{"paper_id":"f628bc07-c4f7-46cf-9121-8a26ae9afea9","body_text":"Original Investigation\n102\nCopyright© 2024 The Author. Published by Galenos Publishing House on behalf of Turkish-German Gynecological Association. This is an open access \narticle under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 (CC BY-NC-ND) International License.\nAddress for Correspondence: Gürkan Bozdağ\ne.mail: gbozdag75@yahoo.com ORCID: orcid.org/0000-0002-6679-9623\nDOI: 10.4274/jtgga.galenos.2024.2022-9-4\nIntroduction\nEndometriosis is a chronic disorder that affects approximately \n2-10% of women throughout the reproductive years (1,2). \nWhereas endometriosis is often associated with pain-\nrelated symptoms, including dysmenorrhea, dyspareunia, \nand dyschezia, a significant portion of women do not have \nany symptoms (3,4). Among patients with endometriosis, \n17-44% may have visible ovarian endometrioma  (OMA) on \nultrasonography (US) that represents a more severe stage \nof the disease, according to the revised American Society of \nReproductive Medicine staging (5,6). OMA may be associated \nReceived: 15 June, 2023 Accepted: 08 January, 2024\nAbstract\nObjective: To assess the effect of dienogest treatment on endometrioma (OMA) size, serum anti-Mullerian hormone (AMH) levels and \nassociated pain over a 12-month follow-up period.\nMaterial and Methods:  A longitudinal cohort study of 104 patients with OMA who were treated with dienogest, between January 2017 and \nJanuary 2020. Of the included patients, each had a 12-month follow-up period with transvaginal or pelvic ultrasound and measurement of serum \nAMH concentration at the sixth and twelfth months of follow-up. The alteration in OMA size in the sixth and twelfth months of treatment was \nthe primary outcome measure and the alteration in AMH concentration over the same period was the secondary outcome measure. The only \nexclusion criterion was having surgical intervention for OMA during the follow-up period (n=44). In patients with bilateral OMA (n=21), the \nchange in size of the largest OMA was considered in the analysis.\nResults: A total of 60 patients with a mean ± standard deviation (SD) age of 31.5±8.0 years were included. The mean ± SD OMA size on the day \nthe dienogest was started was 46.3±17.4 mm and the mean AMH level was 3.6±2.4 ng/mL. After six months, the mean OMA size had decreased \nto 38.6±14.0 mm, with a median difference of 7.8 mm [95% confidence interval (CI): 3.0 to 12.6; p=0.003]. The mean AMH level was 3.3±2.7 \nng/mL at 6 months follow-up (95% CI: -0.2 to 0.8; p=0.23) and the average difference was 0.3 ng/mL. At the 12 th-month visit, when compared \nwith the beginning of the treatment, OMA size had again significantly decreased by a median of -8.9 mm (95% CI: -2.9 to -14.9; p=0.005), and the \ndecline in median AMH was also significant (-0.9 ng/mL, 95% CI: -0.1 to -1.7; p=0.045). The initial mean ± SD visual analog scale pain score at \nthe commencement of dienogest treatment was 6.3±3.4. The mean values at the sixth and twelfth months of dienogest therapy were 1.08±1.8 \nand 0.75±1.5, respectively (both p<0.001 compared to baseline).\nConclusion: At the sixth and twelfth months of dienogest treatment a significant decrease in OMA size and reported pain scores were observed, \nwhereas the AMH concentrations did not change significantly. (J Turk Ger Gynecol Assoc 2024; 25: 102-6)\nKeywords: Endometrioma, anti-Mullerian hormone, dienogest, pelvic pain, ovarian reserve\n1Department of Obstetrics and Gynecology, Hacettepe University Faculty of Medicine, Ankara, Turkey\n2Anatolia In Vitro Fertilization and Women Health Centre, Ankara, Turkey\n3Bahçeci In Vitro Fertilization and Women Health Centre, İstanbul, Turkey\n Esra Karataş1,  Bilal Esat Temiz1,  Sezcan Mümüşoğlu1,  Hakan Yaralı1,2,  Gürkan Bozdağ3 \nThe effect of dienogest treatment on anti-Mullerian \nhormone in patients with endometrioma: a 12-month \nfollow-up study\n\nKarataş et al. \nThe effect of dienogest treatment on anti-Mullerian hormone in patients with endometrioma 103\nJ Turk Ger Gynecol Assoc 2024; 25: 102-6\nwith infertility and hence approximately 40% of infertile \nwomen with endometriosis are reported to have visible OMA \ncysts (7). \nThe optimal management of OMA during the reproductive \nyears is c ontroversial. The preferred strategy depends on \nthe patient’s age, desire for childbearing, severity of pain-\nrelated symptoms, presence of bilaterality, and suspicion of \nmalignancy (8,9). Given the high success rate for pain-related \nsymptoms and lack of any harm to the ovarian reserve, medical \ntreatments may be considered in patients with moderate-\nsevere symptoms who do not have any desire to preserve \nfertility. Among the available medical treatment options, \ncombined contraceptive pills or progestin-only drugs, with or \nwithout non-steroidal anti-inflammatory drugs, may be the \nfirst choice due to the low complication rate and high patient \ncompliance (10). Although dienogest is one of the options \nwithin the group of progestin-only drugs, there are constrained \nstatistics approximately its effect on the scale of the OMA and \ntherefore serum anti-Mullerian hormone (AMH) concentration \nin the course of 365 days of compliance with up.\nIn the present study, the aim was to investigate if there were \nstatistically significant changes in the volume of OMA, AMH \nlevels and associated symptoms at one-year follow-up in \npatients with OMA on dienogest.\nMaterial and Methods\nPatients and study design\nAll procedures performed in studies involving human \nparticipants were in accordance with the ethical standards of \nthe institutional research committee and with the 1964 Helsinki \ndeclaration and its later amendments or comparable ethical \nstandards. The study was approved by the Hacettepe University \nNon-Interventional Clinical Research Ethics Committee \n(approval number: 2021/09-30, date: 20.04.2021). Informed \nconsent was obtained from all patients participating in the \nstudy.\nIn the current observational cohort study, consecutive patients \nwith a diagnosis of OMA and treated with dienogest (Visanne, \nBayer, İstanbul, Turkey) between January, 2017 to January, \n2020 at university department of obstetrics and gynecology \nwere recruited. The inclusion criteria were being between the \nages of 20 and 45 years, no patient desire to preserve fertility, \nand the preferred medical treatment was dienogest alone. \nThe exclusion criteria were history of any surgical treatment \n(cystectomy, cyst aspiration/fenestration or sclerotherapy) \nbefore the study period, use of the combined contraceptive \npill in the three months preceding the study and suspicious of \nmalignancy as suggested by US.\nAll included patients received 2 mg orally dienogest per day \nfor at least 12 months. Data concerning the largest OMA \ncyst diameter on US, serum AMH measurement and visual \nanalog scale (VAS) from 0 to 10 (0: no pain to 10: unbearable \npain) were collected. Patients were asked about pelvic pain \n(dysmenorrhea, or non-cyclic pelvic pain) at the beginning, \nsixth, and twelfth months of dienogest treatment. Serum AMH \nwas measured with the Elecsys AMH assay (Roche Diagnostic \nInternational, IN, USA.) All examination with US was conducted \nby a single physician (G.B.). \nStatistical analysis\nA retrospective analysis of prospectively collected data was \nconducted using SPSS, version 23 (IBM Inc., Chicago, IL, USA). \nThe paired t-test was employed to compare numerical values, \nand a statistical significance level of p<0.05 was used.\nResults\nOf 104 patients, 44 (42.3%) were excluded and 60 patients \nwere analyzed. The mean ± standard deviation (SD) of age \nwas 31.5±8.0 years. Demographics of the study population are \npresented in Table 1. At the start of dienogest treatment, the \nmean largest diameter of the OMAs was 46.3 ±17.4 mm, and \nthe mean serum AMH concentration was 3.6 ±2.4 ng/mL. The \nmain symptoms observed among patients were: dysmenorrhea \n(26.7%), chronic pelvic pain (41.7%), and menstrual irregularity \n(13.3%). A total of 30% of the patients did not exhibit any \nsymptoms. \nAfter six months of treatment, the mean OMA size decreased \nto 38.6 ±14.0 mm, with a mean difference of 7.8 mm  \nTable 1. Study population characteristics at baseline\nCharacteristics \nNumber of patients 60\nAge, years 31.5±8.0\nBody mass index, kg/m2 23.4±4.0\nSymptoms, n (%)\nDysmenorrhea 16 (26.7)\nChronic pelvic pain 25 (41.7)\nMenstrual irregularity 8 (13.3)\nAsymptomatic 18 (30.0)\nVAS score at baseline 6.3±3.4\nUltrasound type, n (%)\nTransvaginal 32 (53.3)\nPelvic ultrasound 28 (46.7)\nBaseline endometrioma size, mm 46.3±17.4\nPatients with bilateral endometrioma, n (%) 21 (35%)\nBaseline AMH, ng/mL 3.6±2.4\nVAS: Visual analog score, AMH: Anti-Mullerian hormone \n\nKarataş et al. \nThe effect of dienogest treatment on anti-Mullerian hormone in patients with endometrioma104\n J Turk Ger Gynecol Assoc 2024; 25: 102-6\n[95% confidence interval (CI): 3.0 to 12.6; p=0.003]. The mean \nAMH level was 3.3 ±2.7 ng/mL, with a mean difference of 0.3 \nng/mL (95% CI: -0.2 to 0.8; p=0.23).\nAfter 12 months of treatment, the mean OMA diameter was \n37.5±15.7 mm, with a mean difference of 8.9 mm (95% CI: 2.9 \nto 14.9; p=0.005). Similarly, the mean AMH concentration was \n2.7±1.9 ng/mL, with a mean difference of 0.9 ng/mL (95% CI: 0.1 \nto 1.7; p=0.045) at 12 months compared to baseline. However, \nthere was no significant difference in the OMA diameter or \nAMH concentration between the sixth and twelfth months of \ntreatment measurements. OMA size at baseline, six, and twelve \nmonths of dienogest treatment was presented in Figure 1.\nSerum AMH concentration at baseline, six, and twelve months \nof dienogest treatment was shown in Figure 2.\nIn the study population, at the beginning of the dienogest \ntreatment, mean ± SD VAS score was 6.3 ±3.4. There was a \nsignificant improvement in VAS scores at both the sixth and \ntwelfth months compared to baseline (1.08 ±1.8; p<0.001 and \n0.75±1.5; p<0.001, respectively). Table 2 presents the changes \nin the OMA dimensions, AMH levels and endometriosis-related \nVAS pain score at baseline, six, and 12 months.\nDiscussion\nIn the current study, there was a significant decrease in the \nlargest diameter of OMA after 12 months of treatment with 2 mg \nof dienogest daily in which the largest proportional change was \nseen over the first six months of treatment. However, serum \nAMH concentration showed a slight and insignificant decline \nat the end of 12 months when compared with initial levels. \nNotably, endometriosis-related pain symptoms decreased \nsignificantly at both six and 12 months of treatment compared \nto baseline.\nThe optimal management for preserving ovarian reserve, \nreflecting the primordial follicle pool, is unclear among \npatients with OMA cysts. In a recent systematic review and \nmeta-analysis, the authors reported that the presence of an \novarian OMA was associated with a decreased number of \nantral follicles (11). Although those findings might be attributed \nto the obstacles to clear visualization of antral follicles with US, \nKitajima et al. (11) found that the follicular density in the ovary \nwith OMA was significantly lower and the number of atretic early \nfollicles were higher when compared with the contralateral \nunaffected ovary (12). These results suggest that there might be \na genuine decrease in the number of antral follicles in women \nTable 2. Comparison of mean endometrioma diameters, AMH levels and VAS scores at baseline, six months, \nand 12 months of treatment with dienogest\nMeasurements Baseline 6 months\nPercentage \nchange in \nmean value\np at six-months\nversus \nbaseline*\n12 \nmonths\nPercentage \nchange in \nmean value\np-value 12 \nmonths versus \nbaseline*\nEndometrioma \ndiameter (mm) 46.3±17.4 38.6±14.0 16.6 0.003 37.5±15.7 19 0.005\nAMH level (ng/mL) 3.6 ± 2.4 3.3±2.7 8.3 0.23 2.7±1.9 25 0.045\nEndometriosis-related \nVAS pain score 6.3±3.4 1.08±1.8 82.8 0.001 0.75±1.5 88.1 0.001\n*Student’s t-test, values are presented as mean ± standard deviation. AMH: Anti-Mullerian hormone, VAS: Visual analog scale\nFigure 1. OMA size (mm) at baseline, six, and twelve months \nof dienogest treatment (mean ± SD)\nOMA: Endometrioma, SD: Standard deviation\nFigure 2. Serum AMH (ng/mL) concentration at baseline, \nsix, and twelve months of dienogest treatment (mean ± SD)\nAMH: Anti-Mullerian hormone, SD: Standard deviation\n\n\nKarataş et al. \nThe effect of dienogest treatment on anti-Mullerian hormone in patients with endometrioma 105\nJ Turk Ger Gynecol Assoc 2024; 25: 102-6\nwith OMA, rather than a practical issue in the visualization. In \nthe current analysis, based on a high inter-cycle variability of \nantral follicle count (13), and its inherent drawbacks, such as \noperator dependency, we preferred to follow the patients with \nAMH instead.\nIn the context of a comparison with non-endometriotic ovarian \ncysts, a systematic review and meta-analysis showed that the \npresence of an ovarian OMA was associated with a significant \ndecrease in serum AMH levels when compared with otherwise \nhealthy women (11). Furthermore, in a prospective cohort study \nby Kasapoglu et al. (13), it was noted that the serum AMH value \ndecreased at the sixth month with the expectant observation \nof the patient with OMA (n=40), which was significantly higher \nthan in an age-matched healthy control group (7.4%, n=40, \np=0.01) (14). However, an observational cross-sectional study \nincluding 267 patients showed that serum AMH levels increased \nwith OMA size in women without prior history of surgery (15). \nMore recently, a follow-up study of 332 women with OMA, \nmainly size >6 cm, and regardless of age or bilaterality had \nsignificantly elevated preoperative AMH levels were significantly \nelevated, thus confirming these earlier findings (16). As high \nAMH concentrations in women with large ovarian OMAs have \nbeen reported in two different populations of women suffering \nfrom endometriosis by different teams, such an unexpected \npattern might be explained by two hypotheses: 1) an increased \nleakage to the circulatory system due to increased local \nblood clearance boosted by an increase in ovarian blood flow \nassociated with inflammation and neoangiogenesis in the \nnearby cortical tissue (15); and/or 2) expanded production of \nAMH from dysfunctional granulosa cells because of altered \nmicro-environment because of increased expression of \ngenes in the prostaglandin and corticosteroid pathways, in \nincreased transformation of the cellular cytoskeleton, histone \nadjustments and DNA methylation at particular genes involved \nin steroidogenesis (17). \nDienogest is a fourth-generation progestogen and the only \noral, disease-specific treatment for endometriosis. Given its \nexcessive tolerability and efficacy, dienogest has become an \nessential choice for the treatment of endometriosis. Studies \nhave shown that dienogest has high specificity for progesterone \nreceptors; it exhibits antiandrogenic, antiproliferative, \nantiangiogenic and anti-inflammatory effects in endometriotic \nimplants (18,19). Although dienogest has been reported to yield \na significant reduction in OMA size/volume (20) its role on the \ndynamics of AMH is relatively less well known. According to the \nonly study published to date, a reduction of 40% in diameter \nof OMA was observed in 32 patients without any change in \nAMH concentration when compared with baseline levels (21). \nAs our study with a slightly larger sample size confirmed, the \nlack of any drop and even the presence of a plateau in AMH \nconcentration after six months, one may suggest that dienogest \nmay be useful to halt or at least slow-down the classical \ndecrease in AMH concentration in the short term.\nIn theory, the observed improvement in the expected \ndecline of AMH  concentration might be related to decreased \ninflammation and angiogenesis in nearby cortical tissue or \nrecovery of granulosa cell function due to an altered micro-\nenvironment after administration of dienogest. Further \npreclinical studies are needed to address the exact interaction \nbetween the endometriotic tissue lining the internal surface of \nOMAs and the closely associated tissues of the ovarian cortex.\nSeven out of ten women diagnosed with endometriosis \nhave abdominal pelvic pain, dysmenorrhea, or menorrhagia. \nPelvic pain significantly affects the quality of life and has \nan important place in the treatment of endometriosis (22). \nDienogest has demonstrated equal efficacy to GnRH analogues \nin the treatment of endometriosis and is efficient in alleviating \nendometriosis-related pain (23). Strowitzki et al. (23), in a \ndouble-blind placebo-controlled study, showed that dienogest \nwas significantly more effective than placebo in reducing \nendometriosis-related pelvic pain over 12 weeks in 198 \nwomen (24). In their prospective cohort study with 37 patients, \nKizilkaya et al. (25) demonstrated a 31% reduction in OMA \nsize over a three-month follow-up period among individuals \nreceiving dienogest 2 mg/day. Furthermore, there was a \nsignificant decrease in pain scores, including a 35.5% reduction \nin dysmenorrhea VAS score, a 37.5% reduction in dyspareunia \nVAS score, and a 38.5% reduction in chronic pelvic pain VAS \nscore (25).  In the current study and concordant with the \nliterature, a significant reduction in pain scores was observed \nat the sixth and twelfth months of treatment compared with \nbaseline VAS scores.\nThe lack of a control group limits the possibility of drawing firm \nconclusions about the efficacy and effectiveness of a particular \ntreatment or intervention. However, as there is earlier evidence \nof the pattern of AMH in patients without any treatment (11), \nwe believe that the results of AMH concentrations at certain \ntime-points after commencement of dienogest is still useful. \nThe second limitation might be the retrospective design of the \nstudy and its inherent drawback, but the paucity of data with \nrespect to a follow up of 12-months makes the results of the \nstudy clinically informative.\nConclusion\nIn conclusion, daily administration of 2 mg of dienogest \nresulted in a significant decrease in the diameter of OMA \nafter six months of treatment. Furthermore, there was a \nsignificant change in mean AMH concentrations after 12 \nmonths of treatment. This latter finding may be related to an \n\nKarataş et al. \nThe effect of dienogest treatment on anti-Mullerian hormone in patients with endometrioma106\n J Turk Ger Gynecol Assoc 2024; 25: 102-6\nimprovement in inflammation and angiogenesis in the nearby \nnon-endometriotic cortical tissue.\nEthics Committee Approval:  The study was approved by \nthe Hacettepe University Non-Interventional Clinical Research \nEthics Committee (approval number: 2021/09-30, date: \n20.04.2021).\nInformed Consent:  Informed consent was obtained from all \npatients participating in the study.\nAuthor Contributions:  Surgical and Medical Practices: E.K., \nS.M., G.B.; Concept: H.Y., G.B.; Design: S.M., H.Y., G.B.; Data \nCollection or Processing: E.K., B.E.T., S.M., G.B.; Analysis or \nInterpretation: E.K., S.M., G.B.; Literature Search: E.K., B.E.T., \nS.M.; Writing: E.K., B.E.T., S.M., H.Y., G.B.\nConflict of Interest:  No conflict of interest is declared by the \nauthors.\nFinancial Disclosure:  The authors declared that this study \nreceived no financial support.\nReferences\n1. 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A \nprospective study examining the effect of dienogest treatment on \nendometrioma size and symptoms. Gynecol Endocrinol 2022; 38: \n403-6.","source_license":"CC0","license_restricted":false}