Abstract
This retrospective cohort study was aimed to investigate the impact of endometriosis on the IVF/ICSI outcomes. A total of 1027 cycles of patients undergoing IVF/ICSI treatment in a reproductive medicine unit of academic hospital were enrolled. In the present study, 431 cycles of patients with endometriosis constituted the study group, including 152 cycles of patients with stage I-II endometriosis and 279 cycles of patients with stage III-IV endometriosis, while 596 cycles of patients with tubal factors infertility were considered as the control group. Ovarian stimulation parameters and IVF/ICSI outcomes were compared. Patients with stage I-II and stage III-IV endometriosis required higher dosage and longer duration of gonadotropins, but had lower day 3 high-quality embryos rate, when compared to patients with tubal infertility. In addition, the number of oocytes retrieved, the number of obtained embryos, the number of day 3 high-quality embryos, serum E2 level on the day of hCG, fertilization rate were lower in patients with stage III-IV endometriosis than those in tubal factors group. Except reduced implantation rate in stage III-IV endometriosis group, no differences were found in other pregnancy parameters. This study suggests that IVF/ICSI yielded similar pregnancy outcomes in patients with different stages of endometriosis and patients with tubal infertility. Therefore, IVF/ICSI can be considered as an effective approach for managing endometriosis-associated infertility.
Keywords: Endometriosis, IVF, fertilization rate, implantation rate, clinical pregnancy rate
Introduction
Endometriosis is a condition in which endometrial tissue is present outside the uterine cavity. The prevalence rate of endometriosis has been estimated to reach around 10-15% in reproductive-age women [1]. Women with endometriosis typically present dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, an adnexal mass or completely asymptomatic disease [2,3]. Approximately, 25-50% of infertile women may be affected by endometriosis and 30-50% patients with endometriosis may suffer from infertility [1]. It is widely accepted that endometriosis exerts negative effects on the fecundity of women. However, the mechanism of endometriosis associated infertility remains incompletely understood. Several mechanisms have been proposed for the association of endometriosis and infertility, including distorted pelvic anatomy [4], impaired ovary function [4-6], altered microenvironment [7-9], affected endometrial receptivity [10-12], and reduced oocyte/embryo quality [13-15].
Although Assisted Reproductive Technology is believed as the most effective therapy of endometriosis associated infertility [16-19], there is no consensus concerning the impact of endometriosis on the IVF/ICSI outcomes. Several previous studies suggested that the IVF/ICSI results of patients with endometriosis were significantly worse than the results of patients with tubal factors [7,20]. A meta-analysis by Barnhart et al. [21] proposed that the chance of achieving pregnancy was lower for endometriosis patients compared to those with tubal factor infertility (OR 0.56; 95% CI, 0.44 to 0.70). The inferior IVF/ICSI outcomes of endometriosis women may result from decreasing number of retrieved oocytes [21,22], affected quality of oocytes/embryos [15,23], impaired uterine receptivity [7,11,20] and inhibited sperm motility [24]. In contrast, several studies presented that the endometriosis patients who underwent IVF/ICSI achieved comparable outcomes to infertile patients with tubal factors [17,25-27]. The improvement of Controlled Ovarian Hyperstimulation (COH) with GnRH-a down-regulation and the application of ICSI technology may suppress some negative influence of endometriosis on pregnancy [17,20]. The present study was undertaken to compare IVF/ICSI outcomes of women with endometriosis to those with tubal factors who underwent IVF/ICSI during the same period of time, to supply further evidence of impact of endometriosis on pregnancy, and to investigate whether endometriosis affects pregnancy results in contemporary IVF/ICSI treatment.
Materials and methods
Patients
This was a retrospective, non-interventional, single-center cohort study of patients undergoing IVF/ICSI treatment at reproductive medicine center, Tongji hospital between January 2011 and July 2012. A total of 1027 cycles were enrolled. The study groups included 152 cycles of patients with stage I-II endometriosis and 279 cycles of patients with stage III-IV endometriosis, while 596 cycles of patients with tubal factors infertility were considered as the control group. All patients in endometriosis groups underwent complete removal of endometriosis lesion by laparoscopy before IVF/ICSI treatment. Endometriosis was staged according to the American Society for Reproductive Medicine (ASRM) 1996 classification [3]. All patients in the control group were diagnosed as tubal infertility by laparoscopy, and patients with other factors for infertility besides tubal pathology, such as polycystic ovarian syndrome, uterine malformation, underlying immune conditions, and paternal abnormalities were excluded. Institutional Review Board approval was not necessary, since all patients in the cohort underwent the routine IVF/ICSI treatment in our center and no additional intervention was applied.
Protocol for COH and IVF/ICSI
Patients with endometriosis underwent COH with GnRH-a long protocol or GnRH-a prolonged protocol. Briefly, the patients who underwent prolonged down-regulation received 3.75 mg intramuscularly GnRH-a (Leuprorelin Acetate, Takeda, Japan) every 28 days for 3 months before COH. As for patients taking long protocols, subcutaneous injection of 0.1 mg GnRH-a (Decapeptyl (Ferring, Switzerland) or Diphere-line (Ipsen, Australia)) was administrated daily from midluteal phase of the preceding cycle, which was reduced to 0.05 mg once adequate down-regulation was achieved. The complete pituitary suppression was confirmed by serum E2 level <30 pg/mL and serum LH level <2 mIU/mL. All patients with tubal factors received GnRH-a long protocol.
Ovarian stimulation with recombinant FSH (Gonal-F (Serono, Switzerland) or Puregon (Organon, Netherlands)) was started with administration of 150 IU/d intramuscularly. The dosage of FSH was adjusted according to ovarian response which was assessed by ultrasound and serum E2 level. Recombinant hCG (Serono, Switzerland) was given to trigger follicle maturation when at least two follicles reached a mean diameter of 18 mm. Oocytes retrieval was performed transvaginally 34-36 hours after hCG injection. ICSI was performed when sperm quality was unexpectedly low on the day of oocytes retrieval.
Main variables in assessment of embryos included the cleavage rate, equality of blastomeres, the degree of fragmentation, and mononuclearity in blastomeres. Embryos were classified as Class 1 to Class 4: Class 1 embryos were defined as 4-6 cells on day 2, 8-10 cells on day 3, equal, fragmentation <10%, and no multinucleated blastomeres. Class 2 embryos were defined as 3 or >6 cells on day 2, 6-7 or >10 cells on day 3, equal or less equal, fragmentation 10-20%, and no multinucleated blastomeres. Class 3-4 embryos were those 0-2 cells on day 2, 1-5 cells on day 3, unequal, fragmentation >25%, with or without multinucleated blastomeres. Class 1 and Class 2 embryos were considered as high-quality embryos. Fewer than three embryos were transferred on the day 3 after oocyte retrieval, and excessive high-quality embryos were cryopreserved for subsequent FET cycles. Injections with 60 mg progesterone intramuscularly were administrated as luteal phase support from the day of oocyte retrieval.
Outcomes measures
In the present study, primary outcomes included implantation rate, clinical pregnancy rate (CPR) per initiated cycle, CPR per embryo transfer cycle, and live birth rate. Secondary outcomes were COH and embryo parameters, such as dosage and duration of gonadotropins, the number of oocytes retrieved, E2 level on the day of hCG, fertilization rate, the number of obtained embryos, the number and rate of day 3 high-quality embryos. Clinical pregnancy was defined as a serum hCG level >20 IU/L and confirmed by observation of gestational sac on transvaginal ultrasound scan 5-7 weeks after transfer. Implantation rate was defined as the number of gestational sacs present on ultrasound scan 5-7 weeks after transfer divided by the number of embryos transferred [28].
Statistical analysis
Shapiro-Wilks test was used to evaluate the distribution of the data. The Continuous data with normal distribution were given as mean±SD. Data with non-normal distribution were presented as median (range). Groups were compared with one-way analysis of variance (ANOVA) with Bonferroni adjustment or Kruskal-Wallis test as appropriate. Categorical variables were presented as percentage and number. Differences between proportions or rates were evaluated with chi-square test and the Fisher exact test. Multiple logistic regression analysis was performed for adjustment of clinical features. A P value <.05 was considered statistically significant. SPSS version 13.0 (SPSS Inc.) was used for statistical analysis.
Results
Demographic data and clinical characteristics are shown in Table 1. The BMI and basal serum FSH level were lower in endometriosis groups than those in tubal factors group. Moreover, patients with stage III-IV endometriosis had fewer antral follicles as compared to patients with tubal factors. No differences were found in age, infertility type, duration of infertility, basal serum LH, E2 level, and day 3 endometrial thickness.
Table 1.
Demographics and clinical characteristics
| Stage I-II endometriosis | Stage III-IV endometriosis | Tubal factors | |
|---|---|---|---|
| No. of initiated cycles | 152 | 279 | 596 |
| No. of embryo transfer cycles | 124 | 228 | 505 |
| Age (years) | 31.0±3.2 | 30.7±3.8 | 30.8±4.7 |
| BMI (kg/m2) | 20.6±2.1a | 20.9±2.4a | 21.5±2.6 |
| Infertility type | |||
| Primary infertility (%) | 53.9 (82/152) | 54.1 (151/279) | 52.0 (310/596) |
| Secondary infertility (%) | 46.1 (70/152) | 45.9 (128/279) | 48.0 (286/596) |
| Duration of infertility (years) | 5 (5-16) | 5 (5-20) | 5 (2-20) |
| Basal serum FSH level (mIU/mL) | 6.81 (2.00-25.33)b | 6.78 (1.79-37.23)b | 7.13 (1.02-36.78) |
| Basal serum LH level (mIU/mL) | 4.41 (1.74-12.70) | 3.93 (0.29-25.01) | 3.72 (2.10-11.30) |
| Basal serum E2 level (pg/mL) | 54.9 (0.50-170.66) | 61.61 (0.19-190.41) | 52.92 (25.44-122.20) |
| Antral follicle count | 13.1±5.8 | 10.6±5.6a | 13.4±5.5 |
| Day 3 endometrial thickness (mm) | 5.1±1.6 | 5.4±2.0 | 4.6±1.7 |
< 0.01.
= 0.02.
COH performances are presented in Table 2. Women with endometriosis required more days and higher dosage of ovarian stimulation, but had lower day 3 high-quality embryos rate when compared to patients with tubal infertility patients, irrespective of stage of endometriosis. Additionally, the number of oocytes retrieved, the number of obtained embryos, the number of day 3 high-quality embryos, serum E2 level on the day of hCG, fertilization rate were lower in patients with stage III-IV endometriosis than those in patients with tubal factors.
Table 2.
COH performances and embryo parameters
| Stage I-II endometriosis | Stage III-IV endometriosis | Tubal factors | |
|---|---|---|---|
| No. of initiated cycles | 152 | 279 | 596 |
| No. of embryo transfer cycles | 124 | 228 | 505 |
| IVF (%) | 81.6 (124/152) | 82.8 (231/279) | 80.9 (482/596) |
| ICSI (%) | 18.4 (28/152) | 17.2 (48/279) | 19.1 (114/596) |
| Duration of Gonadotropins (days) | 11 (6-23)c | 11 (2-23)c | 10 (3-17) |
| Dosage of Gonadotropins (ampules) | 38.8±14.7a | 39.0±15.3a | 34.1±12.8 |
| No. of oocytes retrieved | 12.9±7.2 | 9.2±6.3a | 12.4±6.3 |
| Serum E2 level on the day of hCG (pg/mL) | 4378.89±3000.25 | 3955.73±2674.91b | 4479.39±2595.50 |
| Postwash sperm concentration (X106) | 68.1±29.7 | 64.4±26.8 | 68.2±28.5 |
| Postwash sperm motility (%) | 55.8±15.2 | 53.7±17.0 | 58.0±15.6 |
| Fertilization rate (%) | 62.5 (1223/1958) | 61.6 (1568/2545)b | 64.0 (4753/7428) |
| No. of obtained embryos | 8.1±5.5 | 5.6±4.6a | 8.0±4.8 |
| No. of day 3 high-quality embryos | 5.7±4.6 | 4.0±3.9a | 6.3±4.5 |
| Day 3 high-quality embryos rate (%) | 70.6 (864/1223)a | 70.1 (1099/1568)a | 78.4 (3728/4753) |
< 0.01.
= 0.03.
= 0.04.
IVF/ICSI outcomes were illustrated in Table 3. The cycle cancellation rate, biochemical pregnancy rate were similar among the three groups. Patients with stage III-IV endometriosis obtained lower implantation rate and lower proportion of pregnancy with two gestational sacs than patients with tubal infertility. No differences were found in other pregnancy parameters among the three groups, in terms of CPRs, live birth rate, miscarriage rate and ectopic pregnancy rate.
Table 3.
IVF/ICSI outcomes
| Stage I-II endometriosis | Stage III-IV endometriosis | Tubal factors | |
|---|---|---|---|
| No. of initiated cycles | 152 | 279 | 596 |
| No. of embryo transfer cycles | 124 | 228 | 505 |
| Cycle cancellation rate (%) | 18.4 (28/152) | 18.3 (51/279) | 15.3 (91/596) |
| Biochemical pregnancy rate (%) | 3.2 (4/124) | 3.9 (9/228) | 1.8 (9/505) |
| Implantation rate (%) | 35.0 (85/243) | 29.1 (126/433)b | 34.5 (345/999) |
| Pregnancy with single gestational sac (%) | 60.7 (37/61) | 76.2 (77/101)a | 63.1 (159/252) |
| Pregnancy with two gestational sacs (%) | 39.3 (24/61) | 23.8 (24/101)a | 36.9 (93/252) |
| CPR per initiated cycle (%) | 40.1 (61/152) | 36.2 (101/279) | 42.3 (252/596) |
| CPR per embryo transfer cycle (%) | 49.2 (61/124) | 44.3 (101/228) | 49.9 (252/505) |
| Live birth rate (%) | 78.8 (67/85) | 81.7 (103/126) | 82.0 (283/345) |
| Miscarriage rate (%) | 16.5 (14/85) | 15.1 (19/126) | 13.6 (47/345) |
| Ectopic pregnancy rate (%) | 4.7 (4/85) | 3.2 (4/126) | 4.4 (15/345) |
=0.02.
=0.04.
To adjust the endometriosis and tubal infertility groups for clinical features in BMI, basal serum FSH level and antral follicle count, multiple logistic regression analysis was undertaken. In the present study, BMI, FSH, as well as antral follicle count was not associated with chance of achieving pregnancy (Table 4).
Table 4.
Multiple logistic regression analysis of clinical features
| OR (95% CI) | P value | |
|---|---|---|
| BMI | 0.99 (0.90-1.09) | 0.85 |
| Basal serum FSH level | 1.00 (0.92-1.09) | 1.00 |
| Antral follicle count | 1.01 (0.96-1.05) | 0.76 |
Discussion
In the present study, we found that patients with endometriosis responded worse to ovarian stimulation than patients with tubal factors, as indicated by longer duration and higher dosage of gonadotropins required in endometriosis groups. In addition, patients with moderate/severe endometriosis obtained lower E2 level on the day of hCG and fewer retrieved oocytes, suggesting that besides the decreased ovarian response, the follicle-genesis may also be affected. Our results were in general agreement with previous studies [22,26,27].
There was evidence suggesting that impaired oocyte/embryo quality may be one of the causes of endometriosis-associated infertility [13-15]. Indeed, decreased day 3 high-quality embryos rate was found in patients with minimal/mild endometriosis, which suggests that minimal/mild endometriosis lesion can affect embryo-development, but the fertilization rate, the number of obtained embryos and the number of day 3 high-quality embryos were not significantly affected. As for moderate/severe endometriosis cases, fertilization rate, the number of obtained embryos, the number of day 3 high-quality embryos and the day 3 high-quality embryos rate were all decreased. Moderate/severe endometriosis lesion can impair the follicle/oocytes quality, embryogenesis and subsequent embryo viability.
Although it has been widely accepted that endometriosis can adversely influence fecundity and pregnancy, there are still controversies on the impact of endometriosis on pregnancy results in IVF/ICSI treatment cycles. Some studies described that although patients with endometriosis obtained inferior COH performance and/or inferior embryos when compared to patients with tubal factors, these differences did not transfer to pregnancy results [17,29]. However, other studies reported adverse effects of endometriosis on pregnancy results in IVF/ICSI cycles, with respect to decreased implantation rate and/or CPRs [7,20,21]. Our data showed that IVF/ICSI treatment yielded comparable pregnancy results in patients with stage I-II endometriosis and those with tubal infertility. In patients with stage III-IV endometriosis, CPRs and live birth rate were similar to patients with tubal factors, whereas the implantation rate and the proportion of pregnancy with two sacs were lower. Comparable CPRs indicate that patients with moderate/severe endometriosis have similar probability to becoming pregnant as patients with tubal infertility, while reduced implantation rate and likelihood of two-embryo pregnancy suggest abnormalities in the course of embryo implantation, which might be due to impaired embryo-quality and/or alterations of endometrium. Further studies were needed to elucidate whether embryo factor or endometrial factor is the main cause of impaired implantation in patients with moderate/severe endometriosis.
Despite the less well ovarian response, reduced oocyte/embryo quality, impaired implantation, patients with endometriosis obtained acceptable IVF/ICSI outcomes, as indicated by similar CPRs and live birth rate comparing to tubal infertile patients, irrespective of stage of endometriosis. Such results may attribute to the following facts. First, in order to yield more retrievable oocytes, higher doses of gonadotropins were used in our unit. Relatively aggressive COH might reduce some negative effects of endometriosis on ovaries and induce more available oocytes, which offers an elevated possibility to obtain high-quality embryos. Indeed, treatment with superovulation or ovulation was reported to yield superior outcomes in patients with endometriosis [30-32]. Second, appropriate GnRH-a down-regulation seemed to be essential to IVF/ICSI success. The mechanisms responsible for the beneficial effects of GnRH-a down-regulation remain elusive. GnRH-a may not exclusively prevent an endogenous LH surge but also suppress a number of inflammatory cytokines and soothe the toxic effects of peritoneal cytokines on oocytes and embryos [15]. Additionally, GnRH-a may also correct the endometrial alterations in endometriosis patients [33,34]. Lastly, laparoscopy may also play an important role in increasing the pregnancy rate in endometriosis patients. The efficacy of laparoscopic procedures in managing endometriosis related infertility was reported by previous studies [35,36].
Endometriosis has been associated with infertility. However, the mechanism has not been identified. Some studies suggested that the infertility in endometriosis patients mainly depend on the impaired ovarian reserve and reduced ovarian response, as indicated by lower anti-müllerian hormone, higher FSH and aberrant expression of some proteins [6,23]. Besides, affected endometrial receptivity in endometriosis patients may also contribute to endometriosis-associated infertility. Some studies demonstrated that the expression pattern of various endometrial receptivity related factors were altered in endometriosis patients, such as Integrin, LIF, HOXA-10, IL-11 and P53 [10-12,37-39]. Based on the data of our study, we proposed that endometriosis adversely impacts ovarian function, oocyte/embryo-development, which may be related to infertility. Furthermore, embryo implantation is affected in patients with advanced stage endometriosis, which also may constitute as a cause of endometriosis-associated infertility.
In conclusion, despite less well ovarian response, reduced embryo quality, and impaired implantation in moderate/severe cases, endometriosis patients obtained comparable IVF/ICSI success to patients with tubal factors infertility. Combination effect of aggressive COH, appropriate pituitary suppression, and efficient surgery before IVF seemed to be crucial in IVF/ICSI success of patients with endometriosis. Therefore, IVF/ICSI can be considered as an effective approach for managing endometriosis-associated infertility.
Acknowledgements
This work was supported by National Natural Science Foundation of China (No. 81170619).
Disclosure of conflict of interest
There were no conflicts of interest.
References
- 1.Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39:535–549. doi: 10.1016/j.ogc.2012.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Senapati S, Barnhart K. Managing endometriosis-associated infertility. Clin Obstet Gynecol. 2011;54:720–726. doi: 10.1097/GRF.0b013e3182353e06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98:591–598. doi: 10.1016/j.fertnstert.2012.05.031. [DOI] [PubMed] [Google Scholar]
- 4.Schenken RS, Asch RH, Williams RF, Hodgen GD. Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions. Fertil Steril. 1984;41:122–130. doi: 10.1016/s0015-0282(16)47552-7. [DOI] [PubMed] [Google Scholar]
- 5.Mio Y, Toda T, Harada T, Terakawa N. Luteinized unruptured follicle in the early stages of endometriosis as a cause of unexplained infertility. Am J Obstet Gynecol. 1992;167:271–273. doi: 10.1016/s0002-9378(11)91673-1. [DOI] [PubMed] [Google Scholar]
- 6.Yoo JH, Cha SH, Park CW, Kim JY, Yang KM, Song IO, Koong MK, Kang IS, Kim HO. Serum anti-Mullerian hormone is a better predictor of ovarian response than FSH and age in IVF patients with endometriosis. Clin Exp Reprod Med. 2011;38:222–227. doi: 10.5653/cerm.2011.38.4.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Coccia ME, 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. Acta Obstet Gynecol Scand. 2011;90:1232–1238. doi: 10.1111/j.1600-0412.2011.01247.x. [DOI] [PubMed] [Google Scholar]
- 8.Chen ML, Lee KC, Yang CT, Hung KH, Wu MH. Simultaneous laparoscopy for endometriotic women undergoing in vitro fertilization. Taiwan J Obstet Gynecol. 2012;51:66–70. doi: 10.1016/j.tjog.2012.01.013. [DOI] [PubMed] [Google Scholar]
- 9.Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75:1–10. doi: 10.1016/s0015-0282(00)01630-7. [DOI] [PubMed] [Google Scholar]
- 10.Xiao Y, Sun X, Yang X, Zhang J, Xue Q, Cai B, Zhou Y. Leukemia inhibitory factor is dysregulated in the endometrium and uterine flushing fluid of patients with adenomyosis during implantation window. Fertil Steril. 2010;94:85–89. doi: 10.1016/j.fertnstert.2009.03.012. [DOI] [PubMed] [Google Scholar]
- 11.Dimitriadis E, Stoikos C, Stafford-Bell M, Clark I, Paiva P, Kovacs G, Salamonsen LA. Interleukin-11, IL-11 receptoralpha and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J Reprod Immunol. 2006;69:53–64. doi: 10.1016/j.jri.2005.07.004. [DOI] [PubMed] [Google Scholar]
- 12.Lu H, Yang X, Zhang Y, Lu R, Wang X. Epigenetic disorder may cause downregulation of HOXA10 in the eutopic endometrium of fertile women with endometriosis. Reprod Sci. 2013;20:78–84. doi: 10.1177/1933719112451146. [DOI] [PubMed] [Google Scholar]
- 13.Garrido N, Navarro J, Remohi J, Simon C, Pellicer A. Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update. 2000;6:67–74. doi: 10.1093/humupd/6.1.67. [DOI] [PubMed] [Google Scholar]
- 14.Mansour G, Sharma RK, Agarwal A, Falcone T. Endometriosis-induced alterations in mouse metaphase II oocyte microtubules and chromosomal alignment: a possible cause of infertility. Fertil Steril. 2010;94:1894–1899. doi: 10.1016/j.fertnstert.2009.09.043. [DOI] [PubMed] [Google Scholar]
- 15.Pellicer A, Oliveira N, Ruiz A, Remohi J, Simon C. Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod. 1995;10(Suppl 2):91–97. doi: 10.1093/humrep/10.suppl_2.91. [DOI] [PubMed] [Google Scholar]
- 16.Dmowski WP, Pry M, Ding J, Rana N. Cycle-specific and cumulative fecundity in patients with endometriosis who are undergoing controlled ovarian hyperstimulation-intrauterine insemination or in vitro fertilization-embryo transfer. Fertil Steril. 2002;78:750–756. doi: 10.1016/s0015-0282(02)03343-5. [DOI] [PubMed] [Google Scholar]
- 17.Opoien HK, Fedorcsak P, Omland AK, Abyholm T, Bjercke S, Ertzeid G, Oldereid N, Mellembakken JR, Tanbo T. In vitro fertilization is a successful treatment in endometriosis-associated infertility. Fertil Steril. 2012;97:912–918. doi: 10.1016/j.fertnstert.2012.01.112. [DOI] [PubMed] [Google Scholar]
- 18.Assisted reproductive technology in the United States: 2010 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproduction registry [database on the Internet] 2012.
- 19.Ozkan S, Arici A. Advances in treatment options of endometriosis. Gynecol Obstet Invest. 2009;67:81–91. doi: 10.1159/000163071. [DOI] [PubMed] [Google Scholar]
- 20.Lin XN, Wei ML, Tong XM, Xu WH, Zhou F, Huang QX, Wen GF, Zhang SY. Outcome of in vitro fertilization in endometriosis-associated infertility: a 5-year database cohort study. Chin Med J (Engl) 2012;125:2688–2693. [PubMed] [Google Scholar]
- 21.Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148–1155. doi: 10.1016/s0015-0282(02)03112-6. [DOI] [PubMed] [Google Scholar]
- 22.Suzuki T, Izumi S, Matsubayashi H, Awaji H, Yoshikata K, Makino T. Impact of ovarian endometrioma on oocytes and pregnancy outcome in in vitro fertilization. Fertil Steril. 2005;83:908–913. doi: 10.1016/j.fertnstert.2004.11.028. [DOI] [PubMed] [Google Scholar]
- 23.Prieto L, Quesada JF, Cambero O, Pacheco A, Pellicer A, Codoceo R, Garcia-Velasco JA. Analysis of follicular fluid and serum markers of oxidative stress in women with infertility related to endometriosis. Fertil Steril. 2012;98:126–130. doi: 10.1016/j.fertnstert.2012.03.052. [DOI] [PubMed] [Google Scholar]
- 24.Oral E, Arici A, Olive DL, Huszar G. Peritoneal fluid from women with moderate or severe endometriosis inhibits sperm motility: the role of seminal fluid components. Fertil Steril. 1996;66:787–792. doi: 10.1016/s0015-0282(16)58637-3. [DOI] [PubMed] [Google Scholar]
- 25.de Ziegler D, Gayet V, Aubriot FX, Fauque P, Streuli I, Wolf JP, de Mouzon J, Chapron C. Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes. Fertil Steril. 2010;94:2796–2799. doi: 10.1016/j.fertnstert.2010.05.056. [DOI] [PubMed] [Google Scholar]
- 26.Hickman TN. Impact of endometriosis on implantation. Data from the Wilford Hall Medical Center IVF-ET Program. J Reprod Med. 2002;47:801–808. [PubMed] [Google Scholar]
- 27.Matalliotakis IM, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sakkas D. Women with advanced-stage endometriosis and previous surgery respond less well to gonadotropin stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril. 2007;88:1568–1572. doi: 10.1016/j.fertnstert.2007.01.037. [DOI] [PubMed] [Google Scholar]
- 28.Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, Sullivan E, van der Poel S. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod. 2009;24:2683–2687. doi: 10.1093/humrep/dep343. [DOI] [PubMed] [Google Scholar]
- 29.Barri PN, Coroleu B, Tur R, Barri-Soldevila PN, Rodriguez I. Endometriosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach. Reprod Biomed Online. 2010;21:179–185. doi: 10.1016/j.rbmo.2010.04.026. [DOI] [PubMed] [Google Scholar]
- 30.Abu Hashim H, El Rakhawy M, Abd Elaal I. Randomized comparison of superovulation with letrozole vs. clomiphene citrate in an IUI program for women with recently surgically treated minimal to mild endometriosis. Acta Obstet Gynecol Scand. 2012;91:338–345. doi: 10.1111/j.1600-0412.2011.01346.x. [DOI] [PubMed] [Google Scholar]
- 31.Fedele L, Bianchi S, Marchini M, Villa L, Brioschi D, Parazzini F. Superovulation with human menopausal gonadotropins in the treatment of infertility associated with minimal or mild endometriosis: a controlled randomized study. Fertil Steril. 1992;58:28–31. doi: 10.1016/s0015-0282(16)55132-2. [DOI] [PubMed] [Google Scholar]
- 32.Tummon IS, Asher LJ, Martin JS, Tulandi T. Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil Steril. 1997;68:8–12. doi: 10.1016/s0015-0282(97)81467-7. [DOI] [PubMed] [Google Scholar]
- 33.Imai A, Takagi A, Tamaya T. Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro. Am J Obstet Gynecol. 2000;182:1142–1146. doi: 10.1067/mob.2000.104804. [DOI] [PubMed] [Google Scholar]
- 34.Lessey BA. Medical management of endometriosis and infertility. Fertil Steril. 2000;73:1089–1096. doi: 10.1016/s0015-0282(00)00519-7. [DOI] [PubMed] [Google Scholar]
- 35.Beretta P, Franchi M, Ghezzi F, Busacca M, Zupi E, Bolis P. Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation. Fertil Steril. 1998;70:1176–1180. doi: 10.1016/s0015-0282(98)00385-9. [DOI] [PubMed] [Google Scholar]
- 36.Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of >3 cm in diameter. Hum Reprod. 2001;16:2583–2586. doi: 10.1093/humrep/16.12.2583. [DOI] [PubMed] [Google Scholar]
- 37.Petracco R, Grechukhina O, Popkhadze S, Massasa E, Zhou Y, Taylor HS. MicroRNA 135 regulates HOXA10 expression in endometriosis. J Clin Endocrinol Metab. 2011;96:E1925–1933. doi: 10.1210/jc.2011-1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Paskulin DD, Cunha-Filho JS, Souza CA, Bortolini MC, Hainaut P, Ashton-Prolla P. TP53 PIN3 and PEX4 polymorphisms and infertility associated with endometriosis or with post-in vitro fertilization implantation failure. Cell Death Dis. 2012;3:e392. doi: 10.1038/cddis.2012.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W, Strom BL. Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab. 1994;79:643–649. doi: 10.1210/jcem.79.2.7519194. [DOI] [PubMed] [Google Scholar]