The problem of recurrence of ovarian endometriomas

Introduction

Endometriosis is a hormone-dependent gynecological disease characterized by the growth of functional endometrial-like tissue outside the uterine cavity [1]. Endometriosis remains one of the difficult problems of clinical medicine, since the disease has features of an inflammatory process, autoimmune pathology, tumor growth, and immune dysfunction [2].

External genital endometriosis (EGE) is one of the widespread gynecological benign diseases, the high incidence of which occurs at reproductive age. According to the latest data, more than 176 million women aged 15–49 suffer from genital endometriosis in the world. In the Russian Federation, the number of women with endometriosis is 3.3–5 million [3][4]. According to classification by lesion location, genital endometriosis is divided into peritoneal endometriosis, deep infiltrative endometriosis, and ovarian endometrioma (OE) [5]. OE is one of the EGE subtypes affecting approximately 2–10% of women of reproductive age and 25–50% of women with infertility [6, 7]. Despite its benign nature, the functional tissue of the ovary is destroyed with the long-term existence of endometrioma, which in turn adversely affects the ovarian reserve [8]. Ovarian endometriosis occurs in 17–44% of patients with endometriosis and accounts for 35% of all benign ovarian lesions [9].

One of the most dangerous and insidious problems of this disease is its late diagnosis, which is associated with its asymptomatic course in 30–50% of cases. According to the opinion of many authors, the diagnosis may be delayed for 8–10 years due to the misinterpretation of clinical symptoms, which is related mainly to the similarity of ovarian endometriosis symptoms to symptoms of other gynecological or extragenital diseases [9, 10]. The characteristic symptoms of OE include dysmenorrhea (83%), dyspareunia (72%), infertility (72.9%), and others [10]. In the case of a prolonged course of the disease, these clinical symptoms adversely affect family relationships, quality of life, and fertility. In most cases, OE is a random finding during ultrasound of pelvic organs. In 10% of cases, a false-positive OE diagnosis can be associated with functional cysts or cystadenomas with a similar echostructure [11].

The size of the endometrioid ovarian cyst > 4 cm in diameter, combined infertility, and the ineffectiveness of drug therapy are the indications for the surgical treatment of patients with OE [11][12].

Despite the widespread use of surgical treatment of OE, the problem of disease recurrence and relapse prevention remains extremely relevant. This is due to a reduction in repeated, and sometimes multiple, surgical interventions, as well as a decrease in the psychological burden on patients and meeting their need for fertility.

OE recurrence rate

Currently, there are various theories for the development of recurrent OE; the main ones are the following: 1) in situ regrowth of microscopic lesions that were not completely removed during surgery; 2) growth of microscopic endometrioid lesions that were not detected during surgery; 3) de novo lesion; 4) combinations of the first two theories [11][12].

Surgical treatment of OE includes various methods such as cystectomy, electrocoagulation, laser ablation, plasma-energy ablation, and combined methods. ESHRE recommendations suggest that the surgical “stripping” method is the recommended treatment option for OE [13]. Cystectomy using the “stripping” method is associated with a lower OE relapse rate and recurrence of pain syndrome, as well as with better postoperative fertility rates [14][15]. However, later concerns were expressed that in some cases, this technique could lead to the unintended removal of healthy ovarian tissue [16].

According to the data of Yang et al. (2023), the OE recurrence rate after surgical treatment during the first year was 6.27%, 1–2 years – 35.85%, 2–3 years – 55.38%, 3–4 years – 65%, and more than 5 years – 56.82%, respectively [17]. That is, already 3–4 years after surgery, more than half of the operated women had OE relapse. About 62% of women with endometriosis could tolerate repeated surgical interventions, while the average interval from the moment of the first operation was only 2 years [18].

In the study of Orazova et al., it was noted that in 88.7% of cases during repeated surgery, newly occurring heteropias were located in the same area as during the first surgical intervention [19].

The recurrence rate after surgery remains high even against the background of drug hormonal therapy. According to the data of Li Chao et al., the OE recurrence rate was 29–56% after conservative laparoscopic surgery after 2 years, and after 5 years – 43%. However, the frequency of OE recurrence significantly decreased to 3–11% after 2 years and to 6% after 5 years while undergoing postoperative medical drug therapy [20].

At an average postoperative observation time of 2.5 years, the recurrence rate of OE without subsequent drug treatment at the age of 20–30 years was 24.2%, at the age of 31–40 years – 17.7%, and at the age of 41–45 years – 7.9%. This indicates a more aggressive course of the disease in younger women. It is also worth noting that the age range from 33 to 35 years is the “dilemma window”, the threshold age value when patients should be treated very carefully in order to predict and prevent OE relapse [20].

Laparoscopic cystectomy is one of the most frequent organ-saving operations in OE. However, in some situations, the already occurred OE relapse requires repeated surgery that undoubtedly negatively affects the state of the ovarian reserve. For a long time, a gentler sclerotherapy method existed and was used to preserve healthy ovarian tissue, but with a higher frequency of relapse. Muzii et al. report that the recurrence rate after cystectomy was 14%, and after sclerotherapy – 34.1% [21].

At the same time, aspiration of OE under ultrasound control, without sclerosing agents in patients with infertility, was also not widespread, even for relieving pain symptoms and restoring fertility. Thus, according to the data of Shaltout et al., the frequency of OE recurrence when using this method was almost 90% during one month of observation [22].

It was noted that frequently recurrent OE was characterized by more pronounced clinical symptoms (abnormal uterine bleeding – 65.1%, dysmenorrhea – 82.6%, dyspareunia – 82.6%). In the case of a non-recurrent postoperative course, the frequency of these symptoms is significantly lower: 8.2%, 7.1%, and 15.3%, respectively [22].

Thus, the lowest percentage of OE recurrence was observed in cystectomy. At the same time, the main problem is the destruction and removal of healthy ovarian tissue. Repeated similar surgery in the case of OE recurrence has a very negative effect on the ovarian reserve. Besides, an adhesion process occurs [22], which can be an additional factor in reducing fertility.

Association of OE with infertility

In modern gynecological practice, the approach to the treatment of OE has changed significantly. The priority is the preservation of fertility and the treatment of infertility. Approximately 25–50% of patients with reproductive problems are diagnosed with endometriosis, and up to 50% of them are referred for assisted reproductive technologies (ART) [23]. It is worth noting once again that patients with OE are at high risk for the development of premature ovarian failure due to the inevitable surgical intervention and possible anti-relapse treatment [24].

Mechanisms involved in the occurrence of infertility in OE remain not fully understood; this pathology still remains multifactorial [24]. According to literature, the presence of OE likely affects ovarian reserve through several mechanisms, such as squeezing the surrounding tissue, resulting in impaired circulation and loss of follicles. The inflammatory reaction associated with the production of reactive oxygen species, which are powerful inducers of tissue fibrosis, also leads to the loss of follicles [24].

Infertility in EGE is associated both with anatomical disorders as a result of the adhesive process and fibrosis and with endocrine and immunological changes. Surgery can become an additional cause of infertility due to the tubo-peritoneal factor [24].

Some infertile women with EGE have chronic anovulation, luteal phase insufficiency, and hyperprolactinemia, which is due to hypothalamic-pituitary insufficiency [24, 25].

After cystectomy, partial (less often – complete) loss of primordial follicles is observed, which occurs as a result of an additional disorder in the ovarian circulatory system associated with the occurrence of burn necrosis, as well as with the imposition of ligatures [25].

It remains debatable whether OE itself reduces the ovarian reserve or there is a link between the size of the endometrioid cyst and a decrease in the ovarian reserve. According to the data of Kasapoglu et al., based on the results of a prospective study of 40 patients with OE and 40 healthy women in the control group, it was found that the decrease in anti-Mullerian hormone (AMH) in women with OE was faster than in healthy women. Over 6 months of follow-up, the percentage decrease in AMH was 26%, while in the control group it was 7% [26]. Therefore, all women need to conduct a qualitative assessment of the ovarian reserve before surgery for OE, since recent studies indicate that a large number of follicles are contained in the wall of the endometrioid cyst [25, 26].

Today, treatment of infertility caused by endometriosis focuses on the removal or reduction of ectopic endometrioid foci and the restoration of normal pelvic anatomy, with the help of drug therapy and/or surgery, as well as ART in case of the ineffectiveness of the first two treatment options [27].

Tactics for managing women with infertility, including women with OE, should take into account age, the state of the ovarian reserve, the duration of infertility, the stage of the disease, previous and planned surgical treatment, as well as the evidence and success of the use of various technologies for preserving fertility. Cryopreservation of oocytes, embryos, and ovarian tissue remains fundamental in terms of patient management during OE treatment [28].

Methods for early diagnosis and prediction of OE recurrence

A significant problem of OE treatment is the occurrence of postoperative relapse. According to the latest data, the recurrence rate varies from 19 to 50% [29]. Based on clinical and anamnestic data, the recurrence rate of endometriosis is mainly associated with the patient’s age and the presence of postoperative pregnancy. Younger age (< 35 years) is a significant risk factor for endometrioma recurrence associated with the early onset of the disease, having a more aggressive form. According to the data of Yang et al., the relapse rate at the age of 20–29 years was 43.3%, at the age of 30–39 years – 22.5%, and at the age of 40–45 years – 10.2%, which confirms the data on high postoperative relapse in young women [30].

Many authors advise to pay attention to the data obtained as a result of collecting clinical, anamnestic, and endoscopic information that contribute to the recurrence of the disease: intense acyclic pelvic pain, a history of chronic inflammatory processes of the appendages, the presence of surgical interventions in the history of EGE, infertility, a pronounced adhesion process in the small pelvis, large endometrioid cysts, and bilateral damage of ovaries [31][32].

According to Huangi et al., r-AFS > 70 points, concomitant uterine fibroids, and preoperative dysmenorrhea were the risk factors for relapse, and postoperative pregnancy was a protective factor for relapse [12]. Therefore, patients with identified risk factors before surgery for ovarian endometriosis should not neglect medication and the intention to become pregnant as soon as possible in order to reduce relapse.

According to a study by Ding et al., women with OE often have hypercoagulation, potentially associated with the inflammatory nature of endometrioma (according to laboratory research methods) [33]. Ling found an association of APTT, prothrombin, thrombin time, and fibrinogen with the cyst size in patients [34].

A study of proinflammatory cytokines IL-1, 2, 6, the level of which is increased both in serum and in peritoneal fluid of women with EGE, can be used for an early diagnosis of relapse [35].

Endometriosis is characterized by certain processes indicating metastasis, carcinogenesis, including proliferation, adhesion, invasion, angiogenesis, and metaplasia; these mechanisms are directly involved in progression and recurrence. Therefore, the determination of biomarkers and risk factors in the preoperative period can identify patients with a high probability of relapse, prompting intervention and preventing the possibility of relapse [36]. The biomarkers of endometriosis involved in pathogenetic processes can be determined in peritoneal fluid, urine, cervical mucus, and saliva [37].

Diagnostic significance of biomarkers. Currently, numerous studies are underway to look for biomarkers of endometriosis. For this purpose, samples of blood, urine, endometrium, and cervical mucus of patients with endometriosis are studied [38]. A relationship has been established between the level of CA-125 and the severity of the adhesion process. With CA-125 > 35 U/ml, the probability of the adhesion process in the pelvis increases by 5.4 times, and, according to a number of authors, in women of reproductive age with endometriosis, the frequency of the adhesion process ranges from 12 to 60% [27]. Therefore, the levels of CA-125, leukocytes, and fibrinogen can be very useful tools in the prognostic diagnosis of appendage lesions in the form of endometrioma [39].

Such biomarkers as annexin V, slCAM-1, and glycodelin A involved in apoptosis, adhesion, and angiogenesis – the main links in the pathogenesis of endometriosis – have primary importance in the development of non-invasive diagnostic panels. According to the data of Balan, biomarker expression increases rapidly under the influence of proinflammatory cytokines. It was noted that glycodelin A, which is involved in the processes of angiogenesis and apoptosis, had a sensitivity of 82.1% and a specificity of 78.4% in women with OE [39].

There is a necessity to use such markers as follistatin, activin A, and urocortin, which are involved in the processes of decidualization, mast cell degranulation, and the ability to increase vascular permeability. According to the study of these markers, their levels increase at OE. The variety of combined tests will make it possible to bring unity in the unification of results and early diagnosis [39].

Immunohistochemical methods. In ectopic endometrioid tissue, there is a decrease in the expression level of the ER-a receptor and an increase in the expression level of ER-b, which is a key mediator of estrogenic activity, stromal cell proliferation, resistance to apoptosis, and maintenance of the inflammatory process [40]. Detection of ER and PR in endometriosis is useful when prescribing postoperative hormonal treatment [41].

Metastasis-associated protein (MTA-1) is highly expressed in many malignancies. Endometriosis, like a malignant tumor, has the ability to invade and promote angiogenesis. High MTA-1 expression and rAFS levels are high-risk factors for postoperative recurrence of ovarian endometriosis [42].

The levels of reverse transcriptase of human telomerase (h-TERT), whose expression correlates with cell proliferation, and Ki-67-nuclear protein, a marker of apoptosis and cell proliferation, provide insights into the ability to evolve and short-term relapse of disease, as defined by immunohistochemistry, are highly expressed in groups with endometriosis and the recurrent form [42, 43].

Immunohistochemical determination of HOXA-11 and CD10, involved in endometrial homeostasis, alone or in combination, is a useful tool for distinguishing ectopic endometrial tissue from normal, from gynecological tumors, and metastases. In endometrial carcinoma, 42% of cases expressed both markers simultaneously compared to 90% in endometriosis [43].

Increased COG-2 expression, the expression of which is usually induced by proinflammatory agents and growth factors, can also be a biomarker for predicting OE, which is a key stimulator of the expression of steroidogenic acute regulatory protein (StAR) and aromatase, which leads to E2 synthesis and local hyperestrogenism with subsequent hyperproliferation [43].

Increased COG-2 expression, in turn, leads to increased expression of vascular endothelial growth factor-A (VEGF-A), which leads to increased angiogenesis and ensures the survival of tumor cells and endothelium, protecting them from apoptosis [43].

Transcription factor NF-kB – a biomarker of relapse, which is a universal transcription factor that controls the expression of immune response genes, apoptosis, and the cell cycle, is involved in antiviral and antitumor control. Increased NF-kB activation and decreased PR-b immunoreactivity are the two predominant predictors of relapse [44].

The leading role also refers to transforming growth factor TGF-B1 as an inflammatory growth factor that regulates cell adhesion, migration, differentiation, apoptosis, invasion, and angiogenesis. The expression of this factor leads to a decrease in the activity of NK cells; the expression values of these factors are typical for the recurrence of ovarian endometrioid cysts [44].

Increased inflammatory responses activate IL-6, which in turn initiates the KRAS oncogene, BCL6, and SIRT1 overexpression in the eutopic endometrium of women with endometriosis. These markers interfere with progesterone signaling, which leads to estrogen dominance, causing proliferation [44].

The mechanisms that mediate the induction of the proliferative pool of endometrioid heterotopias are a decrease in the activity of p53, a key regulator of apoptosis, and the accumulation of oncoprotein Bcl-2, which has an anti-apoptotic potential [45].

Immunohistochemical studies of the expression of PR-a, Ki-67, NF-kb, and COG-2 in the capsule of the endometrioid ovarian cyst can identify patients with a high risk of relapse immediately after surgical treatment [45].

Histological methods. Histological characteristics of endometrioid ovarian cysts (fibrosis thickness and depth of invasion) have some differences in different age groups. Thus, an age of less than 35 years and a depth of invasion of more than 1.2 mm are significant prognostic risk factors for the development of endometriosis [46][47].

In a study by Xu et al., it was shown that the detection of “live” endometrial cells in the fluid of the endometrioid ovarian cyst and the fluid of postoperative peritoneal drainage demonstrated the possibility of recurrence of endometriosis after surgical treatment of OE [48].

Methods of OE recurrence prevention and their effectiveness

Prophylactic use of hormonal therapy after surgical treatment of endometriosis is recommended for patients with a high risk of relapse [48]. Literature data suggest that 2.9–11.5% of relapse cases occur in women who have received hormone therapy. At the same time, in cases of a drug-free postoperative period, relapse occurs in 45–55% of cases [49][50].

Postoperative pregnancy can reduce relapse rates among patients undergoing OE surgery. Thus, according to Wacharachawana et al., only 13% of operated patients had a relapse of endometriosis after pregnancy [50].

Therapy based on the suppression of endometrioid heterotopias includes combined oral contraceptives (COCs), contraceptives with only a progestogen component, gonadotropin-releasing hormone (GnRH) agonists, and antigonadotropins [50].

COCs are present in the regimens most commonly prescribed for the prevention of endometrioma recurrence in clinical practice [51]. COCs increase apoptosis and reduce cell proliferation in the eutopic endometrium, which can reduce both relapses from small endometrioid foci and the development of disease de novo [48]. At the same time, the domestic clinical guidelines do not indicate the use of COCs for this purpose [52][53].

Dydrogesterone is the only progestogen that does not block ovulation, which is important for patients who wish to become pregnant during therapy. Synthetic progestogen dienogest creates a hypoestrogenic and hyperprogestogenic background; it is the most active anti-inflammatory progestin, which reduces the size of endometrioid lesions. Its long-term use (> 1 year) prevents the development of disease recurrence [18].

According to the study of Bezhenar et al., when using anti-relapse therapy with a combined dienogest-containing oral contraceptive with 30 μg of ethinyl estradiol in the postoperative period, there was a high frequency (20.9%) and severity of disease recurrence, and the lowest frequency of pregnancy. The use of aGnRH as postoperative therapy in women with EGE made it possible to reduce the rate of miscarriage (3%), and the recurrence rate was 5%. The intensity of pain syndrome on the VAS scale at aGnRH and COCs with the use of drugs for 6 months was 1–2 points and 6–7 points, respectively [54].

The use of the intrauterine levonorgestrel-containing system (IUS-LNG) and dienogest are the two leading treatments that reduce the risk of endometriosis recurrence after surgical treatment by 95% and 86%, respectively [54].

According to data of Chernukha, long-term therapy with dienogest at a dose of 2 mg/day serves as a reliable prevention of OE recurrence and repeated surgical interventions associated with a further decrease in the ovarian reserve [55]. The incidence of relapse of endometriosis when taking dienogest was 24%, in patients receiving aGnRH – 14%, and with combination therapy aGnRH + dienogest – 38% [55].

Cystectomy, followed by hormonal therapy, completely or partially relieved the symptoms of the disease in 95%. Relapse with endometrium after 2 years was 1.4%, after 3 years – 3.7% [55].

Some publications have noted the effectiveness of radon balneotherapy in combination with gonadoliberin agonists. The study revealed a decrease in proinflammatory cytokines [56].

The use of traditional Chinese medicine (acupuncture) provides the release of neurohumoral factors (NA, AC, dopamine), a decrease in estrogen levels, contributing to the suppression of ectopic endometrial growth, and an increase in NK-cells. Yoga helps to relieve muscle tension, thereby improving blood circulation in muscles and tissues [56].

Postoperative drug treatment can effectively delay relapse. According to the data, after more than 5 years, some patients presented complaints when relapses occurred [56]. Also, one should not neglect the lack of a positive effect of drug therapy during the 6 months of the postoperative period. In this case, it is necessary to make a decision on the advisability of repeated surgery, changing the drug therapy regimen [56][57].

Conclusion

Endometriosis remains the most mysterious gynecological disease, and OE is the most common form of genital endometriosis. Moreover, there are many factors of OE recurrence after surgical treatment [57]. One of these factors is the fact that in most cases, these patients underwent surgery in the advanced stages of the disease, which is itself a high risk factor for relapse.

Investigation and implementation of various methods of forecasting and prevention are urgently needed to improve the strategy for managing patients with endometriosis. The determination of biomarkers in some situations can reduce the time of diagnosis of endometriosis and the degree of its prevalence. Unfortunately, all studied markers are not specific for endometriosis, and a change in their level is observed in other gynecological diseases. In the long term, the search and development of reliable biomarkers entail the development of great potential in the prediction and prevention of OE recurrence.

The authors of the clinical recommendations of all the world’s leading associations of obstetrician-gynecologists are of one mind on the opinion that postoperative medical treatment can effectively reduce the incidence and, in some cases, delay the recurrence of endometriosis. At the same time, currently, there is a fairly wide range of hormonal drugs in the arsenal of obstetrician-gynecologists.