Abstract
Purpose
The reproductive outcomes of patients with endometriosis who are infertile have attracted recent attention. We aimed to explore whether endometriosis affects endometrial receptivity by observing pregnancy outcomes following a euploid blastocyst frozen embryo transfer.
Methods
This retrospective cohort study analyzed the data of patients with endometriosis from the reproductive hospital affiliated to Shandong University between January 2015 and December 2021. Control groups were matched using the 1:3 propensity score. The live birth, clinical pregnancy, biochemical pregnancy, clinical abortion, premature birth, and aneuploid rates were compared between the control group and endometriosis group.
Results
A total of 625 patients who underwent preimplantation genetic testing (PGT) prior to embryo implantation were included in the analysis. There were no significant differences in the live birth, clinical pregnancy, biochemical pregnancy, clinical abortion, and premature birth rates between the two groups. The aneuploidy rate of blastocysts obtained from the endometriosis group was higher than that of the control group (P = 0.012).
Conclusion
Pregnancy outcomes using frozen embryos after PGT in patients with endometriosis did not differ from those in other women experiencing infertility. However, endometriosis may affect the quality of oocytes, resulting in a higher rate of aneuploidy.
Keywords: Endometriosis, Euploid blastocyst transfers, ART, Preimplantation genetic testing, Frozen embryo transfer
Introduction
Ectopic tissue similar to endometrial tissue that grows beyond the uterus is a common benign gynecologic illness in women of reproductive age, known as endometriosis [1]. Endometriosis can impair fertility. While assisted reproductive technology is a useful technique to help address fertility issues in patients with endometriosis, some studies have found that these patients have poorer pregnancy outcomes [2].
It is unclear whether there is a direct cause and effect relationship between endometriosis and low fertility. However, a previous study suggested that ectopic endometrial-like tissue provokes elevated oestradiol, HOXA10 gene expression, and progesterone resistance, thus reducing endometrial receptivity in patients with endometriosis and blocks embryo implantation [3]. Therefore, endometrial receptivity appears to be impaired in endometriosis. Moreover, previous studies have shown that patients who received oocytes donated by people with endometriosis had a lower implantation rate than those who received donor oocytes from people without endometriosis. This finding contrasts with the assumption that endometrial receptivity alone influences pregnancy outcomes [4]. Damaged oocytes and embryos both contribute to low pregnancy rates in patients with endometriosis.
Based on available animal and cellular experiments, those with endometriosis are more prone to producing oocytes with chromosomal abnormalities and meiosis errors [5, 6]. Such abnormalities may affect the aneuploidy rate of the embryos produced by patients with endometriosis; however, available clinical studies are insufficient. Furthermore, several studies have demonstrated that frozen embryo transfers can lead to better clinical outcomes in patients with endometriosis; however, most of these studies did not perform preimplantation genetic testing before embryo transfer. Therefore, this study aimed to investigate whether endometriosis affects endometrial receptivity after excluding the influence of aneuploid embryos. Moreover, we investigated whether endometriosis influences the rate of aneuploidy.
Materials and methods
Patients
This retrospective cohort study analyzed the data of patients with endometriosis and those without endometriosis experiencing infertility from the reproductive hospital affiliated to Shandong University between January 2015 and December 2021. Infertility was defined as the inability to conceive after regular sex for > 1 year without contraception. The reasons for preimplantation genetic testing (PGT) in our patients include chromosomal abnormality, advanced female age, monogenic disease, adverse pregnancy history, and other reasons. Patients in our control group included chromosomal abnormality (53.4%) and chromosomal normality (46.6%). Among the patients in the control group, 50.4% cases combined with tubal factors, 20.6% cases combined with male factor, and the rest of 29% of patients did not combine with tubal or male factors, only a simple chromosomal disease or monogenic disease or adverse pregnancy history.
Inclusion and exclusion criteria
Patients received routine gynecological ultrasonography examinations prior to assisted reproductive technology. The endometriosis group consisted of patients surgically diagnosed with endometriosis. Conversely, the control group included patients without endometriosis.
Patients who had recurrent implant failure, antiphospholipid syndrome, unexplained recurrent miscarriages, and major data gaps were excluded from the study.
Baseline characteristics
All patients’ basal hormone levels, including AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2), were recorded and examined in this retrospective cohort study. Baseline characteristics, such as age, BMI, and history of prior endometrial polyp surgery, were also compared. Furthermore, the conditions of ART cycles in terms of endometrial thickness, fertilization rate, MII, and 2PN between two groups were compared. In addition, the rate of aneuploidy in embryos was analyzed in two groups; furthermore, subgroup analyses were performed in different types of chromosomal abnormality.
Ovarian stimulation and PGT
Gonadotropins were administered between days 3 and 5 of the menstrual cycle to promote follicular development. Human chorionic gonadotropin (HCG) or a gonadotropin-releasing hormone agonist (GnRH-a) was injected once until at least one follicle with a diameter of 18 mm grew. Follicular development was monitored via ultrasonography. Around 34–36 hours after triggering oocyte maturation, the oocytes were retrieved using transvaginal ultrasound.
Using intracytoplasmic sperm injection (ICSI), mature oocytes were fertilized and cultured to the blastocyst stage. On day 5 or 6, trophoblast ectoderm biopsies were performed on blastocysts with a good grade. For PGT, each accessible blastocyst with a Gardner blastocyst morphology grade greater than 4BC was analyzed.
Once the timing of FET was determined, progesterone was administered daily either orally or transvaginally. The primary outcome of our study was the live birth rate, defined as the delivery of at least one viable neonate after 28 gestational weeks. Clinical pregnancy was defined as the detection of an intrauterine gestational sac observed via transvaginal ultrasonography after 6 weeks of FET. Biochemical pregnancy was defined as a blood β-HCG level of 10 IU/L 2 weeks after the embryo transfer. Preterm birth was defined as delivery at < 37 weeks’ gestation. Miscarriage was defined as the loss of pregnancy < 24 weeks gestation. If pregnancy was successful after a single blastocyst transfer, luteal phase support was continued until 12 weeks of intrauterine gestation.
Statistical analysis
The statistical analysis was performed using SPSS 26.0. SPSS software was used to conduct propensity score matching (PSM) between the endometriosis group and control group according to the 1:3 matching principle. To compare baseline characteristics between groups and to show the mean and standard deviation of continuous variables, descriptive statistics were used. The clinical outcomes of each group were examined using the T-test and the chi-square test. P < 0.05 was considered statistically significant. Using the generalized estimating equations, adjustments were made for repeated oocyte retrieval cycles.
Result(s)
Basic characteristics between two groups
A total of 174 frozen embryo transfer cycles were performed on 128 patients in the endometriosis group, and a total of 522 frozen embryo transfer cycles were performed on 497 patients in the control group.
The rate of oocyte retrieval did not significantly differ between the two groups. After genetic testing, all transfers were single transfers. Compared with the control group, the hysteroscopic treatment history of endometrial polyps in the endometriosis group was significantly higher. Additionally, HCG day E2 and the start-up dosage of gonadotropin (Gn) of patients in the endometriosis group were higher than those in the control group (Table 1).
Table 1.
Patient baseline characteristics in frozen embryo transfer cycles
| Characteristic | Endometriosis (N = 174) | Control (N = 522) | P |
|---|---|---|---|
| No. of patients | 128 | 497 | |
| No. of FET cycles | 174 | 522 | |
| Age (y) | 32.11 ± 4.201 | 31.74 ± 4.741 | 0.330 |
| BMI | 23.24 ± 3.056 | 23.76 ± 3.238 | 0.064 |
| AMH | 3.98 ± 2.742 | 3.75 ± 2.644 | 0.314 |
| Basal FSH (IU/ML) | 6.76 ± 2.860 | 6.58 ± 1.885 | 0.434 |
| Basal LH (IU/ML) | 6.06 ± 5.271 | 5.32 ± 3.024 | 0.080 |
| Basal E2 (pg/ML) | 42.91 ± 50.076 | 47.95 ± 108.251 | 0.553 |
| HCG day P | 0.80 ± 0.431 | 0.73 ± 0.558 | 0.151 |
| HCG day E2 | 4351.43 ± 2701.520 | 3816.32 ± 2171.446 | 0.019* |
| Start-up dosage of Gn (U) | 188.08 ± 83.402 | 174.14 ± 53.071 | 0.040* |
| Total dosage of Gn (U) | 1952.71 ± 977.197 | 1937.31 ± 841.758 | 0.842 |
| Oocytes retrieved | 12.80 ± 6.050 | 13.09 ± 6.358 | 0.606 |
| No. of MII oocytes | 11.11 ± 5.851 | 11.50 ± 5.856 | 0.455 |
| No. of 2PN | 9.37 ± 4.885 | 9.28 ± 4.699 | 0.830 |
| No. of blastocysts | 5.23 ± 3.309 | 4.89 ± 2.832 | 0.229 |
| Endometrial thickness on HCG day | 1.04 ± 0.206 | 1.03 ± 0.207 | 0.751 |
| Number of large follicles | 11.78 ± 5.780 | 11.44 ± 4.967 | 0.497 |
| Oocyte retrieval rates | 1.12 ± 0.408 | 1.15 ± 0.334 | 0.344 |
| MII oocyte retrieval rates | 0.89 ± 0.193 | 0.89 ± 0.165 | 0.813 |
| Fertility rate | 0.79 ± 0.220 | 0.77 ± 0.228 | 0.245 |
| Polyp history | 26 (14.9%) | 42 (8.0%) | 0.008* |
| Hydrosalpinx | 4 (2.3%) | 11 (2.1%) | 1.000 |
| PCOS | 14 (8.0%) | 53 (10.2%) | 0.414 |
Values are presented as mean ± standard deviation or n (%)
BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, E2 estrogen, P progestogen, Gn gonadotropin, IVF in vitro fertilization, PCOS polycystic ovary syndrome
Fertility rate: number of fertilized oocyte/number of MII oocyte
*P < 0.05
Various parameters during controlled ovarian hyperstimulation
Between the two groups, there were no discernible differences between the control and endometriosis groups regarding age, baseline hormone status, endometrial thickness, 2PN number, MII number, rate of oocyte retrieval, mature oocytes, or fertilization rate. Moreover, regarding the stimulation protocols, group differences were only found among the ultralong protocols (Table 2).
Table 2.
Ovarian stimulation protocols in the endometriosis and the control group
| Item | Endometriosis (n = 174) | Control (n = 522) | P |
|---|---|---|---|
| Protocol, n (%) | |||
| Long protocol | 68 (39.1%) | 233 (44.6%) | 0.200 |
| Short protocol | 41 (23.6%) | 84 (16.1%) | 0.026 |
| Antagonist protocol | 49 (28.2%) | 186 (35.6%) | 0.071 |
| Ultralong protocol | 9 (5.2%) | 7 (1.3%) | 0.003* |
| Other protocol | 7 (4.0%) | 12 (2.3%) | 0.227 |
Data are presented as n/N (%)
*P < 0.05
Other protocol: (1) luteal phase stimulation: after a woman’s natural ovulation cycle is completed, the remaining immature oocytes are treated with drugs to continue to promote development; (2) natural cycle: according to the menstrual cycle follicular monitoring, triggers, and oocyte extraction when the follicle naturally matures
Results of clinical outcomes
The live birth rate was slightly decreased in patients with endometriosis; however, it was not statistically significant (52.3% vs 57.3%, P = 0.252). There were also no significant differences in other clinical outcomes such as the clinical pregnancy, biochemical pregnancy, clinical abortion, and preterm birth rates (P > 0.05) (Table 3). Moreover, a subgroup analysis in endometrioma cysts was performed. The results showed that the clinical outcomes in the endometrioma cyst group were similar to the control group, with no statistical difference (Table 4).
Table 3.
Pregnancy outcomes in the endometriosis and the control group
| Endometriosis (n = 174) | Control (n = 522) | P | |
|---|---|---|---|
| Biochemical pregnancy rate | 118 (67.8%) | 379 (72.6%) | 0.226 |
| Clinical pregnancy rate | 110 (63.2%) | 352 (67.4%) | 0.308 |
| Live birth rate | 91 (52.3%) | 299 (57.3%) | 0.252 |
| Clinical abortion rate | 8 (4.6%) | 34 (6.5%) | 0.358 |
| Preterm birth rates | 6 (3.4%) | 25 (4.8%) | 0.458 |
Data are presented as n/N (%)
Table 4.
Pregnancy outcomes in the endometrioma cysts group and the control group
| Endometrioma (n = 54) | Control (n = 162) | P | |
|---|---|---|---|
| Biochemical pregnancy rate | 37 (68.5%) | 111 (68.5%) | 1.000 |
| Clinical pregnancy rate | 36 (66.7%) | 97 (59.9%) | 0.374 |
| Live birth rate | 29 (53.7%) | 78 (48.1%) | 0.479 |
| Clinical miscarriage rate | 4 (7.4%) | 17 (10.5%) | 0.691 |
| Preterm birth rates | 2 (3.7%) | 5 (3.1%) | 1.000 |
PGT-A outcomes
PGT biopsies were performed on 2940 blastocysts, including 745 from endometriosis patients and 2195 from control individuals. The blastocyst aneuploidy rates are presented in Fig. 1.
Fig. 1.
Aneuploidy rate
The blastocyst aneuploid rate in the endometriosis group was higher than that in the control group (26.3% vs 21.8%, P = 0.012) (see Fig. 1). After subgroup analysis, there was statistically significant difference in the normal chromosome subgroup (29.2% vs 23.0%, P = 0.025). But there was no statistically significant difference in the abnormal chromosome subgroup (24.7% vs 20.7%, P = 0.089) (see Fig. 1).
Then, we further compared the rate of aneuploidy in different chromosomal disorders between the two groups, such as mutual translocation, Roche translocation, numerical abnormalities, and other chromosomal abnormalities. Notably, when the mother had a Roche translocation, the aneuploidy rate was significantly higher in the endometriosis group(49.3% vs 32.3%, P = 0.007). However, this phenomenon was not repeated in other chromosomal disorders (P > 0.05) (Table 5).
Table 5.
Aneuploidy rates for subgroup analyses
| Type | Group | Aneuploidy | P |
|---|---|---|---|
| Inversion (n = 49) | Endometriosis (n = 12) | (21.4%) | 0.582 |
| Control (n = 37) | (18.0%) | ||
| Balanced translocation (n = 171) | Endometriosis (n = 36) | (14.2%) | 0.500 |
| Control (n = 151) | (16.4%) | ||
| Roche translocation (n = 81) | Endometriosis (n = 17) | (49.3%) | 0.007* |
| Control (n = 64) | (32.3%) | ||
| Abnormal number of sex chromosomes (n = 56) | Endometriosis (n = 12) | (34.0%) | 0.158 |
| Control (n = 44) | (23.9%) | ||
| Others (n = 24) | Endometriosis (n = 7) | (21.4%) | 0.575 |
| Control (n = 17) | (25.7%) |
Data are presented as n/N (%)
*P < 0.05
Discussion
According to our study, the live birth rate slightly decreased in endometriosis, but it was not statistically significant. There were no significant differences in other clinical outcomes such as the clinical pregnancy rate, the biochemical pregnancy rate, the biochemical abortion rate, clinical abortion rate, and the rate of premature birth.
ART is extensively utilized in patients with endometriosis as well as in those without endometriosis who experience infertility [7]. Numerous clinical studies have demonstrated that patients with endometriosis typically experience worse clinical results than other infertile women; however, many studies have also reported similar clinical outcomes in age-matched women with or without endometriosis [8]. The meta-analysis by Dongye et al. [9] demonstrated that endometriosis has no effect on the morphological quality of embryos, including the rate of high-quality embryos, cleavage rate, and embryo formation rate. To confirm the ART outcomes in endometriosis, we performed this retrospective study after excluding the influence of aneuploidy embryos.
Various theories have been developed regarding the pathophysiology of the poor reproductive results seen in endometriosis. Some people believe that poor clinical outcomes are inextricably linked to the endometrial receptivity [7], whereas others believe that endometriosis may result in lowered oocyte quality and poor embryo implantation potential, which can impact the success of assisted reproduction. Impaired endometrial receptivity, poor oocyte quality, and a high proportion of abnormal embryos are all possible mechanisms contributing to poor clinical outcomes. The outcomes are now assumed to result from a combination of pathological mechanisms, involving a confluence of genetic, hormonal, immunological, angiogenic, and environmental variables [10, 11].
In conventional in vitro fertilization (IVF), embryos are chosen to transfer by morphological criteria, although even embryos with great morphological scores still have a possibility of aneuploidy. And it is true that embryos with worse morphology are more likely to develop aneuploidy [12]. The chromosomal condition is an important aspect that affects an embryo’s viability [13]. It is believed that euploid embryo transfer can improve implantation rates and lower early miscarriages and obtain more live births [14]. In our study, we transferred the euploidy blastocysts and homogenized the embryos to some extent, to better observe the endometrial receptivity. We found that pregnancy rates in those with endometriosis were reduced compared to the control group; however, this was not statistically significant, indicating that endometriosis did not significantly affect endometrial receptivity.
Prenatal diagnosis techniques including PGT-A (aneuploidy), PGT-M (monogenic), and PGT-SR (structural rearrangements) are applied in couples with single-gene diseases and chromosomal abnormalities as well as in high-risk populations of IVF failure, such as advanced maternal age (AMA) and recurrent miscarriage (RPL) [15, 16]. We routinely screen for aneuploidy at our reproductive center to determine whether we should perform PGT-A, PGT-M, or PGT-SR. Employing cytogenetic methods to select aneuploid embryos can greatly increase the implantation and live birth rates of transferred embryos [16]. In our study, we enrolled patients who underwent PGT due to chromosomal abnormalities, monogenic diseases, or advanced maternal age.
According to our findings, there was a significant difference in the rate of aneuploidy between the endometriosis and control group, both before and after adjustment, which is contrary to the results of earlier studies. The study by Juneau et al. [17] included a small sample size, which may account for the differences in our conclusions. Moreover, Yan et al. [18] analyzed the rate of aneuploidy in women with endometriomas who underwent PGT-M for a monogenic disorder and did not have a diagnosis of infertility. Their study showed that endometrioma had a negative impact on oocyte production and the number of mature oocytes, with a significantly higher rate of euploidy in the endometrioma group. Intriguingly, we discovered that embryos in the endometriosis group had a higher rate of aneuploidy among parents with chromosomal Roche translocations (P = 0.007). In the endometriosis group, patients with chromosomal Roche translocations obtained up to 49.3% of aneuploid embryos.
Koert et al. [19] demonstrated that people with uneven chromosomal structures are more likely to produce imbalanced gametes, which can cause problems during pregnancy and disease in the offspring. Chromosome abnormalities are linked to an increased incidence of child karyotyping imbalance [20]. Studies have revealed that different types of infertility have a major impact on meiosis mistakes, raising the probability of chromosomal mistakes and increasing the rate of aneuploidy [21]. Previous research have examined whether endometriosis has an impact on the embryo’s aneuploidy rate in recent years. In animal research, Mansour et al. [21] demonstrated that peritoneal fluid from patients with endometriosis increased abnormal damage in mouse oocytes. Subsequently, Sharma et al. [22] showed that endometriosis may have altered oocyte spindle cell complexes, which might compromise the spindle’s structural integrity. Simultaneously, experiments performed on cow oocytes by Da Broi et al. [23] reached similar conclusions as the previous authors. Nonetheless, other study have generated opposing results, indicating that the incidence of aberrant meiotic division of oocytes in the middle of the second trimester II in patients with endometriosis did not differ significantly from that of the control group [24]. According to our study, if the chromosome abnormality was more complicated, the ability of oocyte repair and the chance of euploidy formation in endometriosis were decreased, suggesting that oocytes in endometriosis are somewhat damaged and may affect the embryonic developmental potential. Therefore, patients with endometriosis have a greater probability of obtaining aneuploid blastocysts.
This study has some limitations. First, we did not carry out a power analysis and this was a single-center study. Therefore, we aim to expand the sample size and do follow-up research. Second, not all patients of our control group underwent laparoscopy to rule out the possibility of endometriosis. But most of our patients underwent PGT due to chromosomal problems or monogenic disease, so it is less likely to have undiagnosed endometriosis patients. And the quality of the embryo in our study was controlled to a certain extent, and the endometrial receptivity can be better explored. Finally, the mechanism and relationship between endometriosis and chromosomal abnormalities are worth further exploration.
Conclusion
Overall, we found a similar pregnancy outcome in patients with endometriosis after a single frozen euploid blastocyst transfer, indicating that endometrial receptivity may not be significantly affected by endometriosis. However, endometriosis may impair the quality of oocytes and affect the developmental potential of euploid embryos.
Acknowledgements
We thank all authors for the help in performing the study.
Author contribution
HQ, YD, and LY conceived and designed the study. HL and YK provided clinical knowledge and guidance in paper writing. HQ and LY analyzed the data and wrote the manuscript. LY and YD modify the paper. All authors read and approved the final manuscript.
Funding
This study was supported by the National Key Research and Development Program of China (2022YFC2704002) and the National Natural Science Foundation of China (81571414) and the Natural Science Youth Foundation of Shandong Province (ZR2020QH058).
Data availability
The data underlying this article are available from the corresponding author on reasonable request.
Declarations
Ethics approval
The study has been approved by the Institutional Review Board (IRB) of the Reproductive Hospital affiliated to Shandong University (2020–14).
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Lei Yan, Email: duyanboivf@163.com.
Yanbo Du, Email: yanlei@sdu.edu.cn.
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Associated Data
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Data Availability Statement
The data underlying this article are available from the corresponding author on reasonable request.