The effect of endometriosis on oocyte quality: mechanisms, diagnosis and treatment

Abstract

Endometriosis significantly impacts the physical and mental health of women of reproductive age. While some patients can achieve pregnancy through surgery or in vitro fertilization (IVF), many still struggle with IVF failure due to poor oocyte quality. This presents a major clinical challenge that requires immediate attention. The causes of oocyte quality decline in endometriosis patients are diverse and have not yet been definitively identified. Furthermore, effective diagnostic mechanisms and therapeutic strategies remain elusive. To provide possible clinical solutions to improve pregnancy rates in patients with endometriosis, this review evaluates the current literature on the impact of endometriosis on oocyte quality, the possible mechanisms and management strategies of endometriosis leading to poor oocyte quality.

Introduction

Endometriosis is a chronic inflammatory disease characterized by the presence of endometrium-like epithelium outside the uterine cavity [1, 2]. It manifests with symptoms such as pelvic pain, dysmenorrhea, infertility, dyspareunia and dyschesia [3]. The estimated prevalence of endometriosis ranges from 2 to 10% in the general female population and from 25 to 50% in infertile women [4–7]. Currently, infertility patients with endometriosis are pivotal for infertility diagnosis and treatment. The mechanisms through which endometriosis leads to infertility remain unclear. Proposed mechanisms mainly include pelvic deformity anatomy, altered endocrine function, endometrial receptivity changes, decreased ovarian reserve, and decreased oocyte and embryo quality (Fig. 1) [8–12].

Fig. 1.

Effects of endometriosis on oocytes

Ovulation, oocyte count, and oocyte quality are three critical parameters specific to oocytes that influence fertility and pregnancy success. The first two can be assessed using indicators such as anti-Mullerian hormone levels, follicle stimulation, and antral follicle count. Evaluation of oocyte quality, however, relies solely on in vitro fertilization (IVF)-related criteria [13, 14]. In vitro fertilization (IVF) represents an effective treatment option for infertility associated with endometriosis [15, 16]. However, studies have indicated that endometriosis can reduce the quality of oocytes in patients. Compared to control groups, patients with endometriosis often exhibit reduced rates of oocyte maturation, fertilization, blastocyst formation, and embryo implantation, alongside an increased rate of spontaneous abortion [17–19]. This article provides a comprehensive review of the effects, mechanisms, and potential solutions related to the impact of endometriosis on oocyte quality.

Effect of endometriosis patients on oocyte quality

Clinical outcomes in endometriosis influenced by oocyte quality

Clinical studies have shown that compared to patients with other infertility conditions, oocytes from patients with endometriosis appear to be more susceptible to in vitro fertilization failure and poor clinical outcomes [20–24]. A retrospective analysis by Wu et al. [25] investigated the impact of endometriosis on IVF/intracytoplasmic sperm injection (ICSI) outcomes in a cohort of 1724 patients. The study revealed that endometriosis negatively impacts both oocyte quality and quantity. Moreover, patients with endometriosis who underwent surgical intervention prior to IVF/ICSI treatment had higher rates of oocyte maturation, fertilization and top-quality embryo than those without surgery. Oocyte donation is a common treatment option for women with endometriosis, showing similar implantation and clinical pregnancy rates compared to those without the condition when using oocytes from healthy donors. An observational cohort study by Maignien et al. [26], involving 57 patients with endometriosis compared 244 failed autologous embryo transfer cycles and 90 oocyte donation cycles. The study revealed a significantly higher cumulative live birth rate after oocyte donation cycles from healthy donors, indicating that oocyte donation may enhance the chances of achieving a live birth. In contrast, a retrospective study by Simón et al. [27] included 78 patients with tubal infertility and 59 patients with endometriosis infertility, totaling 192 donor oocyte cycles. The study found significantly lower implantation and clinical pregnancy rates when receiving oocytes from patients with endometriosis. These findings support the hypothesis of poor oocyte quality in patients with endometriosis, suggesting a strong association between infertility in these patients and reduced oocyte quality (Table 1) [26–33].

Table 1.

Summary of findings from studies examining the impact of endometriosis on donor oocyte

Study authors	Study design	Sample size	Oocyte donor	Oocyte recipient	Impact of endometriosis on oocyte quality	Study findings	Country	Year
Simón et al. [27]	Retrospective study	N = 137 (C = 78, EM = 59)	Endometriosis	All	Adverse	The oocyte in endometriosis manifested by a reduced implantation capability	Spain	1994
Sung et al. [28]	Retrospective study	N = 239 (C = 184, EM = 55)	No endometriosis	All	Adverse	Oocyte and embryo factors are more detrimental to female fecundity than implantation factors in patients with endometriosis	US	1996
Remohí et al. [29]	Retrospective study	N = 397 (EM = 397)	No endometriosis	All	Adverse	Endometriosis may have an effect on the oocyte or embryo quality	Spain	1997
Díaz et al. [30]	Prospective study	N = 58 (C = 33, EM = 25)	No endometriosis	All	Adverse	The better the embryo selection, the better the IVF outcome, despite the presence of endometriosis	US	1999
Prapas et al. [31]	Prospective study	N = 240 (C = 120, EM = 120)	No endometriosis	All	Adverse	Endometriosis seems to affect endometrial receptivity	Greece	2012
Kamath et al. [32]	Retrospective study	N = 6675 (C = 5917, EM = 758)	–	Endometriosis	–	It cannot completely rule out the negative impact of oocyte quality on IVF outcomes in women with endometriosis	UK	2022
Maignien et al. [26]	Observational cohort study	N = 57 (EM = 57)	–	All	–	Poor prognoses, poor embryo quality, regardless of the presence of endometriosis, may be a key limiting factor for autologous ART success rates in some patients	France	2023

Oocyte morphology and structure altered in patients with endometriosis

Ultrasound and histological data demonstrate a decrease in ovarian follicle count, increased atresia, and abnormal follicle development in individuals with endometriosis [10, 34]. Endometriosis can also affect the morphology and cellular structure of oocytes. Kasapoglu et al. [35] conducted a study on oocyte morphology in patients with endometriosis and infertility due to male factors. The result revealed that the endometriosis group exhibited a notably higher occurrence of abnormal morphology, such as dark cytoplasm, dark, large or thin zona pellucida, and flat or fragmented polar body. This observation suggests that endometriosis may contribute to suboptimal outcomes in assisted reproduction outcomes by inducing oocyte morphological irregularities. Various studies have also highlighted elevated rates of fetal aneuploidy, cytoplasmic fragmentation, and DNA damage in individuals with endometriosis. The spindle, composed of microtubules, is sensitive to changes in cytokines and oxidative stress. Destruction of the spindle during meiosis can lead to chromosome dispersion and embryo development arrest. The complex abdominal environment in patients with endometriosis may induce spindle alterations, thereby affecting oocyte quality [36]. Goud et al. [37] observed a higher proportion of oocyte with abnormal spindles in endometriosis patients undergoing in vitro maturation (IVM) compared to those with male factor infertility. Additionally, mouse oocytes exposed to peritoneal fluid culture from endometriosis patients exhibited significant damage to microtubules and chromosomes. Possibly due to spindle changes during meiosis [38]. Furthermore, mitochondrial content, structure, and function of oocytes play a crucial role in oocyte quality decline. Xu et al. [11] utilized transmission electron microscopy to analyze 50 MII stage oocytes from patients with laparoscopically diagnosed mild endometriosis and control subjects. Their findings revealed a higher proportion of mitochondria with abnormal structure and reduced overall mitochondrial content in oocytes of endometriosis patients. Real-time quantitative PCR confirmed a lower mtDNA copy number in these oocytes compared to controls, suggesting decreased oocyte quality in mild endometriosis patients.

Possible mechanisms of endometriosis causing poor oocyte quality

Endometriosis can influence fertility by impacting the oocyte quality, but the specific mechanism remains incompletely understood. The follicle microenvironment is believed to play a significant role in follicle fluid. During follicle development, follicular fluid creates an unfavorable microenvironment which impacts embryo quality [39, 40]. In addition, altered synthesis and secretion of reactive oxygen species(ROS), cytokines, lipids, and steroid hormones can also affect oocyte quality [41–43].

ROS

Generally, the production and clearance of ROS maintain a dynamic balance, ensuring a necessary level for cell function. The Redox state influences various cellular processes, such as cell proliferation, differentiation and signal transduction, playing a crucial role in oocyte maturation and embryonic development [44]. In endometriosis patients, elevated ROS levels can increase oocyte vulnerability, leading to spindle instability, chromosomal abnormalities, telomere shortening, and diminished oocyte developmental capacity [45]. Therefore, the imbalance between oxidants and antioxidants in the follicular microenvironment is essential to folliculogenesis, oocyte maturation, ovulation and embryo development [46–48].

Granulosa cells surrounding the follicle are pivotal in regulating oocyte function through direct gap junctions. Endometriosis can significantly impact oocyte quality by compromising granulosa cell function [13]. Lin et al. [49] measured the ROS levels in granulosa cells of patients with endometriosis and tubal infertility, noting a significant increase in ROS levels alongside a decrease in antioxidant enzymes. Furthermore, granulosa cells from individual endometriosis patients exhibit cellular senescence due to oxidative stress, which affects oocyte development and contributes to endometriosis-related infertility. Sanchez et al. [50] demonstrated alterations in the WNT/β-catenin signaling pathway in granulosa cells of endometriosis patients, resulting in heightened follicular atresia and subsequent infertility in the context of endometriosis.

Follicular fluid serves as the medium for oocyte growth and differentiation, containing metabolites from surrounding functional cells and various small molecular substances. These components can directly or indirectly impact oocyte fertility [51, 52]. Research by Michele et al. [47] revealed elevated levels of 8-OHdG, indicating that the increased DNA oxidation in the follicular fluid, potentially affecting oocyte quality in endometriosis patients. Additionally, Hamdan et al. [53] discovered that follicular fluid from endometriosis patients can elevate ROS levels in oocytes, leading to DNA damage through the DNA Damage Response-Spindle Assembly Checkpoint (DDR-SAC) pathway. Activation of ataxia telangiectasia-mutated (ATM) kinase triggers SAC-mediated metaphase arrest, which can be reversed by ROS scavengers. It highlights the importance of reducing oxidative stress in oocytes for managing endometriosis-related infertility.

ROS play a crucial role in the growth and maintenance of endometriosis lesions. At the same time, ROS can contribute to the angiogenesis of ectopic endometrium, anti-apoptosis processes, extracellular matrix degradation and more. Research indicates that ROS directly or indirectly affects the quality of oocytes [54]. Antioxidants have been shown that to prevent chromosome and spindle dislocation, as well as aneuploidy, in mouse oocytes and embryos [18].

Cytokines

Cytokines in follicular fluid are primarily synthesized from local ovarian and plasma sources, playing a pivotal role in regulating various processes such as follicular growth, oocyte maturation, ovulation, steroidogenesis, embryonic development and pregnancy. These cytokines are instrumental in the intricate processes of folliculogenesis and oocyte maturation [55, 56]. Changes in cytokine levels within the follicular fluid have the potential to impact oocyte quality, subsequently influencing clinical pregnancy outcomes [57]. Research by Lee et al. [58] highlighted alterations in nitric oxide(NO) levels within the follicular fluid of individuals with infertility-related conditions, while variations in tumor necrosis factor-alpha(TNF-α) levels were shown to impact oocyte quality. Additionally, studies by Yang et al. [59] demonstrated that elevated levels of interleukin-6(IL-6) in follicular fluid could enhance clinical pregnancy rates and decrease embryo debris. Wang et al. [60] conducted research on cytokine levels of insulin-like growth factor II(IGF-II), insulin-like growth factor binding protein-3(IGFBP-3), and insulin-like growth factor binding protein-4(IGFBP-4), along with decreased levels of pregnancy-associated plasma protein-A(PAPP-A), may indicate improved oocyte maturation and early embryonic development. Conversely, high levels of insulin-like growth factor binding protein-1(IGFBP-1) and IGFBP-4 coupled with lower levels of insulin-like growth factor-I(IGF-I), could be beneficial for late embryonic development. These findings suggest a close relationship between IGF and IGFBP levels in the ovaries and the quality of both oocyte and embryo.

Endometriosis is a chronic inflammatory disease that can impact the follicular microenvironment, leading to issues such as ovulation dysfunction, poor oocyte quality and reduced implantation rate [61]. Researches have demonstrated alterations in cytokine levels in the follicular fluid of individuals with endometriosis, affecting the metabolism and oocyte quality [62–64]. Studies have highlighted increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines in endometriosis patients compared to normal controls [56]. Certain cytokines, like interleukin-8(IL-8), interleukin-12(IL-12) and adrenomedullin(ADM) have been found over-expressed and negatively correlated with oocytes maturity and embryo quality. These inflammatory markers have been linked to predicting the quality and oocyte and embryos and IVF outcome [65]. Furthermore, factors such as interleukin-10(IP-10) and its receptor C-X-C chemokine receptor type 3(CXCR3) have been associated with fertilization rates and embryo quality, suggesting a potential impact on oocyte quality in endometriosis-related infertility [66]. Further studies are needed to fully elucidate these mechanisms.

Others

Endometriosis is known to be influenced by estrogen, although its precise pathogenesis remains unclear. Recent studies focusing on the relationship between endometriosis, steroid metabolism and ovarian function have revealed that endometriosis can impact follicle development and oocyte quality through hormone metabolism. Wen et al. [67] highlighted the connection between oocytes and hormone metabolism, noting that estrogen levels in follicles are linked to progesterone levels when oocytes are present, while after ovulation, follicle-stimulating hormone (FSH) is associated with the androgen. It was also observed that estrogen levels alone are not sufficient to predict oocyte quality accurately. A more reliable assessment of oocyte quality can be obtained by considering the ratio of estrogen to androgen and the ratio of estrogen to progesterone. Additionally, Ben-Rafael et al. [68] demonstrated that elevated levels of progesterone in the follicular fluid can promote then hance oocyte maturation of oocytes. Endometriosis is a disease known for its resistance to the specific effects of progesterone, with varying results on progesterone concentration in the follicular fluid of patients with endometriosis [69–71]. It has been observed that the expression of Steroidogenic acute regulatory (StAR) mRNA, crucial in the key step of steroidogenesis, is significantly reduced in granulosa cells of patients with endometriosis. This reduction may lead to delayed follicular development and an imbalance in follicular steroid hormone levels, potentially impacting oocyte quality [72]. In summary, endometriosis can influence follicular development and oocyte quality by affecting the synthesis and secretion of steroid hormones like estrogen and progesterone within the follicle.

Endometriosis has been linked to changes in endogenous lipid metabolism. In a study by Dutta et al. [73], alterations in the lipid profile of endometriosis mice were detected using mass spectrometry. It revealed dysregulation in components such as phosphatidylcholine, sphingomyelin, phosphatidylethanolamine and triglyceride. The study also highlighted the close relationship between lipid metabolism and processes such as differentiation, metabolism, inflammation, and immunity of cell membranes. Specifically, the imbalance of triglyceride levels may be attributed to the inflammatory state of the peritoneum. Ferrero et al. [74] conducted single-cell transcriptome sequencing on oocytes from individuals with endometriosis. Their findings revealed the found that the up-regulation of lipid metabolic-related genes like APOE and DUSP1, suggesting that lipid metabolism within oocytes. This heightened metabolic activity could be linked to oxidative stress within the body, subsequently impacting the growth and development of oocytes and diminishing their quality. However, further research is required to elucidate the specific molecular mechanisms involved. Additionally, the study identified the upregulation of the WEEI gene in the endometriosis patients’ oocytes, potentially leading to the oocyte cycle arrest in the G2/M phase. This inhibition of meiosis maturation and restriction of normal oocyte development could further reduce the oocyte quality. Furthermore, the oxidative stress environment surrounding oocytes may impact mitochondrial function of oocytes and hinder normal oocyte development, potentially contributing to decreased oocyte quality.

Solution of poor oocyte quality due to endometriosis

The management of endometriosis is primarily determined by the severity of symptoms, extent and location of the disease, patient’s age and fertility requirements. Tailored treatment for endometriosis-related infertility is crucial to alleviate patient discomfort, preserve fertility and devise assisted reproduction strategies. Understanding how endometriosis impacts oocyte quality can help enhance treatment outcomes by reducing oocyte damage and ultimately improving the clinical pregnancy and live birth rates. Current approaches to endometriosis encompass surgical interventions and various drug therapies, including hormone therapy, anti-inflammatory agents and traditional Chinese medicine treatment.

Surgical treatment

The primary objective of endometriosis surgery is to remove the lesions, alleviate patients’ pain, address local inflammatory changes and enhance patient quality of life [6, 75]. The choice of surgical method depends on the individual patient’s condition with laparoscopy being the preferred approach for those with ovarian endometriosis. Surgical techniques typically involve cyst removal, cyst puncture or fenestration, and cyst wall cauterization. While cystectomy has lower recurrence and cumulative pregnancy rates compared to cauterization, it may result in the inevitable loss of ovarian tissue during the operation, potentially impacting ovarian reserve function [76–78]. Although the impact on oocytes quality in endometriosis patients remains understudied, it is speculated that removing endometriosis lesions can improve local oxidative stress and inflammations, thereby reducing factors that may compromise oocyte quality.

Hormone therapy

Endometrioid lesions are believed to be linked to hormone imbalances, including increased estrogen and progesterone resistance [79]. Current medical treatments for endometriosis focus on lowering estrogen levels and creating a non-estrogenic environment using oral contraceptives, gonadotropin-releasing hormone agonists, androgen agents, or aromatase inhibitors [80–82]. Elagolix, a commonly used GnRH antagonist for oral administration, differs from GnRH agonists by partially inhibiting estradiol preventing patients from experiencing low estrogen levels and reducing adverse reactions. This medication effectively alleviates symptoms like dysmenorrhea and pelvic pain [83]. There is evidence to suggest that using gonadotropin medications before undergoing IVF may enhance fertility outcomes by improving oocyte quality and endometrial receptivity [84]. In the study by Georgiou et al. [85], they gave patients gonadotropin agonist pretreatment compared with no pretreatment for 3 months. It was no significant differences between the two groups in the average number of oocytes retrieved, embryos, miscarriage rate, clinical pregnancy rate, and the live birth rate. Additionally, progesterone is also a common component of infertility treatments for patients with endometriosis, potentially enhancing fertility. Muller et al. [86] treated patients with dienogest and GnRH agonist triptorelin after laparoscopic surgery and before ovarian stimulation in IVF cycles. Compared with control, endometriosis patients had significantly higher numbers of 14 mm follicles, retrieved oocytes, and high-quality embryos. However, there is a scarcity of both basic and clinical studies investigating the impact of hormone therapy on oocytes in endometriosis patients. The majority of clinical search focuses on the effect of hormone therapy on dysmenorrhea and pelvic pain in these patients, warranting further exploration through high-quality studies.

Antioxidants

The antioxidants commonly used in treating endometriosis, such as vitamin C and E, as along with newer research on melatonin, resveratrol, xanthohumol, N-acetyl-L-cysteine, and astaxanthin as shown significant improvements in reducing oxidative stress markers, lesion volume and ectopic endometrial implantation. These improvements have a positive impact on oocyte quality by protecting them from chromosome and spindle misalignment, as well as aneuploidy [54, 87–91]. Rostami et al. [92] conducted a randomized, triple-blind, placebo-controlled clinical trial on astaxanthin, which demonstrated reductions in TNF-α and IL-6 level in follicular fluid, total oxidation status, and oxidation index compared to the placebo group. This drug has the potential to enhance the oocytes and embryo quality in assisted reproductive technology for endometriosis patients. Lin et al. [49] demonstrated that melatonin can effectively suppress endoplasmic reticulum stress and mitigate granulosa cell senescence. Additionally, their study showed an enhancement in fertility in endometriosis mouse models, suggesting that the antioxidant properties of melatonin could serve as an adjunctive therapy to counteract the decrease in fertility associated with oxidative stress. He et al. [93] revealed that melatonin, an antioxidant, is produced by mouse oocyte mitochondria. Treatment of in vitro matured (IVM) mouse oocytes with melatonin led to a reduction in ROS production and inhibited the formation of 8-hydroxy-deoxyguanosine. Melatonin administration was also associated with an increase in the mitochondrial mt-DNA copy number, and a decrease in the proportion of oocytes with abnormal spindle formation, and an overall improvement in the quality of resulting zygote blastocysts obtained. Numerous studies have indicated that antioxidants can enhance oocyte quality by ameliorating the oxidative stress environment in follicular fluid, improving granulosa cell function, and enhancing mitochondrial activity in patients with endometriosis. Nevertheless, the specific antioxidant treatment protocols require further evaluation regarding optimal dosing and drug safety.

Conclusion

Endometriosis in patients can lead to decreased quality and quantity of oocytes, resulting in relatively poorer clinical outcomes. The impact of endometriosis on oocytes is primarily through factors like ROS, cytokines, and hormonal changes within the growth and development microenvironment. However, current studies have small sample size and yield differing results. Larger studies are necessary to be conducted to validate the specific mechanisms. In terms of treating of endometriosis-related infertility, surgical interventions, hormone therapy, antioxidant therapy, and other common clinical treatments are effective in preserving patients’ fertility. Yet there is no established treatment plan, necessitating further research and evaluation.

Author contributions

Yuhang Fan: manuscript writing and editing. Qingmei Yang: manuscript writing and editing. Yifeng Lin: data analysis and manuscript editing. Xiaoying Fu: manuscript editing. Jing Shu: manuscript editing.

Funding

No funding was received for conducting this study.

Data availability

No data were generated or analyzed in this study.

Declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.