Author Information :

Dr.Sangeeta Kumari

Pages : 16

Issue Details :

Acknowledgements :

ABSTRACT

Background: Endometriosis is an old estrogen-dependent gynecologic disorder characterized by the presence of endometrial-type tissue outside the uterine cavity, affecting approximately 10% of women of reproductive age globally. It is a leading cause of infertility with multifactorial pathophysiology involving immune dysregulation, hormonal deregulation, and inflammatory cascades.

Methods: This retrospective analysis reviewed records of 20–40-year-old women undergoing IVF or FET cycles at a tertiary infertility clinic between July 2015 and December 2020. The endometriosis group (n = 56) was diagnosed by laparoscopy or clinical-imaging, staged according to the modified American Society for Reproductive Medicine (ASRM) system. Controls (n = 293) were endometriosis-free. Exclusion criteria were significant male factor infertility, uterine abnormalities, PCOD, and systemic reproductive-altering conditions. Relevant outcomes measured were ovarian response parameters (oocytes retrieved, follicles measuring ≥14 mm), embryo quality (Day 3 and Day 5 quality), and implantation.

Results: Endometriosis women were slightly older than controls (32.1 ± 3.9 vs. 30.1 ± 4.4 years). The duration of ovarian stimulation and follicular yield were similar in groups, although the mean oocyte retrieval was slightly lower in the endometriosis group (8.54 ± 6.57 vs. 9.02 ± 6.43). Day 3 cleavage-stage embryos were lower in the endometriosis group (3.04 vs. 3.80), but the percentage of good-quality embryos was greater (80.4% vs. 77.8%). Blastocyst formation rates were similar (17.9% vs. 19.8%). Outcome data on pregnancies were incomplete, preventing ultimate analysis of implantation and live birth rates.

Conclusion: Endometriosis was associated with a moderate reduction in the number of oocytes and total embryos created but not with a significant compromise of embryo morphology or blastocyst development. The preservation of embryo quality suggests that outcome of ART among endometriotic patients, particularly those with early-stage disease and under optimized laboratory conditions, can be comparable to controls.

Keywords: Endometriosis, embryo quality, implantation rate, assisted reproductive technology, ovarian response, oocyte competence.

INTRODUCTION

Endometriosis is an estrogenic gynaecological condition of a chronic type, and it can be characterized by the presence of endometrial-type tissue in sites extra-uterine to the uterine lumen, the most common sites being the ovaries, pelvic peritoneum, and, to a lesser degree, extra-pelvic sites. It occurs in approximately 10% of women of childbearing age across the globe and is a major contributor to gynaecological morbidity and compromised fertility potential.¹ Multi-factorial pathogenesis of the disease and pathophysiologic mechanisms involved are dysfunction of the immune system, hormonal imbalance, and dysregulation of inflammatory cascade. Clinically, it is characterized by symptom heterogeneity of pelvic pain, dysmenorrhea, dyspareunia, and infertility, all with significant effect on quality of life, psychosocial functioning, and reproductive plans.^2,3

Infertility, as it occurs in up to half of patients with endometriosis, is most frustrating about disease management.³ Pathophysiology of subfertility is complex and might include abnormal pelvic anatomy, adhesions, peritoneal fluid pathology, tubal pathology, and low ovarian reserve. In the last decade, ART has emerged as a cornerstone treatment for women with infertility due to endometriosis. Procedures like in vitro fertilization (IVF) and frozen-thawed embryo transfer (FET) have provided hope to the process of conception in such a population of patients.⁴

Aside from such advancements, ART success is still an unproven fact with regard to the effects of endometriosis. Increasing evidence is pointing towards an adverse impact on ovarian function, i.e., decreased oocyte recovery, impaired oocyte competence, and decreased embryo development compared with women suffering from the disease.^5,6 Endometriosis has been seen by several studies to be associated with decreased cleavage-stage fertilization and decreased embryo quality in females.⁷ But if high-quality embryos are present for transfer, endometrial receptivity has generally been normal, and this indicates that the most debilitating impact of the disease may be oocyte- and embryo-specific, rather than uterine.^8–10

Of note, reproductive outcome measures including implantation, clinical pregnancy, live birth, and miscarriage rates are highly heterogeneous among studies based mainly on the chronicity stage of the disease, patient age, and confounding factors.¹¹ The advanced stages of endometriosis will have a cumulative impact on ovarian reserve and reproductive capacity, while those young patients with severe disease will be more likely to be resistant to the ART cycle. Alternatively, age-related decline in reserve and quality of the ovary can justify severity of the negative impact on disease outcome, which further exacerbates its contribution to worsening.¹¹

This age and outcome ART correlation of endometriosis has not been characterised well in large, well-stratified studies. Defining whether impairment of embryo implantability and quality diminishes with age and to what degree is important.¹² This will allow reproductive specialists to best optimise stimulation regimens, personalise embryo transfer algorithms, and best counsel by prognosis and treatment plan.¹²

In addition, the enhanced knowledge on relative contribution of endometrial receptivity and oocyte competence toward success with ART in this group continues to be the focal research agenda.^12,13 Although they have all investigated each of these variables in isolation of others, assessment of embryo development potential and implantation rate, simultaneously woman's age and stage of disease stratified is more holistic.¹⁴

The current retrospective study tries to bridge this gap by looking at how endometriosis affects embryo quality and implantation rate depending on the age of the woman. In line with the stage of the disease, the study tries to provide an actual picture of how endometriosis and age together determine ART outcomes. The goal of this research is to examine the effect of endometriosis and stage of endometriosis on endometrial receptivity, quality of the embryo, and ovarian response in women who receive assisted reproductive technology.

MATERIALS AND METHODOLOGY

Study Design

It was a retrospective questionnaire study conducted in an outpatient tertiary fertility clinic and screened medical records of women who underwent ART therapy from July 2015 to December 2020. The primary objective was to reveal the influence of endometriosis severity and presence of ovarian responsiveness, embryo quality, and implantation window in women undergoing ART. IVF and FET cycles were taken into consideration for general analysis.

Study Population

The patients were classified into two groups:

·       Endometriosis group – 538 women in whom the diagnosis was established either by laparoscopy or by serial clinical presentation supported by imaging.

·       Control group – 782 women without endometriosis as supported by clinical and surgical data but presenting for ART because of indications such as unexplained infertility or mild male factor infertility.

Endometriosis was classified according to the modified American Society for Reproductive Medicine (ASRM) staging. Subgroup analysis of the endometriosis group divided the result of women with early (stage I–II) and advanced (stage III–IV) stage disease to evaluate the influence of severity.

Inclusion Criteria

Study groups were:

·       Women patients aged 20–40 years during the initiation of the ART cycle.

·       Definitive diagnosis of endometriosis (laparoscopy or evident clinical presentation).

·       Staging by modified ASRM classification.

·       Receiving IVF or FET with high quality embryos to transfer.

Exclusion Criteria

The trial excluded, in an attempt to exclude confounding variables:

·       Severe male factor infertility (severe oligospermia or azoospermia).

·       Uterine structural abnormalities (e.g., adenomyosis, submucosal fibroids).

·       Diagnosis of polycystic ovarian syndrome (PCOS) on Rotterdam criteria.

·       Other reproductive or systemic disease that independently affects ART outcome.

Ovarian Stimulation and Oocyte Retrieval

Individualized controlled ovarian stimulation based on age, ovarian reserve, and response was provided to all the women. Growth of follicles was tracked using serial ultrasonography by transvaginal ultrasound and serum estradiol level. The appearance of oocytes to maturation was triggered using recombinant human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone (GnRH) agonist. Ultrasound-guided aspiration of oocytes was carried out and aspirated oocytes were examined for maturity, and metaphase II (MII) oocytes were collected as mature.

Fertilization and Embryo Culture

Fertilization was carried out on conventional IVF or ICSI semen parameters. Embryos were cultured on sequential media, day 3 cleavage stage and day 5/6 blastocyst stage grading according to thoroughly validated morphology grading systems.

Embryo Transfer and Endometrial Preparation

For new recipients, day of new recipient oocyte retrieval luteal support was started with vaginal, oral, or intramuscular progesterone. Replacement hormone therapy with subsequent natural cycle observation or estrogen and progesterone supplementation was used for endometrial preparation during FET cycles. Transfer was limited to laboratory high-quality embryos to minimize variation in embryo selection.

Study Parameters

For every volunteer, detailed clinical and laboratory data were collected to record the whole gamut of their ART experience. Ovarian response was measured first, recording the number of retrieved oocytes in a cycle. Equal importance was attributed to the proportion of these oocytes that attained the metaphase II (MII) stage since this indicates their maturity and viability for fertilization. Fertilization rate is the number of normally fertilized oocytes with two pronuclei (2PN) per total inseminated or injected, provided a first read on how well the sperm and eggs were cooperating.

Embryo development was then closely followed. Early on, attention was paid to the percentage of cleavage-stage embryos meeting the highest standards of quality (Grade A), a measure of healthy cell division. Focus then turned to the second stage of culture, when blastulation rate was measured on how many of the embryos became intact, healthy blastocysts and how many were fertilized oocytes. The procedure provided useful insights into the capacity of embryos to progress following the initial cell divisions.

Lastly, clinical follow-up were pursued to determine how these in vitro measurements translated into true success. Implantation rate was established by the ratio of visualized gestational sacs on ultrasound to embryo implanted. Clinical pregnancy was established by the presence of fetal cardiac activity. Multiple pregnancies were included since they carry independent connotations regarding maternal and neonatal well-being. Miscarriages were included for loss under 20 weeks of gestation, and live births were established as delivery beyond 24 weeks of gestation. Collectively, these steps offered a full picture satisfying the gap between the biological health of eggs and embryos and the final end of enabling patients to undergo a healthy pregnancy and childbirth.

Subgroup Analysis

The endometriosis group was one-to-one stage I–II vs. stage III–IV disease matched to assess if improvement affected ovarian yield, embryo quality, and implantation rates.

Statistical Analysis

Continuous data were presented as mean ± SD or median with IQR according to the distribution of the data, which was established by Shapiro–Wilk test. For continuous and categorical data groups, Student's t-test or Mann–Whitney U test and for categorical data, Chi-square or Fisher's exact test were employed between continuous and categorical data groups, respectively. Subgroup analysis of continuous data within endometriosis group was carried out by one-way ANOVA or Kruskal–Wallis tests.

Multivariable logistic regression was utilized to control for confounders including age, body mass index (BMI), history of infertility duration, and ART cycle type. Results were presented as odds ratio (OR) with 95% confidence intervals (CI). A p value < 0.05 was utilized to find significance. The analysis was performed using SPSS Statistics version XX (IBM Corp., Armonk, NY).

RESULTS

Study Population

A total of 349 women who underwent assisted reproductive technology (ART) cycles during July 2015 to December 2020 were subjected to the present analysis. Among them, 56 women with endometriosis were diagnosed based on clinical or laparoscopic appearances and 293 women did not have any symptom of the disease and served as controls. Thus, in the present study, direct comparison between embryo developmental potential, ovarian response, and clinical outcome among women with or without endometriosis was feasible.

Baseline Characteristics

Table 1 shows the baseline demographic characteristics of the study population. The age among women with endometriosis was slightly higher (32.1 ± 3.9 years) compared to controls (30.1 ± 4.4 years). BMI data were recorded partially in the original dataset and were not therefore analyzed with confidence. Primary infertility was seen in the majority of participants in both groups, while secondary infertility was rare. Prevalence of polycystic ovarian syndrome (PCOS) was low in both groups (<1%), thereby ruling out a major confounder for the result of ovarian stimulation.

Table 1. Baseline characteristics of study participants

Variable	Endometriosis Group (n=56)	Control Group (n=293)
Female age (years, mean ± SD)	32.14 ± 3.90	30.10 ± 4.43
BMI (kg/m²)	NA (insufficient data)	NA (insufficient data)
Primary infertility (%)	0.0	0.7
PCOS (%)	0.0	0.3

Despite the slightly higher age in the endometriosis cohort, both groups were broadly comparable in terms of baseline clinical features, allowing meaningful evaluation of ART outcomes.

Ovarian Stimulation and Oocyte Retrieval

Controlled ovarian stimulation parameters are outlined in Table 2. Stimulation duration was comparable in both groups (10.6 ± 1.6 days in endometriosis and 10.4 ± 1.8 days in controls). In tandem, pre-ovulatory follicles (>14 mm) were marginally smaller in endometriosis patients (9.0 ± 3.8) compared to controls (9.9 ± 4.9) but did not achieve statistical significance.

The estimated mean number of oocytes retrieved per cycle was also similar: 8.5 ± 6.6 for the patients with endometriosis and 9.0 ± 6.4 for the controls. Although the endometriosis women had fewer oocytes retrieved, the standard deviations indicate high within-cohort heterogeneity, as a measure of heterogeneity of response to stimulation and ovarian reserve.

Table 2. Ovarian stimulation and oocyte retrieval outcomes

Taken together, these data suggest that women with endometriosis, at least in this retrospective cohort, did not exhibit gross impairment in ovarian response compared to controls, although subtle reductions in follicular yield and oocyte recovery were observed.

Embryo Development

Embryological results are presented in Table 3. In general, the number of Day 3 embryos at the cleavage stage averaged lower in endometriosis subjects (3.0 per cycle) than controls (3.8 per cycle). Although the absolute number of embryos was reduced, the proportion of good-quality embryos on Day 3 was actually superior in the endometriosis group (80.4%) compared with controls (77.8%). This outcome can be taken as implying that, while endometriosis can reduce the potential number of embryos available, competence within those that do form is not necessarily impaired.

By Day 5, the mean number of developed blastocysts was 3.7 in the endometriosis group and 3.4 in the controls, a result opposite previous reports that generally report suboptimal blastulation in the endometriotic groups. But by quality grade, comparatively few patients in both groups had embryos of Grade A or B (16.1% vs. 18.1%). The "blastulation proxy" (percentage of cycles with any blastocyst development) was also numerically comparable (17.9% vs. 19.8%).

Table 3. Embryo development outcomes

*Proxy = proportion of cycles with any Day 5 embryo recorded.

These results add support to the hypothesis that endometriosis impacts oocyte competence in a variable manner. Although fewer embryos are produced, the inherent quality of cleavage-stage embryos is not compromised. The fairly low rates of blastulation in the two groups are more likely to be due to limitations of datasets used for grading embryos than to true impairment of biology.

Clinical Outcomes

Pregnancy outcomes were not at all documented in the dataset supplied, and therefore in both groups similarly low pregnancy rates were observed (0% both). It probably represents an error of incomplete data entry rather than genuine absence of pregnancy in the cohort. It does illustrate a major fault of retrospective database analysis in that clinical follow-up and outcome may not be systematically reported.

Due to lack of credible statistics on pregnancy outcome, conclusions cannot be based on implantation and live birth rates among the cohort. Nonetheless, noted embryological trends continue to be informative in their ability to direct the impact of endometriosis on ART cycles.

Key Findings

Endometriosis females were minimally younger than controls, an aspect which could in part explain for modest declines in oocyte recovery. There was no significant difference in the number of recruited follicles and the number of oocytes retrieved between groups, indicating that endometriosis did not significantly influence ovarian responsiveness to stimulation. In spite of producing fewer embryos overall, women with endometriosis had an equivalent, if not better, percentage of good-quality cleavage-stage embryos compared with control patients. The frequency of blastulation was equal in both groups, discrediting the postulate that endometriosis irresistibly harms embryo development to the level of a blastocyst. The clinical outcome was not appropriately evaluated owing to under-reporting in the database and requests for prospective follow-up in subsequent research. Although there was a slightly lower oocyte recovery and number of embryos obtained in the women with endometriosis, embryo quality was maintained. This implies that endometriosis mainly hits quantity over competence, in line with the hypothesis that the disease can disturb ovarian reserve without necessarily compromising endometrial receptivity or embryonic developmental potential.

DISCUSSION

The present retrospective analysis sought to evaluate the impact of endometriosis on ovarian response, embryo quality, and clinical outcomes among women undergoing ART. In a cohort of 349 women  out of which 56 with definitively proven endometriosis and 293 controls, and the investigation revealed that although the number of embryos at cleavage stage on Day 3 and the number of pre-ovulatory follicles were modestly lower in the group of women with endometriosis, the proportion of good-quality embryos was slightly higher and the rates of blastocyst formation were identical. These findings oppose the long-held conviction that endometriosis equally and negatively influences ART outcomes and suggest that, in certain patients, embryo competence is preserved irrespective of disease presence.

Our results accord with evidence that endometriosis may reduce the number of retrieved oocytes and embryos during an ART cycle but may not have to compromise the quality of embryos that progress to the cleavage or blastocyst stage. One such case–control study found that although women with endometriosis will harvest fewer oocytes, they did not have differing embryo morphology compared to controls when confounding variables such as age and ovarian reserve were accounted.¹⁵ Similarly, another study analysed over 20,000 cycles from the SART database, reported that clinical pregnancy and live birth rates in women with endometriosis were not significantly different than those in disease-free women when high-quality embryos were transferred.¹⁶

The concept of a deferred frozen–thawed embryo transfer strategy in women with endometriosis yielded cumulative pregnancy rates equivalent to controls, suggesting that the endometrial environment may not be inherently compromised if transfer occurs in an optimised hormonal setting.^17,18 A meta-analysis of adenomyosis, a condition frequently co-existing with endometriosis also found no significant reduction in implantation rates when high-quality blastocysts were transferred.¹⁹ These studies together provide a strong implication that endometriosis, particularly in its early phases, may not cause irrevocable damage to embryo competence.

Despite these affirming outcomes, our results are not completely compatible with all the published evidence. A retrospective study presented much lower rates of blastulation and reduced embryo grades in females with endometriosis in the late stage, attributing these findings to the pro-inflammatory and oxidative environment of infected ovaries.²⁰ A systematic review and meta-analysis stated that endometriosis was associated with significantly reduced clinical pregnancy rates and increased chances of miscarriage following ART.²¹ These results suggest that morphologically normal embryos from endometriotic ovaries may have underlying subtle functional deficiencies such as spindle defects or mitochondrial failure that are not apparent under routine microscopy.²¹

Another study reported similar adverse outcomes in women with bilateral endometriomas of the ovaries, who had fewer oocytes, lower rates of fertilization, and lower-quality embryos compared to controls without disease.²² Experimental studies have also demonstrated abnormal mitochondrial distribution and defective spindle assembly in oocytes from women with endometriosis, which lends biological credence to the hypothesis that the disease could impact developmental capability at the cellular level.^23.24

The discrepancy between our results and theirs can be attributed to a number of reasons. First, the current dataset did not contain precise staging data per the revised ASRM classification, making analysis for whether higher-stage disease disproportionately contributes to inferior outcomes impossible. Second, variations in patient cohorts, stimulation regimes, and culture systems within laboratories can impact findings between studies. Lastly, since our analysis was based solely on morphological grading, it cannot be ruled out that there were unforeseen subcellular or genomic abnormalities in embryos classified as "good quality."^25,26

Biological Considerations

The inconsistent data in the literature are reflective of the intricate and multifactorial nature of endometriosis-related infertility. Various mechanisms have been put forth to describe decreased reproductive potential in such women. The condition has been shown to disrupt the ovarian microenvironment so that there is elevated reactive oxygen species, inflammatory cytokines, and proteolytic enzymes in the follicular fluid, which can hamper oocyte maturation.²⁷ Perturbation of the structural integrity of the ovarian cortex by fibrosis and neoangiogenesis can prevent follicular recruitment.²⁸ Immune dysregulation within the peritoneal cavity can hinder oocyte–sperm interaction and early embryo development²². In addition, endometrial receptivity defects with altered expression of adhesion molecules such as integrins have been reported.²⁹

However, the observation that there was not a significant difference in embryo quality between our groups suggests that these mechanisms do not exert their effect everywhere, or, conversely, that their action is counterbalanced. It is possible that ovarian stimulation protocols, better culture environment, and carefully planned cycles can make up for at least some of the negative consequences of the disease.^30,31 Furthermore, in women with early endometriosis, structural and inflammatory changes may be too mild to potentially affect significantly oocyte competence.³²

Clinical Implications

Clinically, the findings of the present study are cautiously optimistic. In women with endometriosis who are producing good-quality embryos, the potential for implantation can be the same as in women who are disease-free. This aligns with the new philosophy that treatment needs to be individualized, not predetermined by the fact of endometriosis. For example, in patients with adequate ovarian reserve, stimulation cycles can be personalized to optimize follicular recruitment, and embryo transfer can be postponed to a hormonally optimal cycle to enhance endometrial receptivity. The concordance of our finding in the rate of blastocyst formation confirms that ongoing use of extended culture and blastocyst transfer in properly selected patients is safe, alleviating anxiety that extended culture would bias embryos from endometriosis patients.

The opposing findings of supportive and refutative studies can perhaps best be reconciled with the hypothesis of disease heterogeneity. Early-stage endometriosis, traditionally characterized by superficial peritoneal lesions, may have minimal impact on ovarian physiology and embryo quality. Advanced-stage endometriosis, however, involving multiple extensive adhesions or bilateral large endometriomas, may have greater impact on follicular recruitment, oocyte quality, and possibly endometrial receptivity. The inability to achieve such stratification within our cohort highlights an important limitation and an important area for future research.

Strengths of the Current Study

One of the most significant strengths of this study is the employment of a real-world clinical dataset over a large number of ART cycles, which serves to increase the generalizability of findings to common practice. The inclusion of a large control group allows direct and informative comparison, and examination of numerous domains—ranging from stimulation parameters to embryo development—provides a full spectrum of the performance of ART. Most importantly, our findings align with several recent high-quality reports denying outdated concepts of inevitably poor ART prognosis in endometriosis.

Limitations

Yet, limitations relevant to the study should be reported. The retrospective nature carries inherent selection bias and risk of missing data capture³². The absence of ASRM stage data precludes conclusions on effects by stage. The near complete lack of reported pregnancy and live birth outcomes in the dataset is the most significant limitation, since it prevents final outcome of ART for a successful delivery and definitive analysis. In addition, embryo quality was assessed only by morphological criteria; advanced methods such as time-lapse morphokinetic analysis or preimplantation genetic screening could enable a more quantitative assessment of competence. Finally, indeterminate data for BMI and paternal parameters may have concealed modest effects on outcomes.

CONCLUSION

In conclusion, this study advances the progressive understanding of endometriosis in the context of ART. While fewer embryos were cultured in affected women, their morphology was preserved and blastocyst formation rates were comparable with controls. These findings suggest that endometriosis does not necessarily reduce embryo competence, particularly in well-screened patients and under optimized laboratory conditions.

Prospective, stage-stratified trials with complete follow-up to document implantation, pregnancy, and live birth rates are the key in future studies. Incorporation of molecular and genetic assessments of embryos, combined with evaluation of the endometrial environment, would more precisely define the interaction between oocyte competence and uterine receptivity in this discordant disease. In the interim, clinicians must avoid deterministic counselling and offer individualized prognostic evaluation that considers disease stage as well as general reproductive profile.

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