evidence-based management of endometriosis-associated infertility hassan n. sallam, md, frcog, phd...
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Evidence-based management of endometriosis-associated
infertilityHassan N. Sallam,
MD, FRCOG, PhD (London)Professor in Obstetrics and Gynaecology
The University of Alexandria, andClinical and Scientific Director,
Alexandria Fertility Center, Alexandria, Egypt
3rd Congress of Society of Reproductive Medicine, 5 – 9 October
2011, Antalya / Turkey
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The old Alexandria medical school
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The uterus (after Soranos of Ephesus)
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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)
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Prevalence of endometriosis (Mahmoud and Templeton, 1991) (OS)
0
5
10
15
20
25
Sterilization Infertility Pain DUB/TAH
Mahmoud and Templeton, Hum Reprod 6(4): 544-9, 1991
6%
21%
15%
25%
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Laparoscopic surgery v/s no surgery (RCT) (Canadian Collaborative Group,
Marcoux et al, 1997)
Surgery (n=172)
No surgery
(n= 169)
P value
CPR30.7%17.7%0.006
Fecundity4.7%2.4%<0.05
Marcoux et al, N Engl J Med 337(4):217-22, 1997
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AID in minimal endometriosis(Fecundity rates per month of
exposure)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1 3 5 7 9 11 13 15
Normal pelvis
Endometriosis
Jansen RP, Fertil Steril 46 (1): 141-3, 1986
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IVF in endometriosis versus tubal infertility (CPR)
Barnhart et al, Fertil Steril 77(6): 1148-55, 2002
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How does endometriosis affect infertility?
1. Tubal adhesions2. Impaired gamete
interaction3. Impaired implantation
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i.e. Endometrial receptivity does not play a role in diminished pregnancy rates in
endometriosis
Oocytes from normal controls to
endometriosis patients
Oocytes from endometriosis
patients to normal controls
Reduced implantation rates
Similar implantation rates
Cross-over oocyte donation study (Pellicer et al, 2001)
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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)
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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)
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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 (Garcia-Velasco et al,
2002)
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Effect of GnRHa on the endometrium in endometriosis
(CCT)
Mohamed et al, Eur J Obstet Gynecol Reprod Biol 156(2):177-80 , 2011
Frozen cycles
Fresh cycles
P value
LBR16.9 %11.9 % <0.05
CPR18.2 %12.7 %<0.05
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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
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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
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Problems in the evaluation of management options
1. Any management option should be compared to expectant
management2. The monthly fecundity rate (MFR)
is more meaningful than the pregnancy rate (PR)
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Expectant management in endometriosis (Prospective cohort
study PCS)Degree of
endometriosisCumulative pregnancy rate (CPR)
Monthly fecundity rate (MFR)
Mild52.9%5.7%
Moderate25%3.2%
Severe0%0%
All cases24.4%3.1%
Olive et al, Fertil Steril 44(1):35-41, 1985
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Expectant management of stage I and II endometriosis (CCT)
Cumulative pregnancy
rate
Miscarriage rate
No treatment55%14.3%
MPA71%6.3%
Danazol46%11%
P valueNSNS
Hull et al, Fertil Steril 47(1):40-4, 1987
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Management of endometriosis-associated
infertility1. Surgical treatment 2. Medical treatment
3. Combined medical and surgical therapy
4. Controlled ovarian hyperstimulation +/- IUI
5. Assisted reproductive techniques
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Problems in evaluating surgical management of
endometriosis
1. Few studies are controlled2. Few studies report the fecundity
rate3. Techniques/skills differ
4. Recognition of “atypical” lesions5. Use of adhesion prevention
agents
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White endometriosis, clear endometriosis, red endometriosis and
powder burn lesions.
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Powder burns on the right uterosacral ligament causing painful intercourse
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Surgical treatment of endometriosis
1. Ablation and/or resection of laparoscopic
lesions2. Drainage +/-
excision/ablation of
endometriomas
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Surgical treatment of endometriosis
1. Ablation and/or resection of laparoscopic
lesions2. Drainage +/-
excision/ablation of
endometriomas
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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
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Resection or ablation for minimal or mild endometriosis - Canadian Collaborative
Group (RCT)Resection
or ablation
(n = 172)
Diagnostic laparoscop
y(n = 169)
P
value
Clinical pregnancy
rate
30.7%17.7%<0.01
Fecundity rate
4.7%2.4%<0.05
Miscarriage rate
20.6%21.6%0.91Marcoux et al, N Engl J Med 337(4):217-22, 1997
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Resection or ablation for minimal or mild endometriosis (RCT)
Resection or
ablation(n = 54)
Diagnostic laparoscop
y(n = 47)
P
value
Clinical pregnancy
rate
24%29%NS
Birth rate19.6%22.2%NS
Miscarriage rate
16.7%23.1%NS
Parazzini et al, Hum Reprod 14:1332-4, 1999
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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
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Resection or ablation for moderate and severe endometriosis (stages
III and IV)
Cumulative pregnancy
rate
Fecundity rate
Luciano et al, 1992 (OS)
70%6.7%
Busacca et al, 1999 (OS)
57.5%2.4%
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Surgical treatment of endometriosis
1. Ablation and/or resection of laparoscopic
lesions2. Drainage +/-
excision/ablation of
endometriomas.
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leads torecurrence in 50-100%
of cases
(Nezhat et al, 1988; Vercillini et al, 1992;
Olive, 1989)
Simple drainage of endometriomas
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Excision of endometriomas
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Drainage + resection/ablation of cyst wall
StudynTechniqueCPR
Daniell et al, 199132Laser + stripping38%
Marrs et al, 199123KTP laser ablation
30.4%
Wood et al, 199252Cyst stripping50%
Bateman et al, 1994
21Cyst stripping42.8%
Montanino et al, 1996
11Stripping + GnRHa
45%
Donnez et al, 1996814
CO2Laser + GnRHa
51%
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Drainage + resection/ablation of cyst wall (cont…)
StudynTechniqueCPR
Sutton et al, 199766CO2 Laser + KTP45%
Hemings et al, 1998
84Cyst stripping50%
Beretta et al, 1998
64Cyst stripping66.7%
Busacca et al, 1999
57Cyst stripping57.5%
Milingos et al, 1999
32Cyst stripping53%
Jones & Sutton, 2002
39KTP laser/diathermy
39.5%
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Surgical versus non-surgical therapy
Adamson and Pasta, Am J Obstet Gynecol 171:1488-504, 1994
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Laparoscopic excision versus electro-coagulation in mild endometriosis
(CCT)Electro-
coagulation(n = 48)
Excision(n = 53)
P valu
e
Pregnacy rate
57.1%53.5%NS
Miscarriage rate
12.5%17.4%NS
Duration to
pregnancy
10.7 months13.3 months
Tulandi and Al-Took, Fertil Steril 69(2):229-31, 1998
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Laparoscopy versus laparotomy(Cumulative pregnancy rates –
CCT)
Laparoscopy
Laparotomy
P value
Stage I & II67.4%74.3%NS
Stage III & IV62.2%44.4%<0.05
Adamson et al, Fertil Steril 59(1): 35-44, 1993
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Laparoscopy versus laparotomy in severe endometriosis – (CCT)
Laparoscopy
(n = 67)
Laparotomy
(n = 149)
P value
CPR44.9%62.7%NS
Recurrence of
dysmenorrhoa
16.4%20.3%NS
Recurrence of
dyspareunia
33.3%15.4NSCrosignani et al, Fertil Steril 66(5): 706-11,
1996
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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
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Medical treatment of endometriosis
(A) Ovarian suppression- Medroxyprogesterone (MPA)
- Gestrinone- GnRH agonists
- Danazol(B) Aromatase inhibitors
- Letrozole(C) Novel approaches
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Ovarian suppression for endometriosis (CPR)
No therapy
Ovarian suppressio
n
P value
Thomas et al, 1987 (RCT) (Gestrinone)
24%25%NS
Bayer et al, 1988 (RCT) (Danazol)
57.4%37.2%NS
Telimaa et al, 1988 (RCT) (Danazol)
46%33%NS
Telimaa et al, 1988 (RCT) (MPA)
46%42%NS
Fedele et al, 1992 (RCT) (Buserelin)
61%37%NS
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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 danazolOR = 1.37 (95% CI = 0.94 – 1.99)
Hughes et al, Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000155
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Effect of letrozole on the ASRM score (OS)
Ailawadi et al, Fertil Steril 81(2): 290-6, 2004
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Letrozole for the treatment of endometriosis (RCT)
Letrozole
(n = 47)
Triptorelin
(n = 40)
Controls(n = 57)
P value
CPR after 12 months
23.4%27.5%28.1%NS
Recur-rence
6.4%5%5.3%NS
Alborzi et al, Arch Gynecol Obstet 284: 105-10, 2011
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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)
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Management of endometriosis-associated
infertility
1. Surgical treatment 2. Medical treatment
3. Combined medical and surgical therapy 4. Controlled ovarian hyperstimulation +/-
IUI5. Assisted reproductive techniques
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Pre-operative medical treatment for endometriosis (CCT)
Danazol Gestrinone Buserelin
Regression of endometriosi
s
30%34% 73% *
Cumulative pregnancy
rate
45%47%58% *
Donnez et al, Int J Fertil 35(5): 297-301, 1990
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Post-operative GnRHa for endometriosis
(Cumulative pregnancy rates - CPR)
Surgery with
GnRHa
Surgery without GnRHa
P valu
e
Parazzini et al, 1994
(RCT)
19%18%NS
Vercellini et al, 1999
(RCT)
11.6%18.4%NS
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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
recurrenceYap et al, Cochrane Database Syst 2004;
(3):CD003678
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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
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COH in stages I & II endometriosis
Intervention
No therapy
COHP value
Simpson et al, 1992 (CCT)
Clomiphene citrate
9%22%<0.05
Fedele et al, 1992
(RCT)
HMG24%37.4%
NS
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COH + IUI in stages I & II endometriosis
No therapy
COH + IUIP value
Deaton et al, 1990 (RCT)
3.3%9.5%<0.05
Tummon et al, 1997 (RCT)
2%11%<0.005
Serta et al, 1992 (CCT)
32%32%NS
Peterson et al, 1994 (CCT)
1.4%15%<0.005
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COH + IUI in endometriosis (Meta-analysis)
Number of studies
Number of cycles
Mean cycle fecundity (SD)
Stage I & II57830.14 *
Stage III & IV
31790.08
Peterson et al, Fertil Steril 62(3):535-44, 1994
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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
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Intracytoplasmic sperm injection (ICSI)
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IVF in endometriosis versus tubal infertility (CPR)
Barnhart et al, Fertil Steril 77(6): 1148-55, 2002
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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)
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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)
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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)
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Corticosteroids before IVF in endometriosis (RCT)
Corticosteroids
(n = 54)
Controls
(n = 57)
P value
CPR42.6%22.8%<0.05
Miscarriage rate
21.7%15.4%NS
Multiple pregnancy
rate
17.4%15.4%NS
Kim et al, J Obstet Gynaecol Res 23(5): 463-70, 1997
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Danazol before IVF in repeated IVF failures (RCT)
Danazol (400 mg/d for 12
wks)
Controls
P value
Number4141
CPR40%19.5%<0.05
Tei et al, J Reprod Med 43(6): 541-6, 1998
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Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
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GnRH agonist v/s no agonist before IVF
(Clinical pregnancy rate per woman)
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
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GnRH agonist v/s no agonist before IVF
(Ongoing pregnancy rate per woman)
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
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GnRH agonist v/s no agonist before IVF (Number of oocytes
retrieved)
Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006
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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
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Effect of GnRHa on adenomyosis (CCT)
Mijatovic et al, Eur J Obstet Gynecol Reprod Biol 151(1):62-5 , 2010
Adenomyosis cycles (n=20)
Control cycles (n=54)
P valu
e
Fertilization48.0 %42.0 %NS
Implantation
31.0 %28.2 %NS
Miscarriage19.0 %26.1 %NS
Preg >12 wks
35.0 %30.0 %NS
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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)
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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)
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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)
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Bibliotheca Alexandrina
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Evidence-based management of endometriosis-associated
infertilityHassan N. Sallam,
MD, FRCOG, PhD (London)Professor in Obstetrics and Gynaecology
The University of Alexandria, andClinical and Scientific Director,
Alexandria Fertility Center, Alexandria, Egypt
3rd Congress of Society of Reproductive Medicine, 5 – 9 October
2011, Antalya / Turkey
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GIFT versus COH+IUI in endometriosis (CCT) (Delivery rate
per cycle)GIFTCOH+IUIP value
Stages I & II28.1%14.7% <0.05
Stages III & IV40.9%12.5% NS
Lodhi et al, Gynecol Endocrinol 19(3):152-9, 2004
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Effect of GnRHa on stage III and IV endometriosis
Ma et al, Int J Gynaecol Obstet 100(2):167-70, 2008
Long term GnRH
agonist
Control cycles
P value
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-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