Transcript Slide 1

Evidence-based management of
endometriosis-associated 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
The old Alexandria medical school
The uterus (after Soranos of Ephesus)
Karl, baron von Rokitansky (1804-1878)
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)
Prevalence of endometriosis
(Mahmoud and Templeton, 1991) (OS)
25
25%
20
21%
15
15%
10
5
6%
0
Sterilization
Infertility
Pain
DUB/TAH
Mahmoud and Templeton, Hum Reprod 6(4): 544-9, 1991
Laparoscopic surgery v/s no surgery (RCT)
(Canadian Collaborative Group, Marcoux et al, 1997)
Surgery
(n=172)
No surgery
(n= 169)
P value
CPR
30.7%
17.7%
0.006
Fecundity
4.7%
2.4%
<0.05
Marcoux et al, N Engl J Med 337(4):217-22, 1997
AID in minimal endometriosis
(Fecundity rates per month of exposure)
1
0.9
0.8
0.7
0.6
Normal pelvis
Endometriosis
0.5
0.4
0.3
0.2
0.1
0
1
3
5
7
9
11
13
15
Jansen RP, Fertil Steril 46 (1): 141-3, 1986
IVF in endometriosis versus tubal infertility (CPR)
Barnhart et al, Fertil Steril 77(6): 1148-55, 2002
How does endometriosis affect
infertility?
1. Tubal adhesions
2. Impaired gamete
interaction
3. Impaired implantation
Cross-over oocyte donation
study (Pellicer et al, 2001)
Oocytes from normal
controls to
endometriosis patients
Oocytes from
endometriosis patients
to normal controls
Similar implantation rates
Reduced implantation rates
i.e. Endometrial receptivity does not play a role in
diminished pregnancy rates in endometriosis
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)
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)
The poor quality of the oocytes is
probably due to the altered follicular
environment (cont…)
• Increased expression of the TNF-α 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 (GarciaVelasco et al, 2002)
Effect of GnRHa on the endometrium
in endometriosis (CCT)
Frozen cycles
Fresh
cycles
P value
LBR
16.9 %
11.9 %
<0.05
CPR
18.2 %
12.7 %
<0.05
Mohamed et al, Eur J Obstet Gynecol Reprod Biol 156(2):177-80 , 2011
Management of endometriosisassociated infertility
1. Surgical treatment
2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/- IUI
5. Assisted reproductive techniques
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
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)
Expectant management in endometriosis
(Prospective cohort study PCS)
Degree of
endometriosis
Cumulative
Monthly
pregnancy rate fecundity rate
(CPR)
(MFR)
Mild
52.9%
5.7%
Moderate
25%
3.2%
Severe
0%
0%
All cases
24.4%
3.1%
Olive et al, Fertil Steril 44(1):35-41, 1985
Expectant management of stage I and II
endometriosis (CCT)
Miscarriage
rate
No treatment
Cumulative
pregnancy
rate
55%
MPA
71%
6.3%
Danazol
46%
11%
P value
NS
NS
Hull et al, Fertil Steril 47(1):40-4, 1987
14.3%
Management of endometriosisassociated infertility
1. Surgical treatment
2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/IUI
5. Assisted reproductive techniques
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
White endometriosis, clear endometriosis, red
endometriosis and powder burn lesions.
Powder burns on the right uterosacral
ligament causing painful intercourse
Surgical treatment of endometriosis
1. Ablation and/or
resection of
laparoscopic
lesions
2. Drainage +/excision/ablation
of
endometriomas
Surgical treatment of endometriosis
1. Ablation and/or
resection of
laparoscopic
lesions
2. Drainage +/excision/ablation
of
endometriomas
Power sources in endoscopic
surgery (Sutton, 1995)
1. Electrocautery (mono or bipolar)
2. CO2 Laser
3. Fibre lasers (KTP, argon, contact
Nd:YAG, tunable dye or diode laser)
4. Harmonic scalpel
5. Helica thermal coagulator
Resection or ablation for minimal or mild
endometriosis - Canadian Collaborative Group
(RCT)
Clinical
pregnancy rate
Fecundity
rate
Miscarriage
rate
Resection Diagnostic
or ablation laparoscopy P value
(n = 172)
(n = 169)
30.7%
17.7%
<0.01
4.7%
2.4%
<0.05
20.6%
21.6%
0.91
Marcoux et al, N Engl J Med 337(4):217-22, 1997
Resection or ablation for minimal or
mild endometriosis (RCT)
Clinical
pregnancy rate
Birth rate
Miscarriage
rate
Resection Diagnostic
or ablation laparoscopy P value
(n = 54)
(n = 47)
24%
29%
NS
19.6%
22.2%
NS
16.7%
23.1%
NS
Parazzini et al, Hum Reprod 14:1332-4, 1999
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
Resection or ablation for moderate and
severe endometriosis (stages III and IV)
Cumulative
Fecundity
pregnancy rate
rate
Luciano et al, 1992
(OS)
70%
6.7%
Busacca et al, 1999
(OS)
57.5%
2.4%
Surgical treatment of endometriosis
1. Ablation and/or
resection of
laparoscopic
lesions
2. Drainage +/excision/ablation
of
endometriomas.
Simple drainage of endometriomas
leads to
recurrence in 50-100%
of cases
(Nezhat et al, 1988;
Vercillini et al, 1992;
Olive, 1989)
Excision of endometriomas
Drainage + resection/ablation of cyst wall
Study
n
Technique
CPR
Daniell et al, 1991
32
Laser + stripping
38%
Marrs et al, 1991
23
KTP laser ablation 30.4%
Wood et al, 1992
52
Cyst stripping
50%
Bateman et al, 1994
21
Cyst stripping
42.8%
Montanino et al, 1996 11 Stripping + GnRHa
Donnez et al, 1996
814 CO2Laser + GnRHa
45%
51%
Drainage + resection/ablation of cyst
wall (cont…)
Study
n
Technique
CPR
Sutton et al, 1997
66
CO2 Laser + KTP
45%
Hemings et al, 1998
84
Cyst stripping
50%
Beretta et al, 1998
64
Cyst stripping
66.7%
Busacca et al, 1999
57
Cyst stripping
57.5%
Milingos et al, 1999
32
Cyst stripping
53%
Jones & Sutton, 2002 39 KTP laser/diathermy 39.5%
Surgical versus non-surgical therapy
Adamson and Pasta, Am J Obstet Gynecol 171:1488-504, 1994
Laparoscopic excision versus electrocoagulation in mild endometriosis (CCT)
Pregnacy
rate
Miscarriage
rate
Duration to
pregnancy
Electrocoagulation
(n = 48)
57.1%
Excision
(n = 53)
P
value
53.5%
NS
12.5%
17.4%
NS
10.7 months
13.3
months
Tulandi and Al-Took, Fertil Steril 69(2):229-31, 1998
Laparoscopy versus laparotomy
(Cumulative pregnancy rates – CCT)
Laparoscopy Laparotomy P value
Stage I & II
67.4%
74.3%
NS
Stage III & IV
62.2%
44.4%
<0.05
Adamson et al, Fertil Steril 59(1): 35-44, 1993
Laparoscopy versus laparotomy in
severe endometriosis – (CCT)
Laparoscopy Laparotomy
P
value
(n = 67)
(n = 149)
44.9%
62.7%
NS
CPR
Recurrence of
dysmenorrhoa
Recurrence of
dyspareunia
16.4%
20.3%
NS
33.3%
15.4
NS
Crosignani et al, Fertil Steril 66(5): 706-11, 1996
Management of endometriosisassociated infertility
1. Surgical treatment
2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/- IUI
5. Assisted reproductive techniques
Medical treatment of endometriosis
(A) Ovarian suppression
- Medroxyprogesterone (MPA)
- Gestrinone
- GnRH agonists
- Danazol
(B) Aromatase inhibitors
- Letrozole
(C) Novel approaches
Ovarian suppression for endometriosis (CPR)
No
therapy
Thomas et al, 1987
(RCT) (Gestrinone)
Bayer et al, 1988
(RCT) (Danazol)
Telimaa et al, 1988
(RCT) (Danazol)
Telimaa et al, 1988
(RCT) (MPA)
Fedele et al, 1992
(RCT) (Buserelin)
Ovarian
P
suppression value
24%
25%
NS
57.4%
37.2%
NS
46%
33%
NS
46%
42%
NS
61%
37%
NS
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
Effect of letrozole on the ASRM score (OS)
Ailawadi et al, Fertil Steril 81(2): 290-6, 2004
Letrozole for the treatment of
endometriosis (RCT)
Letrozole Triptorelin Controls
P
(n = 47)
(n = 40)
(n = 57) value
CPR
after 12
months
Recurrence
23.4%
27.5%
28.1%
NS
6.4%
5%
5.3%
NS
Alborzi et al, Arch Gynecol Obstet 284: 105-10, 2011
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)
Management of endometriosisassociated infertility
1. Surgical treatment
2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/- IUI
5. Assisted reproductive techniques
Pre-operative medical treatment for
endometriosis (CCT)
Danazol
Gestrinone
Buserelin
Regression of
endometriosis
30%
34%
73% *
Cumulative
pregnancy rate
45%
47%
58% *
Donnez et al, Int J Fertil 35(5): 297-301, 1990
Post-operative GnRHa for endometriosis
(Cumulative pregnancy rates - CPR)
Parazzini et al,
1994 (RCT)
Vercellini et
al, 1999 (RCT)
Surgery
with
GnRHa
19%
Surgery
without
GnRHa
18%
P
value
11.6%
18.4%
NS
NS
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
Management of endometriosisassociated infertility
1. Surgical treatment
2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/- IUI
5. Assisted reproductive techniques
COH in stages I & II endometriosis
Intervention
Simpson et Clomiphene
al, 1992
citrate
(CCT)
Fedele et al,
HMG
1992 (RCT)
No
therapy
COH P value
9%
22%
<0.05
24%
37.4%
NS
COH + IUI in stages I & II endometriosis
No therapy COH + IUI
Deaton et al,
1990 (RCT)
Tummon et al,
1997 (RCT)
Serta et al, 1992
(CCT)
Peterson et al,
1994 (CCT)
P
value
3.3%
9.5%
<0.05
2%
11%
<0.005
32%
32%
NS
1.4%
15%
<0.005
COH + IUI in endometriosis
(Meta-analysis)
Number of Number of Mean cycle
studies
cycles
fecundity (SD)
Stage I & II
5
783
0.14 *
Stage III &
IV
3
179
0.08
Peterson et al, Fertil Steril 62(3):535-44, 1994
Management of endometriosisassociated infertility
1. Surgical treatment
2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/- IUI
5. Assisted reproductive techniques
Intracytoplasmic sperm injection (ICSI)
IVF in endometriosis versus tubal infertility (CPR)
Barnhart et al, Fertil Steril 77(6): 1148-55, 2002
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)
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)
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)
Corticosteroids before IVF in
endometriosis (RCT)
CPR
Miscarriage
rate
Multiple
pregnancy rate
Corticosteroids Controls P value
(n = 54)
(n = 57)
42.6%
22.8%
<0.05
21.7%
15.4%
NS
17.4%
15.4%
NS
Kim et al, J Obstet Gynaecol Res 23(5): 463-70, 1997
Danazol before IVF in repeated IVF
failures (RCT)
Number
CPR
Danazol (400
Controls P value
mg/d for 12 wks)
41
41
40%
19.5%
Tei et al, J Reprod Med 43(6): 541-6, 1998
<0.05
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
GnRH agonist v/s no agonist before IVF
(Clinical pregnancy rate per woman)
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
GnRH agonist v/s no agonist before IVF
(Ongoing pregnancy rate per woman)
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
GnRH agonist v/s no agonist before
IVF (Number of oocytes retrieved)
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
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
Effect of GnRHa on adenomyosis
(CCT)
Fertilization
Adenomyosis
Control
P
cycles (n=20) cycles (n=54) value
48.0 %
42.0 %
NS
Implantation
31.0 %
28.2 %
NS
Miscarriage
19.0 %
26.1 %
NS
Preg >12 wks
35.0 %
30.0 %
NS
Mijatovic et al, Eur J Obstet Gynecol Reprod Biol 151(1):62-5 , 2010
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)
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)
Conclusions (cont…)
7. Combining laparoscopic surgery and
medical therapy does not improve pregnancy
rates over surgery alone (A)
8. COH+IUI 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)
Bibliotheca Alexandrina
Evidence-based management of
endometriosis-associated 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
GIFT versus COH+IUI in endometriosis
(CCT) (Delivery rate per cycle)
GIFT
COH+IUI
P value
Stages I & II
28.1%
14.7%
<0.05
Stages III & IV
40.9%
12.5%
NS
Lodhi et al, Gynecol Endocrinol 19(3):152-9, 2004
Effect of GnRHa on stage III and IV
endometriosis
Long term
GnRH agonist
Control
cycles
Ma et al, Int J Gynaecol Obstet 100(2):167-70, 2008
P value
-Mohamed et al, Eur J Obstet Gynecol Reprod
Biol. 2011 Jun;156(2):177-80
- Mijatovic et al, Eur J Obstet Gynecol Reprod Biol.
2010 Jul;151(1):62-5
- Tavmergen et al, Curr Opin Obstet Gynecol.
2007 Jun;19(3):284-8
- Gong et al, Zhong Nan Da Xue Xue Bao Yi Xue
Ban. 2009 Mar;34(3):185-9
- Ma et al, Int J Gynaecol Obstet. 2008
Feb;100(2):167-70
- Tokushige et al. Discovery of a novel biomarker
in the urine in women with endometriosis Fertility
and Sterility 95(1): 46-49, 2011