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Efficacy and safety of IVF/ICSI in patients with severe endometriosis after long-term pituitary down-regulation

Published:October 11, 2013DOI:https://doi.org/10.1016/j.rbmo.2013.09.027

      Abstract

      Long-term pituitary down-regulation with a gonadotrophin-releasing hormone (GnRH) agonist for 3–6 months prior to IVF/intracytoplasmic sperm injection (ICSI) improves clinical pregnancy rates in endometriosis patients. However, some discussion about this treatment strategy still exists. This retrospective study from a tertiary-care university hospital examined the efficacy and safety of IVF/ICSI with and without long-term pituitary down-regulation in severe endometriosis patients (surgically confirmed American Society for Reproductive Medicine stages III and IV). All first IVF/ICSI treatment cycles between January 2009 and January 2012 were analysed. In patients treated with (n = 68) and without (n = 45) long-term pituitary down-regulation, 13 (19.1%) versus nine (20.0%) ongoing pregnancies after fresh embryo transfer (adjusted OR 0.58, 95% CI 0.18–1.86,) and 24 (35.3%) versus 10 (22.2%) ongoing pregnancies after fresh and cryopreserved embryo transfers (adjusted OR 1.62, 95% CI 0.60–4.38) were accomplished, respectively. Three complications (2.7%) and three recurrences (2.7%) were reported, only in patients treated with long-term pituitary down-regulation. The 1-year cumulative endometriosis recurrence rate was 7.3%. IVF/ICSI in patients with severe endometriosis is safe with low complication and recurrence rates. A favourable effect, albeit non-significant, of long-term pituitary down-regulation in achieving an ongoing pregnancy was observed only after including cryopreserved embryo transfers.
      Long-term pituitary down-regulation with a GnRH agonist for 3–6 months prior to IVF or intracytoplasmic sperm injection (ICSI) improves pregnancy rates in endometriosis patients. However, some discussion about this treatment strategy still exists. This retrospective study examined the efficacy and safety of IVF/ICSI with and without long-term pituitary down-regulation in severe endometriosis patients. All first IVF/ICSI treatment cycles between January 2009 and January 2012 were analysed. In patients treated with long-term pituitary down-regulation (n = 68) 13 (19.1%) ongoing pregnancies were accomplished after fresh embryo transfer and 24 (35.3%) after fresh including frozen embryo transfers. In patients treated without long-term pituitary down-regulation (n = 45), nine (20%) ongoing pregnancies were accomplished after fresh embryo transfer and 10 (22.2%) after fresh including frozen embryo transfers. Three complications (2.7%) and three recurrences (2.7%) were reported, only in patients treated with long-term pituitary down-regulation. This study showed that IVF/ICSI in patients with severe endometriosis is a safe procedure with low complication and recurrence rates. Long-term pituitary down-regulation with a GnRH agonist is more beneficial in achieving an ongoing pregnancy after including frozen embryo transfer cycles.

      Keywords

      Introduction

      Endometriosis, a benign gynaecological disorder, occurs in up to 50% of patients associated with subfertility (
      • Meuleman C.
      • Vandenabeele B.
      • Fieuws S.
      • Spiessens C.
      • Timmerman D.
      • D’Hooghe T.
      High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners.
      ). Although the exact mechanisms are still not unravelled, it has been postulated that endometriosis-associated subfertility is based on a disturbed pelvic anatomy, a hostile peritoneal environment, a diminished ovarian reserve and an altered endometrial receptivity, or combinations of those (
      • de Ziegler D.
      • Borghese B.
      • Chapron C.
      Endometriosis and infertility: pathophysiology and management.
      ,
      • Giudice L.C.
      Clinical practice. Endometriosis.
      ).
      In subfertile patients with severe endometriosis, embryo transfer after IVF or intracytoplasmic sperm injection (ICSI) is an appropriate treatment, especially in case of non-patent tubes, but also in male factor or unexplained infertility (
      • Kennedy S.
      • Bergqvist A.
      • Chapron C.
      • D’Hooghe T.
      • Dunselman G.
      • Greb R.
      • Hummelshoj L.
      • Prentice A.
      • Saridogan E.
      ESHRE guideline for the diagnosis and treatment of endometriosis.
      ). Although a few recent studies (
      • Matalliotakis I.M.
      • Sakkas D.
      • Illuzzi J.
      • Matalliotaki C.
      • Arici A.
      Implantation rates remains unaffected in women with endometriosis compared to tubal factor infertility.
      ,
      • Opoien H.K.
      • Fedorcsak P.
      • Omland A.K.
      • Abyholm T.
      • Bjercke S.
      • Ertzeid G.
      • Oldereid N.
      • Mellembakken J.R.
      • Tanbo T.
      In vitro fertilization is a successful treatment in endometriosis-associated infertility.
      ) showed comparable IVF/ICSI treatment outcomes between patients with endometriosis and patients with tubal factor infertility, other studies report significantly decreased pregnancy rates in patients with endometriosis (
      • Barnhart K.
      • Dunsmoor-Su R.
      • Coutifaris C.
      Effect of endometriosis on in vitro fertilization.
      ,
      • Coccia M.E.
      • Rizzello F.
      • Mariani G.
      • Bulletti C.
      • Palagiano A.
      • Scarselli G.
      Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: a stage-dependent interference.
      ). In particular, this seems to be the case in patients with severe endometriosis, American Society for Reproductive Medicine (ASRM) stage III and IV (
      • Coccia M.E.
      • Rizzello F.
      • Mariani G.
      • Bulletti C.
      • Palagiano A.
      • Scarselli G.
      Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: a stage-dependent interference.
      ) and in patients with endometriomas present at the time of ovarian stimulation (
      • Opoien H.K.
      • Fedorcsak P.
      • Omland A.K.
      • Abyholm T.
      • Bjercke S.
      • Ertzeid G.
      • Oldereid N.
      • Mellembakken J.R.
      • Tanbo T.
      In vitro fertilization is a successful treatment in endometriosis-associated infertility.
      ).
      Several nonrandomized trials (
      • Chedid S.
      • Camus M.
      • Smitz J.
      • van Steirteghem A.C.
      • Devroey P.
      Comparison among different ovarian stimulation regimens for assisted procreation procedures in patients with endometriosis.
      ,
      • Dale P.O.
      • Tanbo T.
      • Abyholm T.
      Endometriosis-associated infertility treated by long-term gonadotropin-releasing hormone agonist administration and assisted fertilization.
      ,
      • Dicker D.
      • Goldman G.A.
      • Ashkenazi J.
      • Feldberg D.
      • Voliovitz I.
      • Goldman J.A.
      The value of pre-treatment with gonadotrophin releasing hormone (GnRH) analogue in IVF-ET therapy of severe endometriosis.
      ,
      • Ma C.
      • Qiao J.
      • Liu P.
      • Chen G.
      Ovarian suppression treatment prior to in-vitro fertilization and embryo transfer in Chinese women with stage III or IV endometriosis.
      ,
      • Nakamura K.
      • Oosawa M.
      • Kondou I.
      • Inagaki S.
      • Shibata H.
      • Narita O.
      • Suganuma N.
      • Tomoda Y.
      Menotropin stimulation after prolonged gonadotropin releasing hormone agonist pretreatment for in vitro fertilization in patients with endometriosis.
      ) and one Cochrane systematic review (
      • Sallam H.N.
      • Garcia-Velasco J.A.
      • Dias S.
      • Arici A.
      Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis.
      ) have shown that long-term pituitary down-regulation with a GnRH agonist for 3–6 months prior to IVF/ICSI improves clinical pregnancy rates in endometriosis patients. Still, some discussion about this treatment strategy exists, as the Cochrane recommendation was based on only three small studies (
      • Dicker D.
      • Goldman J.A.
      • Levy T.
      • Feldberg D.
      • Ashkenazi J.
      The impact of long-term gonadotropin-releasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer.
      ,
      • Rickes D.
      • Nickel I.
      • Kropf S.
      • Kleinstein J.
      Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis.
      ,
      • Surrey E.S.
      • Silverberg K.M.
      • Surrey M.W.
      • Schoolcraft W.B.
      Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis.
      ). Nowadays, less aggressive stimulation protocols are used to minimize the risks of ovarian hyperstimulation syndrome and (elective) single-embryo transfer is preferred to prevent the development of multiple pregnancies and its known complications. Since cryopreserved embryo transfers are an important additional benefit of IVF/ICSI in achieving a pregnancy, the question becomes relevant if the prolonged use of a GnRH agonist prior to IVF/ICSI has any effect on the consequential cryopreserved embryo transfers.
      Besides this, it is not inconceivable that clinicians are sceptical about long-term pituitary down-regulation, possibly being afraid that it may lower ovarian response to ovarian stimulation, especially in poor responders. In addition, as uncomfortable side effects, such as vasomotor instability, are often related to this treatment strategy, patients are frequently unwilling to use GnRH agonists for a longer period of time. As a result, other IVF/ICSI treatment strategies are offered, although they are not demonstrated to be effective in this specific group of (severe) endometriosis patients. Recently, continuous use of oral contraceptives is suggested to be an appropriate treatment in those patients, but unfortunately a comparison with the standard long-term pituitary down-regulation with a GnRH agonist regime has not been made (
      • de Ziegler D.
      • Gayet V.
      • Aubriot F.X.
      • Fauque P.
      • Streuli I.
      • Wolf J.P.
      • de Mouzon J.
      • Chapron C.
      Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes.
      ).
      Besides IVF/ICSI treatment efficacy, safety is a key clinical issue in treatment decision making. Only a few studies have reported complications (
      • Benaglia L.
      • Somigliana E.
      • Iemmello R.
      • Colpi E.
      • Nicolosi A.E.
      • Ragni G.
      Endometrioma and oocyte retrieval-induced pelvic abscess: a clinical concern or an exceptional complication?.
      ,
      • Moini A.
      • Riazi K.
      • Amid V.
      • Ashrafi M.
      • Tehraninejad E.
      • Madani T.
      • Owj M.
      Endometriosis may contribute to oocyte retrieval-induced pelvic inflammatory disease: report of eight cases.
      ,
      • Younis J.S.
      • Ezra Y.
      • Laufer N.
      • Ohel G.
      Late manifestation of pelvic abscess following oocyte retrieval, for in vitro fertilization, in patients with severe endometriosis and ovarian endometriomata.
      ) and recurrences (
      • Benaglia L.
      • Somigliana E.
      • Vercellini P.
      • Benedetti F.
      • Iemmello R.
      • Vighi V.
      • Santi G.
      • Ragni G.
      The impact of IVF procedures on endometriosis recurrence.
      ,
      • Benaglia L.
      • Somigliana E.
      • Santi G.
      • Scarduelli C.
      • Ragni G.
      • Fedele L.
      IVF and endometriosis-related symptom progression: insights from a prospective study.
      ,
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      ) of endometriosis after IVF/ICSI. In general, they showed reassuring results. Still, fear exists among clinicians about serious complications, such as development of pelvic inflammatory disease or pelvic organ dysfunction through recurrence of endometriosis. Therefore, there is urgent need for more data on complications and endometriotic recurrence in IVF/ICSI in severe endometriosis patients and a possible protective role of prolonged use of a GnRH agonist in this regard.
      Therefore, this study aimed to investigate the efficacy and safety of IVF/ICSI with and without long-term pituitary down-regulation with a GnRH agonist in severe endometriosis patients.

      Materials and methods

      This study retrospectively analysed endometriosis patients who underwent IVF/ICSI treatment in the period between January 2009 and January 2012. All patients were selected by using the electronic patient database of the IVF centre of the VU University Medical centre. Only patients diagnosed with surgically confirmed severe endometriosis (ASRM stage III and IV) undergoing their first IVF/ICSI treatment cycle were included (Figure 1). The database was validated and supplemented by two researchers (EL, LH). The study was approved by the Medical Ethics Review Committee of VU University Medical Centre (reference no. 2013/2, approved 17 January 2013).
      Figure thumbnail gr1
      Figure 1Flowchart of patient selection. ASRM = American Society for Reproductive Medicine; ICSI = intracytoplasmic sperm injection.
      The primary outcome was ongoing pregnancy rate, including fresh as well as cryopreserved embryo transfer procedures. Secondary outcomes were complication, cycle cancellation and recurrence rates, clinical pregnancy rate per started cycle, total number of oocytes retrieved, total number of embryos and total number of cryopreserved embryos. An ongoing pregnancy was defined as an intact intrauterine pregnancy confirmed by ultrasound at 12 weeks of gestational age. A clinical pregnancy was defined as the confirmation of at least one gestational sac visualized by ultrasound. A miscarriage was defined as the loss of a clinical pregnancy before 12 weeks of gestational age. Ovarian hyperstimulation syndrome, infection, pelvic organ dysfunction and/or hospital admittance within 3 months after IVF/ICSI treatment were defined as complications. Recurrence of endometriosis was defined as the presence of visually/histologically confirmed endometriosis during surgery within 1 year after IVF/ICSI ovum retrieval (
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      ). An indication for surgery was based on: (i) recurrence/increase of complaints suspicious for endometriosis recurrence insufficiently reacting on hormonal suppression therapy; or (ii) need for pelvic surgery in acute situations. Recurrence of complaints without a surgical confirmation of endometriosis was considered to be insufficient evidence to reflect recurrence of endometriosis.
      Data are presented for the total study group. Subgroup analysis was performed to compare patients treated with and without long-term pituitary down-regulation with a GnRH agonist for at least 3 months prior to IVF/ICSI. Down-regulation was performed with leuprolide 3.75 mg depot injections (Lucrin; Abbvie, Hoofddorp, The Netherlands). Exactly 28 days after the last injection, daily subcutaneous injections of triptoreline (Decapeptyl; Ferring, Copenhagen, Denmark) was started and 1 day later followed by the administration of recombinant FSH (Gonal F; Serono, Geneva, Switzerland; or Puregon; MSD, Oss, The Netherlands). In patients treated without long-term pituitary down-regulation, a standard stimulation protocol was performed as previously described (
      • Vergouw C.G.
      • Kieslinger D.C.
      • Kostelijk E.H.
      • Botros L.L.
      • Schats R.
      • Hompes P.G.
      • Sakkas D.
      • Lambalk C.B.
      Day 3 embryo selection by metabolomic profiling of culture medium with near-infrared spectroscopy as an adjunct to morphology: a randomized controlled trial.
      ). Briefly, those patients underwent a standard long agonist protocol (n = 28) or short agonist protocol (n = 17) preceded by continuous use of oral contraceptives (n = 20) or not (n = 25). Long-term pituitary down-regulation is this study centre’s first choice of treatment. Deviation of this treatment strategy was based on patient request (patient was unwilling to use GnRH agonists), practical reasons (patient’s symptoms were already effectively treated with continuous use of oral contraceptives) or the anticipation of a poor ovarian response (because of an increased FSH and/or diminished antral follicle count). Dose of recombinant FSH was determined individually. Follicle growth monitoring, oocyte retrieval, the luteal phase and laboratory’s insemination procedure were performed as previously described (
      • Vergouw C.G.
      • Kieslinger D.C.
      • Kostelijk E.H.
      • Botros L.L.
      • Schats R.
      • Hompes P.G.
      • Sakkas D.
      • Lambalk C.B.
      Day 3 embryo selection by metabolomic profiling of culture medium with near-infrared spectroscopy as an adjunct to morphology: a randomized controlled trial.
      ). Cryopreserved embryo transfers were either performed in a spontaneous or an artificial cycle. In a spontaneous cycle, human chorionic gonadotropin (Pregnyl; MSD, Oss, The Netherlands) was administered when a follicle reaches the size of at least 17 mm in combination with an adequate endometrial thickness of at least 7 mm. An artificial cycle was carried out by administering oestradiol (Progynova; Bayer Schering Pharma, Berlin, Germany) and progesterone (Utrogestan; Bessins Healthcare, Bangkok, Thailand) to prepare the endometrium for implantation. Six days after Pregnyl (spontaneous cycle) or start with progesterone administration (artificial cycle), the embryo transfer was performed.

      Statistical analysis

      Statistical analysis was performed using the Statistical Package for Social Sciences version 16.0 (IBM SPSS, USA). Data were expressed as means ± standard deviations or n (%). Differences between the two subgroups were evaluated with chi-squared or Fisher’s exact tests in categorical data and Students’ t-test in parametric continuous data or Mann–Whitney test in nonparametric data. Multiple logistic regression analysis was performed to evaluate the effect of different confounders (i.e. patient and cycle characteristics) on the primary outcome.
      Life table analysis was used to calculate the cumulative endometriosis recurrence rate (CERR) (
      • Olive D.L.
      Analysis of clinical fertility trials: a methodologic review.
      ). For each patient, date of oocyte pick up was set as date of entry. The endpoint was exactly 12 months after the date of entry or the date of surgical reintervention (in recurrent endometriosis patients), the date of the positive pregnancy test (in ongoing pregnant patients) or the date of patient’s last visit. The log rank test was used to compare the CERR between the two groups.

      Results

      This study included 113 patients, of whom 68 patients were treated with long-term pituitary down-regulation using a GnRH agonist for at least 3 months (median 3 months, range 3–14 months). Patients treated with long-term pituitary down-regulation were significantly younger (P < 0.01), more frequently diagnosed with endometriosis ASRM stage IV (P < 0.01) and obese (BMI ⩾30 kg/m2, P = 0.02) (Table 1). Ovarian stimulation was more frequently started with lower dosages of FSH and resulted in lower oestradiol concentrations on the day of human chorionic gonadotrophin administration in patients treated with long-term pituitary down-regulation versus without. Mean number of oocytes, embryos and cryopreserved embryos was equal for both groups (Table 2).
      Table 1Patient and cycle characteristics.
      Total group (n =113)No long-term pituitary down-regulation (n =45)Long-term pituitary down-regulation (n =68)P-value
      Age (years)33.4 ± 3.634.7 ± 3.832.5 ± 3.2<0.01
      BMI (kg/m2)23.8 ± 3.923.3 ± 2.924.2 ± 4.5NS
       <2576 (67.3)32 (71.1)44 (64.7)0.02
       25–3028 (24.8)13 (28.9)15 (22.1)
       ⩾309 (8.0)0 (0)9 (13.2)
      Subfertility0.01
       Primary71 (62.8)22 (48.9)49 (72.1)
       Secondary42 (37.2)23 (51.1)19 (27.9)
       Duration (months)37 ± 2437 ± 2836 ± 21NS
      ASRM stage<0.01
       III30 (26.5)19 (42.2)11 (16.2)
       IV83 (73.5)26 (57.8)57 (83.8)
      Semen (million)30.5 ± 31.427.0 ± 38.332.7 ± 26.0NS
      Mann–Whitney test.
      AB prophylaxis
      Number of patients per oocyte retrieval.
      17 (16.5)3 (7.1)14 (23.0)0.03
      Fertilization protocolNS
       IVF102 (90.3)38 (84.4)64 (94.1)
       ICSI11 (9.7)7 (15.6)4 (5.9)
      Duration of stimulation (days)11 ± 2.610.8 ± 2.511.2 ± 2.7
      Start dose FSH (IU)<0.001
       1251 (0.9)1 (2.2)0
       15043 (38.1)10 (22.2)33 (48.5)
       22532 (28.3)9 (20.0)23 (33.8)
       30036 (31.9)25 (55.6)11 (16.2)
       4501 (0.9)01 (1.5)
      Total FSH (IU)2440 ± 9792697 ± 9822270 ± 9450.02
      Endometrial thickness on HCG day (mm)9.3 ± 2.49.6 ± 2.89.1 ± 2.1NS
      Oestradiol concentration on HCG day (pmol/l)4952 ± 38675902 ± 44944328 ± 3283NS
      Mann–Whitney test.
      Cancelled cycles
      No oocyte retrieval
      Reasons: low response (long-term pituitary down-regulation n=4; no long-term pituitary down-regulation n=3; in four out of these seven patients an intrauterine insemination was performed); personal reasons (n=1); presence of intracavity fluid due to a hydrosalpinx (n=1); incorrect use of Pregnyl (n=1).
      10 (8.8)3 (6.7)7 (10.3)NS
      No oocytes after oocyte retrieval2 (1.8)1 (2.2)1 (1.5)NS
      Total fertilization failure
      Including one patient who underwent embryo transfer without the notification of 2PN stage.
      4 (3.5)2 (4.4)2 (2.9)NS
      Primary cryopreservation
      Because of the risk of severe OHSS (n=2) and due to being unable to puncture one ovary (n=1).AB=antibiotics. NS=not statistically significant.
      3 (2.7)03 (4.4)NS
      Values are mean ± SD or n (%).
      a Mann–Whitney test.
      b Number of patients per oocyte retrieval.
      c Reasons: low response (long-term pituitary down-regulation n = 4; no long-term pituitary down-regulation n = 3; in four out of these seven patients an intrauterine insemination was performed); personal reasons (n = 1); presence of intracavity fluid due to a hydrosalpinx (n = 1); incorrect use of Pregnyl (n = 1).
      d Including one patient who underwent embryo transfer without the notification of 2PN stage.
      e Because of the risk of severe OHSS (n = 2) and due to being unable to puncture one ovary (n = 1).AB = antibiotics. NS = not statistically significant.
      Table 2Outcome parameters.
      Total group (n=113)No long-term pituitary down-regulation (n =45)Long-term pituitary down-regulation (n =68)
      Total oocytes8.9 ± 6.29.0 ± 6.48.9 ± 6.2
      Fertilization0.57 ± 0.240.56 ± 0.250.58 ± 0.24
      Total embryos5.1 ± 4.15.2 ± 4.55.1 ± 3.8
      Total cryopreserved embryos
      Mann–Whitney test.
      3.3 ± 3.43.2 ± 3.23.2 ± 3.6
      Embryo transfer
      After fresh embryo transfer.
       Single-embryo transfer86 (92.5)35 (92.1)51 (92.7)
       Double-embryo transfer7 (7.5)3 (7.9)4 (7.3)
      Implantation
      Mann–Whitney test.
      ,
      After fresh embryo transfer.
      0.29 ± 0.460.28 ± 0.450.30 ± 0.47
      Clinical pregnancy27 (23.9)10 (22.2)17 (25.0)
      Miscarriage5 (4.4)1 (2.2)4 (5.9)
      Ongoing pregnancy22 (19.5)9 (20.0)
      Three ongoing pregnancies were accomplished in patients pretreated with continuous use of oral contraceptives.
      13 (19.1)
      Patients with ⩾1 cryopreserved embryo64 (56.6)24 (53.3)40 (58.8)
       Ongoing pregnant after fresh ET19 (29.7)8 (33.3)11 (27.5)
       Not ongoing pregnant after fresh ET45 (70.3)16 (66.7)29 (72.5)
      Cryopreserved ET cycles/no. of patients58/4223/1535/27
       Natural cycle54 (93.1)23 (100)31 (88.6)
       Artificial cycle
      An artificial cycle is carried out with oestradiol and progesterone after long-term pituitary down-regulation with a GnRH agonist for at least 3months.
      4 (6.9)04 (11.4)
      Total cryopreserved ET cycles per woman
      Mann–Whitney test.
      1 (0–4)2 (0–3)1 (0–4)
      Total cryopreserved embryos transferred
      Mann–Whitney test.
      ,
      In four cryo-embryo transfer cycles, a double-embryo transfer was performed.
      1 (0–4)2 (0–3)1 (0–4)
      Ongoing pregnancy after cryopreserved ET cycles
      P-value=0.03.
      12 (10.6)1 (2.2)11 (16.2)
      Ongoing pregnancy fresh + cryopreserved ET cycles34 (30.1)10 (22.2)
      Three ongoing pregnancies were accomplished in patients pretreated with continuous use of oral contraceptives.
      24 (35.3)
      Patients with ⩾1 cryopreserved embryo left
      Per number of nonpregnant patients at 1 January 2012.
      11 (24.4)3 (18.8)8 (27.6)
      Complication
      After fresh embryo transfer.
      3 (2.7)03 (4.4)
      Recurrence3 (2.7)03 (4.4)
      Values are mean ± SD, n (%) or median (range).
      a Mann–Whitney test.
      b After fresh embryo transfer.
      c Three ongoing pregnancies were accomplished in patients pretreated with continuous use of oral contraceptives.
      d An artificial cycle is carried out with oestradiol and progesterone after long-term pituitary down-regulation with a GnRH agonist for at least 3 months.
      e In four cryo-embryo transfer cycles, a double-embryo transfer was performed.
      f P-value = 0.03.
      g Per number of nonpregnant patients at 1 January 2012.
      In total, 22 ongoing pregnancies were accomplished after fresh embryo transfer (19.5% per started cycle); 13 after long-term pituitary down-regulation (19.1%) versus nine after treatment without (20.0%). In total, 64 patients had cryopreserved embryos, of whom 12 achieved an ongoing pregnancy (10.6%). Including all cryopreserved embryo transfers, 34 ongoing pregnancies were accomplished (30.1%); 24 (35.3%) after treatment with long-term pituitary down-regulation versus 10 (22.2%) after treatment without (Table 2).
      Multiple logistic regression analysis showed a nonsignificant, slightly lower odds on ongoing pregnancy per started cycle after fresh embryo transfer in patients treated with long-term pituitary down-regulation (OR 0.95, 95% CI 0.37–2.44). Adjusted for baseline patient characteristics (confounders age, primary or secondary infertility, BMI and start dose of FSH), the OR was 0.58 (95% CI 0.18–1.86). Including cryopreserved embryo transfers, a nonsignificant higher ongoing pregnancy rate per started cycle in patients treated with long-term pituitary down-regulation was found (OR 1.91, 95% CI 0.81–4.52). Adjusted for baseline patient characteristics (confounders age, BMI and start dose of FSH) the OR was 1.62 (95% CI 0.60–4.38).
      This study also investigated the effect of treatment on complications and recurrences. Three complications were reported (complication rate of 2.7% per started cycle), occurring only in patients (ASRM stage IV) treated with long-term pituitary down-regulation. In two patients, mild ovarian hyperstimulation syndrome was reported. One of those patients recovered by expectant management. The other patient was admitted and treated with intravenous administration of saline and antibiotics. One patient suffered from gastrointestinal blood loss during follicle stimulation, which did not require an intervention. Three recurrences (recurrence rate of 2.7%) have been reported, all of them in patients treated with long-term pituitary down-regulation. Two patients (ASRM stage III and IV) were treated with a segmental colorectal resection by laparotomy, because of a (partial) stenosis in the rectosigmoid colon of both patients. In one of them, this surgery was combined with neoimplantation of the left ureter. In one patient (ASRM stage IV), salpingoovariolysis, a left tubectomy, cystectomy and appendectomy were performed by laparoscopy, because of the appearance of endometriosis. The overall CERR was 7.3% after a follow up of 12 months; the CERR was 11.4% versus 0.0% (log rank test, not significant) in patients treated with and without long-term pituitary down-regulation, respectively (Figure 2).
      Figure thumbnail gr2
      Figure 2Cumulative endometriosis recurrence rate (CERR) after IVF/intracytoplasmic sperm injection.

      Discussion

      This study demonstrates that IVF/ICSI is a safe procedure with low complication and recurrence rates in patients with severe endometriosis, which is in line with recent studies of
      • Benaglia L.
      • Somigliana E.
      • Vercellini P.
      • Benedetti F.
      • Iemmello R.
      • Vighi V.
      • Santi G.
      • Ragni G.
      The impact of IVF procedures on endometriosis recurrence.
      ,
      • Benaglia L.
      • Somigliana E.
      • Santi G.
      • Scarduelli C.
      • Ragni G.
      • Fedele L.
      IVF and endometriosis-related symptom progression: insights from a prospective study.
      and
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      . The ongoing pregnancy rate after fresh embryo transfer in patients with severe endometriosis is lower than found for all IVF/ICSI treatment cycles in this IVF clinic during the same period (2520 treatments started, 649 ongoing pregnancies after fresh embryo transfer (25.8%), 995 ongoing pregnancies including cryopreserved embryo transfers (39.5%)) which supports earlier observations of significantly decreased pregnancy rates in IVF patients with endometriosis compared with IVF patients with other treatment indications (
      • Barnhart K.
      • Dunsmoor-Su R.
      • Coutifaris C.
      Effect of endometriosis on in vitro fertilization.
      ,
      • Coccia M.E.
      • Rizzello F.
      • Mariani G.
      • Bulletti C.
      • Palagiano A.
      • Scarselli G.
      Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: a stage-dependent interference.
      ). On the other hand, it is in line with this study centre’s recently published data on IVF outcome in patients with severe endometriosis who underwent a segmental bowel resection, showing an ongoing pregnancy rate of 32% per embryo transfer (
      • van der Houwen L.E.E.
      • Lüchinger A.B.
      • Busard M.P.H.
      • van Waesberghe J.H.T.M.
      • Cuesta M.A.
      • Lambalk C.B.
      • Mijatovic V.
      • Hompes P.G.A.
      Long term surgical outcomes after segmental colorectal resection in women with severe endometriosis.
      ).
      This retrospective study has insufficient statistical power to draw firm conclusions about the amount of effect of long-term pituitary down-regulation on ongoing pregnancy after fresh and after fresh including cryopreserved embryo transfers. Nevertheless, the outcomes of this study generate a new and intriguing perspective with regard to the short- and long-term effects of long-term pituitary down-regulation with a GnRH agonist because, after including cryopreserved embryo transfers, the odds ratio on ongoing pregnancy changed to the opposite (favourable) direction. First, does long-term pituitary down-regulation with a GnRH agonist have a short-term negative effect on implantation? Secondly, does long-term pituitary down-regulation with a GnRH agonist improve oocyte quality? Apparently, the possibility exists that among severe endometriosis patients, long-term pituitary down-regulation prior to IVF/ICSI improves oocyte quality given the remarkable positive effect seen in the ongoing pregnancy rate after cryopreserved embryo transfer over patients treated without long-term pituitary down-regulation.
      In contrast to these findings, a Cochrane systematic review (
      • Sallam H.N.
      • Garcia-Velasco J.A.
      • Dias S.
      • Arici A.
      Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis.
      ) showed a significant improvement of pregnancy rates after long-term pituitary down-regulation prior to IVF/ICSI in endometriosis patients. Unfortunately, the mechanism to explain favourable results after long-term pituitary down-regulation with a GnRH agonist is lacking and one may only speculate in order to understand this observed improvement in IVF outcome: it may be based on an improved endometrial receptivity or improved oocyte quality (
      • Sallam H.N.
      • Garcia-Velasco J.A.
      • Dias S.
      • Arici A.
      Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis.
      ). However, the results of the systematic review might be influenced by the inclusion of patients with minimal to mild endometriosis, because in patients with severe endometriosis lower IVF/ICSI pregnancy rates have been observed (
      • Barnhart K.
      • Dunsmoor-Su R.
      • Coutifaris C.
      Effect of endometriosis on in vitro fertilization.
      ). In our current study, only patients with severe endometriosis were included and, in advance, especially in this subgroup of patients improved ongoing pregnancy rates after long-term pituitary down-regulation were expected. However, the current study’s expectations could not be completely confirmed as the odds on ongoing pregnancy after fresh embryo transfer is remarkably not in favour of this treatment strategy. Remarkably, in patients treated with long-term pituitary down-regulation, the ongoing pregnancy rate substantially increased after including cryopreserved embryo transfers.
      This observation supports the idea of an impaired endometrial receptivity directly after using GnRH agonists in ovarian stimulation cycles (
      • Haouzi D.
      • Assou S.
      • Dechanet C.
      • Anahory T.
      • Dechaud H.
      • de Vos J.
      • Hamamah S.
      Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in humans: protocol effects.
      ), which is probably the result of a decreased endometrial expression of genes involved in successful implantation (
      • Xiong M.
      • Zhang H.
      • Jin L.
      • Ai J.
      • Huang Z.
      • Zhu G.
      Association of controlled ovarian hyperstimulation treatment with down-regulation of key regulators involved in embryonic implantation in mice.
      ). Those findings are not only related to patients with endometriosis. However, it is shown in patients with endometriosis in unstimulated cycles that the mid-luteal rise of two specific genes (HOXA10 and HOXA11), both well known to be involved in successful implantation, is already altered compared with controls (
      • Matsuzaki S.
      • Canis M.
      • Darcha C.
      • Pouly J.L.
      • Mage G.
      HOXA-10 expression in the mid-secretory endometrium of infertile patients with either endometriosis, uterine fibromas or unexplained infertility.
      ,
      • Szczepanska M.
      • Wirstlein P.
      • Skrzypczak J.
      • Jagodzinski P.P.
      Expression of HOXA11 in the mid-luteal endometrium from women with endometriosis-associated infertility.
      ,
      • Taylor H.S.
      • Bagot C.
      • Kardana A.
      • Olive D.
      • Arici A.
      HOX gene expression is altered in the endometrium of women with endometriosis.
      ,
      • Zanatta A.
      • Rocha A.M.
      • Carvalho F.M.
      • Pereira R.M.
      • Taylor H.S.
      • Motta E.L.
      • Baracat E.C.
      • Serafini P.C.
      The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review.
      ). Although a GnRH agonist seems to diminish the endometrial receptivity, in the meantime this treatment regime might improve oocyte (and thus embryo) quality, because of the observation of increased ongoing pregnancy rates after cryopreserved embryo transfers in patients treated with long-term pituitary down-regulation. Since the reduced embryo implantation in moderate to severe endometriosis patients is assumed to be mainly based on a diminished oocyte quality (
      • Pellicer A.
      • Navarro J.
      • Bosch E.
      • Garrido N.
      • Garcia-Velasco J.A.
      • Remohí J.
      • Simón C.
      Endometrial quality in infertile women with endometriosis.
      ), it is very important to further investigate the impact and mechanism of action of a GnRH agonist on the oocyte/embryo quality.
      Although IVF/ICSI with long-term pituitary down-regulation is the first-choice treatment in patients with severe endometriosis, almost 40% of these patients surgically diagnosed with severe endometriosis did not receive this treatment regime, which illustrates the need for studies investigating the efficiency of other treatment strategies, such as continuous use of oral contraceptives prior to IVF/ICSI in this specific group of severe endometriosis patients which is supposed to be as effective as long-term pituitary down-regulation (
      • de Ziegler D.
      • Gayet V.
      • Aubriot F.X.
      • Fauque P.
      • Streuli I.
      • Wolf J.P.
      • de Mouzon J.
      • Chapron C.
      Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes.
      ). Unfortunately, the subgroup in this study was too small to calculate reliable (adjusted) odds ratios for the different subgroups.
      As the Cochrane systematic review recommendation is only based on three small studies (
      • Dicker D.
      • Goldman J.A.
      • Levy T.
      • Feldberg D.
      • Ashkenazi J.
      The impact of long-term gonadotropin-releasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer.
      ,
      • Rickes D.
      • Nickel I.
      • Kropf S.
      • Kleinstein J.
      Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis.
      ,
      • Surrey E.S.
      • Silverberg K.M.
      • Surrey M.W.
      • Schoolcraft W.B.
      Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis.
      ) a randomized controlled trial is needed. The studies only reported the endpoint as clinical pregnancy rate, which is no longer an acceptable outcome measure in the literature and should be replaced by (at least) the ongoing pregnancy rate (
      • König T.E.
      • van der Houwen L.E.
      • Lambalk C.B.
      Recombinant LH supplementation in women of 35 years and older undergoing IVF?.
      ). This is also in line with their recommendation for future research. Additionally, the three studies were performed in another IVF/ICSI treatment era with overall lower outcomes than today. In the last decade, new stimulation and IVF/ICSI techniques have resulted in steeply improved ongoing pregnancy rates, which resulted in the preference to perform (elective) single-embryo transfers and cryopreserve all good-quality embryos. A restrained policy on double-embryo transfers is incorporated in our IVF clinic to prevent multiple pregnancies and its complications.
      To investigate the amount of effect of long-term pituitary down-regulation, a well-powered randomized study in severe endometriosis patients undergoing IVF/ICSI with and without long-term pituitary down-regulation should be performed. The ongoing/live birth rate after all embryo transfers of one treatment cycle should be analysed and at least embryo quality and time to pregnancy should be taken into account. Based on these findings, it might be suggested to only perform this treatment strategy in patients with a high potential of cryopreservation. Patients with a poor response after a former IVF/ICSI attempt, signs of imminent ovarian failure (raised basal FSH concentrations beyond 10 IU/l, an antral follicle count lower than 5), or an inability to perform cryopreservation (e.g. because of the presence of hepatitis B/C or HIV infection) should probably be offered an IVF/ICSI treatment without the long-term pituitary down-regulation regime. The question remains whether or not to only perform cryopreserved embryo transfers as stated by
      • Mohamed A.M.
      • Chouliaras S.
      • Jones C.J.
      • Nardo L.G.
      Live birth rate in fresh and frozen embryo transfer cycles in women with endometriosis.
      . However, ongoing pregnancy rates after fresh embryo transfer are still higher compared with cryopreserved embryo transfers (
      • Mohamed A.M.
      • Chouliaras S.
      • Jones C.J.
      • Nardo L.G.
      Live birth rate in fresh and frozen embryo transfer cycles in women with endometriosis.
      ).
      Concerns on the risk of complications, such as developing pelvic abscesses after oocyte retrieval in patients with endometrioma, still exist (
      • Benaglia L.
      • Somigliana E.
      • Iemmello R.
      • Colpi E.
      • Nicolosi A.E.
      • Ragni G.
      Endometrioma and oocyte retrieval-induced pelvic abscess: a clinical concern or an exceptional complication?.
      ,
      • Moini A.
      • Riazi K.
      • Amid V.
      • Ashrafi M.
      • Tehraninejad E.
      • Madani T.
      • Owj M.
      Endometriosis may contribute to oocyte retrieval-induced pelvic inflammatory disease: report of eight cases.
      ,
      • Younis J.S.
      • Ezra Y.
      • Laufer N.
      • Ohel G.
      Late manifestation of pelvic abscess following oocyte retrieval, for in vitro fertilization, in patients with severe endometriosis and ovarian endometriomata.
      ). The current study found a complication rate of only 2.7%, including general IVF/ICSI-related complications, which is in line with the reported complication rate of 1.4% by
      • Benaglia L.
      • Somigliana E.
      • Iemmello R.
      • Colpi E.
      • Nicolosi A.E.
      • Ragni G.
      Endometrioma and oocyte retrieval-induced pelvic abscess: a clinical concern or an exceptional complication?.
      . No pelvic abscesses have been reported, probably because in most patients ovarian endometrioma have been surgically removed prior to IVF/ICSI. Patients with endometrioma in situ have been prophylactically treated with antibiotics.
      Only a few studies investigated the effect of IVF on endometriosis recurrence rates (
      • Benaglia L.
      • Somigliana E.
      • Vercellini P.
      • Benedetti F.
      • Iemmello R.
      • Vighi V.
      • Santi G.
      • Ragni G.
      The impact of IVF procedures on endometriosis recurrence.
      ,
      • Benaglia L.
      • Somigliana E.
      • Santi G.
      • Scarduelli C.
      • Ragni G.
      • Fedele L.
      IVF and endometriosis-related symptom progression: insights from a prospective study.
      ,
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      ).
      • Benaglia L.
      • Somigliana E.
      • Vercellini P.
      • Benedetti F.
      • Iemmello R.
      • Vighi V.
      • Santi G.
      • Ragni G.
      The impact of IVF procedures on endometriosis recurrence.
      was unable to find an association between number of IVF cycles and endometriosis recurrence and their prospective study showed no consistent risk of IVF on endometriosis-related symptoms (
      • Benaglia L.
      • Somigliana E.
      • Santi G.
      • Scarduelli C.
      • Ragni G.
      • Fedele L.
      IVF and endometriosis-related symptom progression: insights from a prospective study.
      ). Another method to describe recurrences is by assessing the CERR by using life table analysis, which allows taking into account the variable time of follow up (
      • Olive D.L.
      Analysis of clinical fertility trials: a methodologic review.
      ). Overall, the current study showed a CERR of 7.3% at 12 months after IVF. Only the study by
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      assessed the CERR and reported a CERR of 7.0% at 21 months after IVF. Although the current duration of follow up is shorter, the CERR is probably overestimated, as some patients had intrauterine insemination before IVF, which is associated with higher recurrence rates (
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      ). Due to the lack of a control group, it is not possible to conclude from these data whether IVF/ICSI in endometriosis patients has an adverse or even protective effect on endometriosis recurrence, as postulated by
      • D’Hooghe T.M.
      • Denys B.
      • Spiessens C.
      • Meuleman C.
      • Debrock S.
      Is the endometriosis recurrence rate increased after ovarian hyperstimulation?.
      . Remarkably, all recurrences were seen in patients treated with long-term pituitary down-regulation, which is thought to protect patients from endometriosis recurrence. However, this is probably due to the fact that patients treated with long-term pituitary down-regulation were more frequently diagnosed with more severe forms of endometriosis.
      In conclusion, IVF/ICSI in patients with severe endometriosis is a safe procedure. In patients treated with long-term pituitary down-regulation, it seems that ongoing pregnancy rates are diminished after fresh embryo transfer. However, including cryopreserved embryo transfers, long-term pituitary down-regulation is beneficial in achieving an ongoing pregnancy.

      Acknowledgements

      The authors would like to thank Jan-Willem Lens for his assistance in using the electronic patient database of the IVF centre of the VU University Medical Centre.

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