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					 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          No surgery            P value
                 (n=172)           (n= 169)

    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
 0.5                                                          Normal pelvis
 0.4                                                          Endometriosis
 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                 Oocytes from
      controls to                endometriosis patients
 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 (Garcia-
            Velasco et al, 2002)
Effect of GnRHa on the endometrium
        in endometriosis (CCT)

                  Frozen cycles             Fresh          P value
                                            cycles

  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 endometriosis-
       associated 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              Cumulative      Monthly
 endometriosis          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)
                          Cumulative               Miscarriage
                          pregnancy                   rate
                             rate
  No treatment               55%                       14.3%
     MPA                         71%                   6.3%
    Danazol                      46%                   11%
    P value                       NS                    NS

          Hull et al, Fertil Steril 47(1):40-4, 1987
  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
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)
                   Resection Diagnostic
                   or ablation laparoscopy P value
                    (n = 172)    (n = 169)
    Clinical          30.7%        17.7%    <0.01
 pregnancy rate
   Fecundity           4.7%                2.4%            <0.05
      rate
  Miscarriage          20.6%              21.6%            0.91
      rate
         Marcoux et al, N Engl J Med 337(4):217-22, 1997
  Resection or ablation for minimal or
      mild endometriosis (RCT)
                  Resection Diagnostic
                  or ablation laparoscopy P value
                   (n = 54)     (n = 47)
    Clinical          24%         29%       NS
pregnancy rate
   Birth rate         19.6%              22.2%          NS

 Miscarriage          16.7%              23.1%          NS
    rate
          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        70%          6.7%
      (OS)
 Busacca et al, 1999       57.5%        2.4%
       (OS)
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      45%
 Donnez et al, 1996    814 CO2Laser + GnRHa     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 electro-
coagulation in mild endometriosis (CCT)
                     Electro-                 Excision           P
                   coagulation                (n = 53)         value
                     (n = 48)
 Pregnacy             57.1%                     53.5%           NS
   rate
Miscarriage            12.5%                    17.4%           NS
   rate
Duration to        10.7 months                  13.3
pregnancy                                      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
                      (n = 67)   (n = 149) value
    CPR                44.9%       62.7%    NS

Recurrence of            16.4%                  20.3%           NS
dysmenorrhoa
Recurrence of            33.3%                   15.4           NS
 dyspareunia

          Crosignani et al, Fertil Steril 66(5): 706-11, 1996
   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
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        Ovarian     P
                       therapy   suppression value
 Thomas et al, 1987     24%         25%       NS
 (RCT) (Gestrinone)
   Bayer et al, 1988   57.4%       37.2%      NS
   (RCT) (Danazol)
 Telimaa et al, 1988    46%         33%       NS
  (RCT) (Danazol)
 Telimaa et al, 1988    46%         42%       NS
    (RCT) (MPA)
  Fedele et al, 1992    61%         37%       NS
  (RCT) (Buserelin)
 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           23.4%             27.5%            28.1%          NS
after 12
months
 Recur-          6.4%               5%              5.3%          NS
 rence


           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 endometriosis-
       associated 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         30%                 34%                 73% *
endometriosis
 Cumulative           45%                 47%                 58% *
pregnancy rate


           Donnez et al, Int J Fertil 35(5): 297-301, 1990
Post-operative GnRHa for endometriosis
  (Cumulative pregnancy rates - CPR)

                   Surgery   Surgery     P
                    with     without   value
                   GnRHa     GnRHa
Parazzini et al,     19%       18%      NS
 1994 (RCT)
 Vercellini et     11.6%     18.4%      NS
al, 1999 (RCT)
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 endometriosis-
       associated 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     No      COH P value
                         therapy
Simpson et Clomiphene      9%      22%     <0.05
  al, 1992    citrate
   (CCT)
Fedele et al, HMG         24%      37.4%    NS
1992 (RCT)
COH + IUI in stages I & II endometriosis

                    No therapy COH + IUI     P
                                           value
  Deaton et al,       3.3%       9.5%      <0.05
  1990 (RCT)
Tummon et al,          2%        11%       <0.005
  1997 (RCT)
Serta et al, 1992     32%        32%        NS
     (CCT)
 Peterson et al,      1.4%       15%       <0.005
  1994 (CCT)
      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 &              3                179                    0.08
    IV


              Peterson et al, Fertil Steril 62(3):535-44, 1994
   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
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)
                  Corticosteroids Controls P value
                     (n = 54)     (n = 57)
    CPR               42.6%        22.8%    <0.05

 Miscarriage             21.7%               15.4%             NS
     rate
   Multiple              17.4%               15.4%             NS
pregnancy rate

        Kim et al, J Obstet Gynaecol Res 23(5): 463-70, 1997
Danazol before IVF in repeated IVF
          failures (RCT)

             Danazol (400    Controls P value
            mg/d for 12 wks)
Number            41           41

 CPR                  40%                  19.5%      <0.05



         Tei et al, J Reprod Med 43(6): 541-6, 1998
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)
                    Adenomyosis     Control       P
                    cycles (n=20) cycles (n=54) value
Fertilization          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                 Control            P value
              GnRH agonist                cycles




      Ma et al, Int J Gynaecol Obstet 100(2):167-70, 2008
   -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

				
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