT)
lt0.005 11 2 Tummon et al, 1997 (RCT)
NS 32 32 Serta et al, 1992 (CCT)
lt0.005 15 1.4 Peterson et al, 1994 (CCT)
55
COH IUI in endometriosis (Meta-analysis)
Mean cycle fecundity (SD) Number of cycles Number of studies
0.14 783 5 Stage I II
0.08 179 3 Stage III IV
Peterson et al, Fertil Steril 62(3)535-44, 1994
56
Management of endometriosis-associated infertility

• 1. Surgical treatment
• 2. Medical treatment
• 3. Combined medical and surgical therapy
• 4. Controlled ovarian hyperstimulation /- IUI
• 5. Assisted reproductive techniques

57
Intracytoplasmic sperm injection (ICSI)
58
IVF in endometriosis versus tubal infertility
(CPR)
Barnhart et al, Fertil Steril 77(6) 1148-55, 2002
59
Surgical approaches to treat endometriosis before
IVF and ICSI

• 1. Surgical removal of endometriomas appears to
  diminish the success rate of IVF/ICSI (Aboulghar
  et al, 2003)
• 2. Laparoscopic cystectomy has no effect (Canis
  et al, 2001 Marconi 2002)

60
Surgical approaches to treat endometriosis before
IVF and ICSI (cont)

• 3. LASER vaporization of the internal wall of
  endometriomas did not affect the outcome (Donnez
  et al, 2001 Wyns et al, 2003)
• 4. Ultrasound-directed cyst aspiration is
  associated with mixed results (Dicker et al,
  1991 Suganuma et al, 2002) and an increased
  incidence of infection (Nargund and Parsons, 1995)

61
Medical approaches to treat endometriosis before
IVF and ICSI

• 1. Corticosteroids (Kim et al, 1997) (RCT but
  small and not repeated)
• 2. Danazol (Tei et al, 1998) (RCT but small and
  not repeated)
• 3. GnRH agonists (Oehninger et al, 1989 Dicker
  et al, 1990 Dale et al, 1990 Nakamura et al,
  1992 Curtis et al, 1993 Marcus et al, 1994
  Chedid et al, 1995 Ruiz-Velasco and Allende,
  1998)

62
Corticosteroids before IVF in endometriosis (RCT)
P value Controls (n 57) Corticosteroids (n 54)
lt0.05 22.8 42.6 CPR
NS 15.4 21.7 Miscarriage rate
NS 15.4 17.4 Multiple pregnancy rate
Kim et al, J Obstet Gynaecol Res 23(5) 463-70,
1997
63
Danazol before IVF in repeated IVF failures (RCT)
P value Controls Danazol (400 mg/d for 12 wks)
41 41 Number
lt0.05 19.5 40 CPR
Tei et al, J Reprod Med 43(6) 541-6, 1998
64
Sallam et al, Cochrane Database Syst Rev
25(1)CD004635, 2006
65
GnRH agonist v/s no agonist before IVF(Clinical
pregnancy rate per woman)
Sallam et al, Cochrane Database Syst Rev
25(1)CD004635, 2006
66
GnRH agonist v/s no agonist before IVF(Ongoing
pregnancy rate per woman)
Sallam et al, Cochrane Database Syst Rev
25(1)CD004635, 2006
67
GnRH agonist v/s no agonist before IVF (Number of
oocytes retrieved)
Sallam et al, Cochrane Database Syst Rev
25(1)CD004635, 2006
68
GnRH agonist v/s no agonist before IVF (Dose of
HMG or FSH required)
Sallam et al, Cochrane Database Syst Rev
25(1)CD004635, 2006
69
Effect of GnRHa on adenomyosis (CCT)
P value Control cycles (n54) Adenomyosis cycles (n20)
NS 42.0 48.0 Fertilization
NS 28.2 31.0 Implantation
NS 26.1 19.0 Miscarriage
NS 30.0 35.0 Preg gt12 wks
Mijatovic et al, Eur J Obstet Gynecol Reprod Biol
151(1)62-5 , 2010
70
Conclusions

• 1. In endometriosis-associated infertility,
  expectant management is associated with 50 CPR
  in stages I and II, while patients with stages
  III and IV rarely become pregnant (B)
• 2. In general, surgical management is associated
  with a significantly higher pregnancy rate
  compared to medical or no treatment (B)
• 3. Simple cyst aspiration results in recurrence
  in 50 of instances (B)

71
Conclusions (cont)

• 4. Drainage of endometriomas ablation or
  resection of their walls results in a higher
  pregnancy rate compared to no therapy (B)
• 5. Laparoscopic ablation and/or resection in
  stages I II is associated with a significantly
  higher pregnancy rate compared to diagnostic
  laparoscopy (A)
• 6. Danazol, gestrinone, MPA, letrozole and GnRH
  agonists do not improve pregnancy rates over
  placebo or no therapy (A)

72
Conclusions (cont)

• 7. Combining laparoscopic surgery and medical
  therapy does not improve pregnancy rates over
  surgery alone (A)
• 8. COHIUI improves the pregnancy rates
  significantly compared to no therapy in stages I
  and II endometriosis (A)
• 9. Women with endometriosis treated with IVF have
  significantly lower pregnancy rates compared to
  tubal infertility (B)
• 10. Long-term GnRHa before IVF improves the
  pregnancy rates significantly (A)

73
Bibliotheca Alexandrina
74
Evidence-based management of endometriosis-associa
ted infertility

• Hassan N. Sallam,
• MD, FRCOG, PhD (London)
• Professor in Obstetrics and Gynaecology
• The University of Alexandria, and
• Clinical and Scientific Director, Alexandria
  Fertility Center, Alexandria, Egypt

3rd Congress of Society of Reproductive Medicine,
5 9
October 2011, Antalya / Turkey
75
(No Transcript)
76
GIFT versus COHIUI in endometriosis (CCT)
(Delivery rate per cycle)
P value COHIUI GIFT
lt0.05 14.7 28.1 Stages I II
NS 12.5 40.9 Stages III IV
Lodhi et al, Gynecol Endocrinol 19(3)152-9, 2004
77
Effect of GnRHa on stage III and IV endometriosis
P value Control cycles Long term GnRH agonist




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