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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.
). 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 (
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 (
) 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 (
) 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 (
). 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 (
) 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).
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 (
). 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 (
). 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 (
). 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 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) (
). 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.
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).
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).
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.
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.
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).
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
. 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 (
). 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 (
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 (
) 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 (
). 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 (
). 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 (
). 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 (
). 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 (
), 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 (
) 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 (
). 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
. 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 (
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 (
). 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
. 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.
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.
Effect of endometriosis on in vitro fertilization.
Declaration: The authors report no financial or commercial conflicts of interest.
Lisette van der Houwen is a PhD researcher in the Endometriosis Center, Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, VU University Medical Centre in Amsterdam, The Netherlands. Her thesis is focusing on fertility in endometriosis patients. She will begin her gynaecology and obstetrics specialization in 2014.