Introduction

Endometriosis is a common gynecologic disease with a reported prevalence of 6% to 10% [1]. Despite numerous studies, the exact pathogenesis and causes of endometriosis have not been fully elucidated [2-4]. While laparoscopic surgery has long been the primary diagnostic and treatment method, recent advances in imaging technology and concerns about the decrease in ovarian reserve following surgery have led to a shift towards medical treatment over surgical intervention for diagnostic purposes [5].

In recent years, imaging diagnosis followed by medical treatment has become widely used for managing endometriomas [5,6]. However, this approach has raised several concerns. First, relying solely on imaging tests for diagnosing endometriosis and subsequently initiating medical treatment can lead to worries about potential hidden malignancies, causing anxiety for both clinicians and patients [7]. According to the endometriosis guidelines published by ESHRE in 2022, the specificity and sensitivity of magnetic resonance imaging (MRI) (91% and 95%, respectively) and transvaginal ultrasonography (96% and 93%, respectively) for diagnosing endometrioma are reported. Although this diagnostic accuracy is remarkably high, there remains a possibility of missing malignant conditions. Second, for long-term medical treatment, the tolerability, quality of life, and adherence of patients are critical factors for the successful management of endometrioma [8]. If the size of the endometrioma remains unchanged despite prolonged medication, it may increase patients’ anxiety and reduce compliance.

Therefore, cyst aspiration followed by cytologic examination and subsequent medical treatment to maintain a decreased cyst size through improved treatment adherence can be considered. In this study, we evaluated the efficacy of conservative treatment with cyst aspiration followed by medical treatment regarding endometrioma size, ovarian reserve, and patient compliance.

Methods

Ethical statements: This study was approved by the Institutional Review Board of Pusan National University Hospital (IRB No. 2023-0489). Written informed consent was obtained from all the patients.

1. Participants

This prospective cohort study was conducted in the Department of Obstetrics and Gynecology at Pusan National University Hospital from January 2019 to July 2023. It included 47 female patients (age range, 24–43 years; mean, 32 years) diagnosed with endometrioma via transvaginal ultrasonography or MRI. Patients were consulted on treatment options for endometriosis, including surgical treatment, medication, and endometriotic cyst aspiration followed by medication. Forty-two patients who opted for cyst aspiration underwent cytological examination followed by medication treatment, while five who desired histologic confirmation received laparoscopic cystectomy.

2. Cyst aspiration and follow-up

Transvaginal aspiration of endometriotic cysts was performed as an outpatient procedure under local anesthesia using lidocaine. The cysts were punctured with 35 cm long, 18-gauge needle under transvaginal ultrasonographic guidance. The contents of the cysts were aspirated and flushed with normal saline. The aspirated fluid was sent to the pathology department for cytologic analysis. After cytological confirmation of the cystic fluid, all patients were started on dienogest 2 mg daily orally and followed up with transvaginal ultrasonography 3 months postoperatively. Patients reported their dysmenorrhea pain scores using a visual analog scale (VAS) score before the procedure, and changes were assessed 3 months post-procedure. Laboratory tests, including complete blood count, cancer antigen 125 (CA-125), and anti-Müllerian hormone (AMH) were conducted before cyst aspiration and at the 3-month follow-up.

3. Statistics

All statistical data were organized into a computerized database. For continuous variables, the number of observations, mean, and standard deviation were calculated and for categorical variables, the frequencies and percentages were presented. Mean values were expressed as mean±standard deviation. Endometrioma size pre- and post-aspiration were compared using a paired t-test. Endometriosis diameter was analyzed using logistic regression models to conduct both univariate and multivariate analyses. p<0.05 was considered statistically significant. All analyses were performed using SPSS version 22 (IBM Corp.).

Results

The study group included 42 patients with ovarian endometrioma. Thirty-one patients were diagnosed with ovarian endometrioma through pelvic MRI, and 11 were diagnosed using transvaginal ultrasonography. Four patients who decided to undergo assisted reproductive technologies (ART) for pregnancy were excluded, leaving 38 patients who continued taking dienogest, without dropouts.

The patients were aged 24 to 43 years, with a mean age of 32.03±5.33 years. The mean diameter of 56 cysts of 38 patients was 4.35±1.91 cm. Of the 38 patients, 18 had bilateral endometriomas, and 20 had unilateral endometriomas (7 on the right side and 13 on the left side) (Table 1).

Hemosiderin-laden macrophages were confirmed in the cystic fluid of all patients. No evidence of malignancy was reported in any cytologic examination.

The size of the cysts, measured as maximum diameter, decreased from 4.73±1.55 to 2.12±1.30 cm in unilateral endometrioma and from 4.14±2.07 to 2.51±1.67 cm in bilateral endometrioma. The endometrioma resolved in four patients with unilateral lesions and three of 36 endometriomas in the bilateral group after cyst aspiration followed by 3 months of dienogest medication, as detected by transvaginal ultrasonography. Serum CA-125 levels significantly decreased from 86.69±71.99 U/mL before the procedure to 37.28±18.58 U/mL, close to the upper limit of the normal range, after 3 months of administration of dienogest. However, there was no statistically significant difference in serum AMH levels (p=0.396) and mean value was increased from 3.14±3.34 ng/mL before the aspiration to 7.80±33.23 ng/mL after the aspiration. The VAS score was reduced from 3.58±1.13 before the cyst aspiration to 0.97±0.88 after the cyst aspiration, near complete pain relief. No major complications associated with cyst aspiration were observed during or after the procedure (Table 2). The logistic analysis of factors affecting the reduction in the size of endometriosis did not identify any significant factors.

Discussion

This prospective study demonstrated a visible reduction in the size of endometriomas within a short period and seven endometriomas disappeared. The mean diameter before aspiration was 4.35±1.91 cm and that after aspiration was 2.37±1.54 cm. The mean difference was –1.97 cm and it is a 45.3% size change.

Regarding the size of endometrioma during medical treatment, long-term medication treatments showed a statistically significant but small reduction in diameter after treatment. Uludag et al. [9] reported that continuous administration of 2 mg dienogest for 6 months resulted in a 41% reduction in cyst volume, from 112.63±161.31 to 65.47±95.69 cm³. Saglik Gokmen et al. [10] observed a decrease in the diameter of endometriomas from 44.0±13 to 39.5±15 mm, 10% reduction at 3 months, and further to 34.4±18 mm, 21.4% reduction at the 6-month follow-up. Additionally, Lee et al. [11] noted a reduction in the mean diameter of recurrent endometriomas from 3.77±1.59 to 2.74±1.53 cm, 27.3% reduction after 24 weeks of treatment. These reports showed a statistically significant reduction of endometrioma after medical treatment, but the differences in diameter were relatively small. In this study, the mean diameter of before aspiration was 4.35 cm and that of after aspiration was 2.37 cm. The mean difference was –1.97cm. The reduction of endometrioma size is more prevalent in this study and especially 7 endometriomas disappeared. Moreover, no patient dropouts were observed. In contrast, Uludag et al. [9] noted a 10% dropout rate during 6 months of medication treatment, with three out of 30 participants unable to complete the treatment due to menstrual irregularities. Saglik Gokmen et al. [10] reported a dropout rate of 15.79%, with 12 out of 76 participants discontinuing treatment as a result of various reasons, including metrorrhagia, secondary amenorrhea, and mood changes. Decreased compliance may be attributed to the lack of or minimal changes in the size of endometriomas despite medical treatment, which can be considered another drawback of long-term medication treatment. We assumed that the noticeable reduction in cyst size might be a key factor in higher compliance.

Additionally, biomarkers related to inflammation, such as white blood cell (WBC) and absolute neutrophil count (ANC), were observed to decrease significantly. The WBC count decreased from 6,602±1,934 cells/μL before aspiration to 5,849±1,345 cells/μL after aspiration. Similarly, the ANC decreased from 4,093±1,725 cells/μL before the procedure to 3,427±1,219 cells/μL after the procedure. Although the neutrophil-lymphocyte ratio (NLR) was not statistically significant (p=0.613), it remained in the range of 2 before and after the procedure. Typically, the normal range for this ratio is between 1 and 2. An NLR within the 2.0 to 3.0 range may suggest an early indicator of various pathological conditions, including cancer, atherosclerosis, infections, inflammation, psychiatric disorders, or stress [12]. This observation leads us to infer that the presence of endometrioma could be associated with a mild systemic inflammatory state.

Although there is no statistical significance, the mean AMH value increased from 3.14±3.34 to 7.80±33.23 ng/mL, and did not decrease. For a long time, laparoscopic surgery has been recommended for the diagnosis and treatment of patients with endometriosis [13]. However, with the introduction of relatively accurate methods for assessing ovarian reserve, such as AMH, it has been confirmed that surgery can significantly reduce ovarian reserve [14,15]. This has raised concerns about performing primary surgery in all endometriosis patients. Consequently, an individualized approach is often considered now [5]. The choice of an individualized approach depends on the patient’s future pregnancy plans, specifically whether they desire pregnancy currently, plan to conceive later, or have no plans for pregnancy at all [5]. Unlike laparoscopic surgery, cyst aspiration did not result in a decrease in AMH levels, making it a potential treatment option for patients who wish to conceive in the future.

Cytologic examination showed no evidence of malignancy and this is supported with imaging studies. It helped clinically rule out hidden malignancies and diagnose endometriosis. According to Barkan et al. [16], endometriosis can be diagnosed through cytologic examination when at least two of the following three findings are observed: endometrial glandular cells, endometrial stromal cells, and hemosiderin-laden histiocytes. However, these diagnostic criteria apply to abdominal endometriosis, and, in fact, diagnostic criteria for ovarian endometrioma through cytologic examination have not yet been established. Therefore, the diagnosis of endometrioma was made when hemosiderin-laden macrophages were identified, as no specimens contained glandular or stromal cells. Establishing a consensus on standard cytological criteria for ovarian endometrioma is considered essential.

Nevertheless, histologic confirmation was not performed, which represents a limitation of this study. This means that the possibility of malignancy cannot be completely ruled out. Although the diagnostic accuracy of imaging studies for endometriomas is very high, a fear of hidden malignancy remains, which can be a source of anxiety for both patients and clinicians [7]. With increasing age, endometriomas can contain retracted blood clots that may be misinterpreted as solid components on ultrasonography [17-19]. It has been reported that 21% of endometriomas in women 45 years or older might exhibit solid components [17]. The risk of ovarian cancer is 1.31% in the general population, but it increases to 2.5% in women with endometriosis [20]. Particularly in cases with atypical ultrasound findings of endometriomas and decreased ovarian function, making clinical decisions becomes more challenging. In such scenarios, cytologic tests are considered useful for ruling out hidden malignancies.

Recently, another treatment method, alcohol sclerotherapy (SCT), has been increasingly applied. SCT reduces the size of endometriomas by destroying the endometrioma lining cells [21]. A meta-analysis of SCT revealed overall recurrence rates ranging from 0% to 62.5% [22]. Regarding ART outcomes, the number of oocytes retrieved was higher than in laparoscopic cystectomy, but there was no significant difference in clinical pregnancy rates (CPR) [22]. Additionally, there was no difference in the number of oocytes retrieved or CPR between the treated and untreated groups [13]. These results suggest that SCT might be a good treatment option for preserving ovarian function. However, adhesion formation in surrounding tissues and loss of tubal function due to alcohol leakage have been reported [21]. Given that no randomized controlled trials (RCTs) confirm these findings, caution is advised when considering SCT for women planning future pregnancies. SCT should be approached particularly carefully unless both tubes are already damaged, necessitating ART.

Since this was a pilot study, it has the disadvantage that it did not compare patients who only underwent medication without surgery, SCT, or cyst aspiration. This limitation is considered inherent to the non-comparative design of this study. However, the findings derived from this study may serve as a foundation for further comparative studies evaluating various treatment modalities for endometrioma. Additionally, while the relatively short follow-up period of 3 months may be perceived as a limitation, it was deemed appropriate to assess changes at this interval, given the natural decline of AMH over time. Nevertheless, longer-term follow-up studies investigating additional changes in AMH levels over time could provide insights into the long-term impact of the therapeutic approach applied in this study on ovarian function. Furthermore, as mentioned earlier, a notable limitation exists concerning cytologic diagnosis in endometrioma, as standardized diagnostic criteria for this context have not yet been established. Further studies, including RCTs, are needed on ovarian reserve, ART outcome, endometrioma size reduction, patient satisfaction, and diagnosis rate of cytological confirmation.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This work was supported by a New Faculty Research Grant of Pusan National University, 2023.

Author contributions

Conceptualization: JKJ. Data curation: JKJ, HEJ. Formal analysis: EHY. Funding acquisition: JKJ. Investigation: HEJ, HJL. Methodology: EHY, HJL. Project administration: JKJ. Resources: JKJ. Software: HEJ. Supervision: YJN, JKJ. Validation: JKJ. Visualization: HJL. Writing - original draft: HEJ, JKJ. Writing - review & editing: HJL, JKJ. All authors read and approved the final manuscript.

References

• 1. Chen LH, Lo WC, Huang HY, Wu HM. A lifelong impact on endometriosis: pathophysiology and pharmacological treatment. Int J Mol Sci 2023;24:7503.ArticlePubMedPMC
• 2. Czyzyk A, Podfigurna A, Szeliga A, Meczekalski B. Update on endometriosis pathogenesis. Minerva Ginecol 2017;69:447–61.ArticlePubMed
• 3. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014;10:261–75.ArticlePubMedPDF
• 4. Wang Y, Nicholes K, Shih IM. The origin and pathogenesis of endometriosis. Annu Rev Pathol 2020;15:71–95.ArticlePubMedPMC
• 5. Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol 2019;15:666–82.ArticlePubMedPDF
• 6. Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, et al. ESHRE guideline: endometriosis. Hum Reprod Open 2022;2022:hoac009.PubMedPMC
• 7. Huang KJ, Li YX, Wu CJ, Chang WC, Wei LH, Sheu BC. Sonographic features differentiating early-stage ovarian clear cell carcinoma from endometrioma with atypical features. J Ovarian Res 2022;15:84.ArticlePubMedPMCPDF
• 8. Barbara G, Buggio L, Facchin F, Vercellini P. Medical treatment for endometriosis: tolerability, quality of life and adherence. Front Glob Womens Health 2021;2:729601.ArticlePubMedPMC
• 9. Uludag SZ, Demirtas E, Sahin Y, Aygen EM. Dienogest reduces endometrioma volume and endometriosis-related pain symptoms. J Obstet Gynaecol 2021;41:1246–51.ArticlePubMed
• 10. Saglik Gokmen B, Topbas Selcuki NF, Aydın A, Yalcin Bahat P, Akca A. Effects of dienogest therapy on endometriosis-related dysmenorrhea, dyspareunia, and endometrioma size. Cureus 2023;15:e34162.ArticlePubMedPMC
• 11. Lee JH, Song JY, Yi KW, Lee SR, Lee DY, Shin JH, et al. Effectiveness of dienogest for treatment of recurrent endometriosis: multicenter data. Reprod Sci 2018;25:1515–22.ArticlePubMedPDF
• 12. Zahorec R. Neutrophil-to-lymphocyte ratio, past, present and future perspectives. Bratisl Lek Listy 2021;122:474–88.ArticlePubMed
• 13. Falcone T, Flyckt R. Clinical management of endometriosis. Obstet Gynecol 2018;131:557–71.ArticlePubMed
• 14. Pais AS, Flagothier C, Tebache L, Almeida Santos T, Nisolle M. Impact of surgical management of endometrioma on AMH levels and pregnancy rates: a review of recent literature. J Clin Med 2021;10:414.ArticlePubMedPMC
• 15. Wang Y, Ruan X, Lu D, Sheng J, Mueck AO. Effect of laparoscopic endometrioma cystectomy on anti-Müllerian hormone (AMH) levels. Gynecol Endocrinol 2019;35:494–7.ArticlePubMed
• 16. Barkan GA, Naylor B, Gattuso P, Kullu S, Galan K, Wojcik EM. Morphologic features of endometriosis in various types of cytologic specimens. Diagn Cytopathol 2013;41:936–42.ArticlePubMed
• 17. Guerriero S, Van Calster B, Somigliana E, Ajossa S, Froyman W, De Cock B, et al. Age-related differences in the sonographic characteristics of endometriomas. Hum Reprod 2016;31:1723–31.ArticlePubMed
• 18. Tanase Y, Kawaguchi R, Takahama J, Kobayashi H. Factors that differentiate between endometriosis-associated ovarian cancer and benign ovarian endometriosis with mural nodules. Magn Reson Med Sci 2018;17:231–7.ArticlePubMedPMC
• 19. Vercellini P, Vigano P, Buggio L, Makieva S, Scarfone G, Cribiu FM, et al. Perimenopausal management of ovarian endometriosis and associated cancer risk: when is medical or surgical treatment indicated? Best Pract Res Clin Obstet Gynaecol 2018;51:151–68.ArticlePubMed
• 20. Tang L, Bian C. Research progress in endometriosis-associated ovarian cancer. Front Oncol 2024;14:1381244.ArticlePubMedPMC
• 21. Hsieh CL, Shiau CS, Lo LM, Hsieh TT, Chang MY. Effectiveness of ultrasound-guided aspiration and sclerotherapy with 95% ethanol for treatment of recurrent ovarian endometriomas. Fertil Steril 2009;91:2709–13.ArticlePubMed
• 22. Cohen A, Almog B, Tulandi T. Sclerotherapy in the management of ovarian endometrioma: systematic review and meta-analysis. Fertil Steril 2017;108:117–24.ArticlePubMed

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References

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