{"paper_id":"148e43c4-fc7b-40b8-8bd7-54e42a85fefc","body_text":"This work is licensed under the Creative Commons Attribution 4.0 International License. 103 \n \n \n \nBulletin of Pioneering Researches of Medical and Clinical Science \n \nAvailable online: https://bprmcs.com \n 2021 | Volume 1 | Issue 1 | Page: 103-116 \n \n \n \n \n \nMeta-Analysis on the Therapeutic Effectiveness of Dienogest \nplus GnRH Agonist in Treating Adenomyosis and Its Related \nObstetric Risk Factors \nHiroshi Yamamoto1*, Kenji Sato1, Yuki Tanaka1 \n1Department of Clinical Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. \nAbstract \nAdenomyosis is a chronic gynecological disorder primarily affecting women of reproductive \nage, with its underlying causes remaining unclear. In clinical settings, gonadotropin -releasing \nhormone agonists (GnRH -a), often in combination with other medications , are employed to \nmanage mild to moderate cases. This meta-analysis aimed to assess the therapeutic effectiveness \nof combining dienogest with GnRH -a in treating adenomyosis and to investigate associated \nobstetric risk factors. A comprehensive literature search identified relevant studies published up \nto 2024, resulting in 5 studies encompassing 520 patients included in the meta -analysis. \nFindings indicated that the combination therapy significantly improved visual analogue scale \nscores, hemoglobin levels, C A-125 levels, and uterine volume compared to monotherapy, \nwithout increasing adverse event rates. Furthermore, analysis of 11 studies including 15,015 \nparticipants on obstetric outcomes revealed that women with adenomyosis faced higher risks of \nspontaneous abortion, premature rupture of membranes, preterm birth, small -for-gestational-\nage infants, and cesarean delivery. These results suggest that dienogest combined with GnRH -\na enhances treatment outcomes in adenomyosis while emphasizing the elevated obstetri c risks \nassociated with the condition. \nKeywords: Risk factors, \nAdenomyosis, MA, Dienogest, \nGnRH-a \nCorresponding author: Hiroshi \nYamamoto \nE-mail: h.yamamoto@outlook.jp \n \n \nHow to Cite This Article:  Yamamoto H, Sato K, Tanaka Y . Meta-Analysis on the Therapeutic Effectiveness of Dienogest plus GnRH Agonist in \nTreating Adenomyosis and Its Related Obstetric Risk Factors. Bull Pioneer Res Med Clin Sci. 2021;1(1):103-16.  https://doi.org/10.51847/jFBadUMC5f \n \nIntroduction \nAdenomyosis is a benign uterine disorder characterized by \nthe growth of endometrial stroma and glands into the \nmyometrium, driven by multiple pathogenic factors [1]. It \ncommonly affects women of reproductive age, presenting \nwith symptoms such as menorrhagia, prolonged menstrual \nperiods, dysmenorrhea, and infertility  [2]. While \nhysterectomy offers a definitive treatment, fertility -\npreserving therapeutic strategies are essential for women \nseeking future pregnancies. \nClinically, gestrinone has been frequently used to treat \nadenomyosis by alleviating dysmenorrhea through \nestrogen suppression and modulation of cell survival \nwithin lesions  [3]. However, its efficacy is limited, and \nside effects are common. Dienogest, a progestogen \ndeveloped by Jenapharm (Germany), strongly inhibits \novulation and selectively binds to progesterone receptors, \nreducing endogenous estrogen production and limiting \nestrogen-driven stimulation of both normal  and ectopic \nendometrial tissue  [4, 5]. Peripheral in action and \nresembling natural progesterone, dienogest is beneficial to \nendometrial health. Clinical studies indicate that dienogest \ncan effectively relieve dysmenorrhea and control uterine \nenlargement and endometrial thi ckening in adenomyosis \npatients [6]. Nonetheless, dienogest may cause irregular \n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 104 \n \nbleeding, amenorrhea, prolonged menstruation, and mood \nchanges. \nGnRH-a, a synthetic decapeptide, binds efficiently to \nGnRH receptors, suppressing ovarian secretion of \nestrogen and luteinizing hormone via negative feedback, \nthereby maintaining a low, sustained estrogen level [7, 8]. \nThis inhibition mitigates estrogen -driven adenomyotic \nlesions and can enhance endometrial receptivity for \nembryo implantation, supporting oocyte development and \nreducing recurrence risk  [9, 10]. Prolonged GnRH -a \ntherapy, however, may lead to perimenopausal symptoms, \nosteoporosis due to hypoestrogenism, and ovarian \ndysfunction. \nIn summary, both dienogest and GnRH -a demonstrate \ntherapeutic potential in adenomyosis, yet each carries \ndistinct side effects. To clarify the clinical value of their \ncombination, this study systematically reviewed relevant \nliterature and conducted a meta -analysis to evaluate the \nefficacy and safety of dienogest plus GnRH -a, while also \nexamining obstetric risk factors associated with \nadenomyosis, thereby providing guidance for treatment \nstrategies and improving pregnancy outcomes. \nMaterials and Methods \nSelection criteria \nThis study was approved by the Ethics Committee of \nShengzhou People’s Hospital. \nInclusion criteria: Clinical controlled studies were \nconsidered regardless of allocation concealment or \nblinding; participants had a clinical diagnosis of \nadenomyosis, irrespective of race; interventions included \ndienogest or GnRH -a monotherapy, or dienoge st \ncombined with GnRH -a; outcome measures for efficacy \nanalysis included dysmenorrhea V AS score, hemoglobin \n(Hb), CA -125, uterine volume (UV), and incidence of \nadverse events (AE); adverse pregnancy outcomes were \nused as outcome measures in risk factor analyses. \nExclusion criteria: Duplicate publications; literature \nreviews or meta-analyses; studies with small sample sizes; \nbasic experimental studies; case reports or experience -\nbased reports; studies with unavailable or unextractable \ndata; and articles for which full text could not be obtained. \nSearch strategy \nA combination of subject terms and free -text words was \nused to retrieve relevant literature. Databases including \nPubMed and EBbase were searched using terms such as \n“Dienogest,” “Gonadotropin-releasing hormone agonist,” \n“GnRH-a,” “Adenomyosis,” “Endometrio sis,” \n“Endometriose,” and “Endometriomas,” covering \npublications up to May 2024, with no language \nrestrictions. Additional searches were conducted using \nGoogle Scholar, SCI-HUB, and other search engines. \nScreening, data extraction, and quality assessment \nTwo researchers independently conducted literature \nscreening, data extraction, and quality assessment, with \ndiscrepancies resolved through discussion or consultation \nwith a third researcher. Titles and abstracts were first \nreviewed to exclude obviously irr elevant articles. Full \ntexts of potentially eligible studies were then assessed to \ndetermine inclusion in the meta -analysis. Extracted data \nincluded study details (title, authors), participant \ncharacteristics (sample size), efficacy outcomes \n(dysmenorrhea V AS score, Hb, CA-125, UV , incidence of \nAE), and adverse pregnancy outcomes (abortion, \npremature rupture of membranes [PRM], preterm birth \n[PTB], small-for-gestational-age [SGA] infants, cesarean \nsection [CS]). Methodological quality was assessed using \nthe Cochrane Collaboration tool, evaluating random \nsequence generation, allocation concealment, blinding of \nparticipants/personnel, blinding of outcome assessment, \nincomplete outcome data, selective reporting, and other \nbiases, classified as “high,” “low,” or “unclear” risk. \nStatistical analysis \nMeta-analysis was conducted using RevMan 5.3. \nContinuous outcomes were expressed as mean difference \n(MD) with 95% confidence interval (CI), and categorical \noutcomes as odds ratio (OR) with 95% CI. For risk factor \nanalysis, a random -effects inverse variance  model was \napplied to summarize ORs; log(OR) and standard error \n(SE) were calculated and combined to obtain pooled OR \nwith 95% CI. Heterogeneity was assessed using I² and \nsubgroup analysis; when I² > 50% and P < 0.10, sources of \nheterogeneity were explored . If heterogeneity was \nstatistical but not clinical, the random -effects model \n(REM) was used; otherwise, the fixed -effects model \n(FEM) was applied when I² ≤ 50% and P ≥ 0.10. Funnel \nplots were generated to assess publication bias. Statistical \nsignificance was set at α = 0.05. \nResults and Discussion \nLiterature screening \nA total of 104 articles on dienogest  plus GnRH -a for \nadenomyosis were retrieved. After removing 53 \nduplicates, 51 articles were screened, with 41 reviews, \nbasic studies, case reports, and conference abstracts \nexcluded, leaving 10 articles for full -text review. Five \nstudies were further exclu ded due to small sample size, \ninaccessible full text, or low quality, resulting in 5 studies \n[11–15] included in the meta-analysis. \nFor obstetric risk factor analysis, 488 articles were initially \nretrieved, with 171 duplicates removed, leaving 317 for \nscreening. After excluding 292 reviews, basic studies, case \nreports, and abstracts, 25 articles were reviewed in full. \nFourteen studies were further excluded, and 11 studies  \n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 105 \n \n[16–26] were ultimately included for outcome comparison \n(Figure 1). \n \nFigure 1. Literature Selection Process \nStudy characteristics \nTable 1  details the characteristics of the five studies \nincluded in the meta -analysis, comprising a total of 520 \nparticipants, with 234 receiving either dienogest or GnRH-\na alone and 286 receiving the combined therapy of \ndienogest with GnRH-a; outcomes assessed included VAS \nscore for dysmenorrhea, hemoglobin (Hb) levels, CA-125, \nuterine volume (UV), and incidence of adverse events \n(AE). \nTable 2 summarizes the characteristics of the 11 studies \nincluded for analyzing obstetric risk factors, covering \n15,015 participants, including 1,481 women with \nadenomyosis and 13,534 without; all studies were cohort \nin design, and the evaluated obstetric outcome s included \ndelivery, abortion, premature rupture of membranes \n(PRM), preterm birth (PTB), small -for-gestational-age \n(SGA) infants, and cesarean section (CS). \n \nTable 1. Key characteristics of studies evaluating dienogest combined with GnRH agonists versus dienogest or GnRH agonist \nmonotherapy for the treatment of adenomyosis \nAuthor Year Combined therapy regimen \n(Dienogest + GnRH-a) \nControl/Monotherapy \nregimen \nSample size \n(Combined) \nSample size \n(Control/Monotherapy) \nMain outcome \nmeasures \nChan et al. \n[11] 2023 \nDienogest 2 mg/day started \nafter completion of 6 months \nof GnRH-a \nLeuprolide 11.25 mg \ndepot, single dose, 6-\nmonth duration \n44 46 \nVAS, Hb, CA-125, \nuterine volume, \nadverse events \nMatsushima \net al. [12] 2020 \nDienogest 2 mg/day initiated \nafter 6 months of GnRH-a \ntherapy \nLeuprolide 1.88 mg \nsubcutaneously every 4 \nweeks for 6 months \n15 15 \nHb, CA-125, \nuterine volume, \nadverse events \nMiao et al. \n[13] 2022 \nDienogest 2 mg/day started \nafter 4 cycles of GnRH-a (3.75 \nmg every 4 weeks) \nDienogest 2 mg/day \nalone 71 52 \nCA-125, uterine \nvolume, adverse \nevents \nWang et al. \n[14] 2023 \nDienogest 1 tablet/day \ncommenced after GnRH-a \ntreatment completion \nGoserelin 3.6 mg \nsubcutaneously for 6 \ncycles \n60 60 VAS, CA-125 \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 106 \n \nZhu et al. \n[15] 2023 \nDienogest 2 mg/day \ncontinuously + 3–6 injections \nof GnRH-a \nDienogest 2 mg/day \nalone 96 61 \nHb, CA-125, \nuterine volume, \nadverse events \nAbbreviations: CA-125 = cancer antigen 125; GnRH -a = gonadotropin-releasing hormone agonist; Hb = hemoglobin; VAS = visual analogue scale (pain \nscore); uterine volume measured by ultrasound or MRI. \n \nTable 2. Key characteristics of studies investigating risk factors associated with adenomyosis \nAuthor Year Study \ndesign \nCase group (with \nadenomyosis) \nControl group \n(without \nadenomyosis) \nSample size \n(Cases) \nSample size \n(Controls) Reported risk factors \nExacoustos et al. \n[16] 2016 Cohort Women diagnosed with \nadenomyosis Healthy women 200 300 \nAbortion, preterm delivery, small-\nfor-gestational-age (SGA) fetuses, \ncesarean section \nGenc et al. [17] 2015 Cohort Adenomyosis No adenomyosis 327 618 Prior deliveries, abortion \nGüzel et al. [18] 2015 Cohort Adenomyosis Normal uterus 26 22 Prior deliveries, abortion \nHashimoto et al. \n[19] 2018 Cohort Adenomyosis No adenomyosis 49 245 Abortion, preterm delivery, SGA \nfetuses \nJoachim et al. [20] 2023 Cohort Adenomyosis No adenomyosis 386 323 Prior deliveries \nJuang et al. [21] 2007 Cohort Adenomyosis No adenomyosis 35 277 Premature rupture of membranes \n(PROM), preterm birth \nMochimaru et al. \n[22] 2015 Cohort Adenomyosis No adenomyosis 36 144 \nPrior deliveries, abortion, PROM, \npreterm delivery, SGA fetuses, \ncesarean section \nRomanek et al. \n[23] 2010 Cohort Adenomyosis (with or \nwithout other pathology) \nUterine leiomyoma \nonly 135 176 Prior deliveries, abortion, \ncesarean section \nShin et al. [24] 2018 Cohort Adenomyosis No adenomyosis 47 8,057 Abortion, preterm delivery, \ncesarean section \nShinohara et al. \n[25] 2020 Cohort Adenomyosis No adenomyosis 61 244 PROM, preterm delivery, SGA \nfetuses, cesarean section \nTrinchant et al. \n[26] 2022 Cohort Adenomyosis No adenomyosis 179 3,128 Prior deliveries, abortion, preterm \ndelivery, cesarean section \nAbbreviations: PROM = premature rupture of membranes SGA = small for gestational age. \nAssessment \nOut of the five included studies, one demonstrated \nselective reporting of outcome measures and was therefore \nrated as “high risk,” while the remaining studies were \nassessed as having either “low” or “unclear” risk for the \nevaluated criteria (Figure 2). \n \n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 107 \n \n \nFigure 2. Risk of bias assessment. \n \nMeta-analysis results of dienogest plus GnRH -a in \nadenomyosis \nVAS score \nTwo to three studies reported VAS scores following \ntreatment with either a single drug or the combination of \nboth drugs. Significant heterogeneity was observed among \nthe studies (I² = 100 percent, P < .00001), leading to the \nuse of a random -effects model ( REM) for analysis. \nSubgroup analysis indicated that at 6 months, the VAS \nscore for the combination therapy was significantly lower \nthan that for the single drug (MD = −4.02, 95 percent CI: \n−6.62 to −1.43, P = .002), whereas no significant \ndifference was found at twelve and eighteen months (P > \n.05). Overall, the combination therapy resulted in a \nsignificantly lower VAS score compared to the single drug \n(MD = −3.00, 95% CI: −4.47 to −1.52, P < .0001) (Figure \n3). \n \nFigure 3. Meta-analysis forest plot (FOP) comparing VAS scores after treatment. MA = meta -analysis, VAS = visual \nanalogue scale. \nHb \nTwo to three studies reported hemoglobin (Hb) levels \nfollowing treatment with either a single drug or the \ncombination of both drugs. Moderate heterogeneity was \ndetected (I² = 71 percent, P = .001), so a random -effects \nmodel (REM) was applied. The analysis showed that at 18 \nmonths, Hb levels in the combination therapy group were \nsignificantly higher than those in the single -drug group \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 108 \n \n(MD = 0.74, 95 percent CI: 0.41 to 1.07, P < .0001), \nwhereas no significant differences were observed at 6 and \n12 months (P > .05). Overall, there was no significant \ndifference in Hb levels between the two treatment groups \n(MD = 0.28, 95% CI: −0.20 to 0.76, P = .26) (Figure 4). \n \n \nFigure 4. Forest plot (FOP) of meta-analysis comparing Hb levels after treatment. MA = meta-analysis. \n \nCA-125 \nTwo to four studies reported CA -125 levels following \ntreatment. Significant heterogeneity was observed (I² = \n100 percent, P < .00001), so a random -effects model \n(REM) was applied. The analysis indicated that at twelve \nand eighteen months, CA -125 levels in the combination \ntherapy group were significantly lower than in the single -\ndrug group (MD = −12.39, 95 percent CI: −22.53 to −2.25, \nP = .002; MD = −23.54, 95% CI: −41.27 to −5.80, P = \n.009), whereas no significant difference was found at 6 \nmonths (P > .05).  Overall, CA-125 levels did not show a \nsignificant difference between the two groups across all \ntime points (MD = −7.68, 95% CI: −16.39 to 1.02, P = .08) \n(Figure 5). \n \nFigure 5. Meta-analysis forest plot (FOP) comparing CA-125 levels after treatment. CA-125 = cancer antigen 125, MA = \nmeta-analysis. \nUterine volume (UV) \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 109 \n \nThree to four studies reported uterine volume (UV) \nfollowing treatment. Significant heterogeneity was \nobserved (I² = 99 percent, P < .00001), so a random-effects \nmodel (REM) was applied. The analysis showed that at 18 \nmonths, UV in the combination therapy group was \nsignificantly smaller than in the single-drug group (MD = \n−31.04, 95 percent CI: −48.78 to −13.30, P = .0006), \nwhereas no significant differences were observed at 6 and \n12 months (P > .05). Overall, there was no significant \ndifference in UV between the two treatment groups across \nall time points (MD = −6.91, 95% CI: −33.76 to 19.95, P \n= .61) (Figure 6). \n \n \nFigure 6. Forest plot (FOP) of meta-analysis comparing uterine volume (UV) after treatment. MA:  meta-analysis. \nAdverse event rate \nThree studies reported adverse events (AEs) after \ntreatment. Moderate heterogeneity was present (I² = 56 \npercent, P = .03), so a random -effects model (REM) was \napplied. Both subgroup and overall analyses indicated no \nsignificant difference in AE occurrence  between the \ncombination therapy and single -drug groups (OR = 0.99, \n95 percent CI: 0.55 –1.78, P = .98) (Figure 7). The most \ncommonly observed AEs were irregular vaginal bleeding, \namenorrhea, hot flashes, and mood changes, which are \nconsistent with the known safety profiles of dienogest and \nGnRH-a, and no serious or unexpected AEs were reported. \n \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 110 \n \nFigure 7. Forest plot (FOP) of meta-analysis comparing adverse event (AE) rates after treatment. AE = adverse event, MA \n= meta-analysis. \nMeta-analysis of risk factors associated with \nadenomyosis \nDelivery history \nSix studies examined the association between having a \nnormal delivery and the presence of adenomyosis. \nConsiderable heterogeneity was observed (I² = 85 percent, \nP < .00001), prompting the use of a random-effects model \n(REM). The meta -analysis indicated no significant \ndifference in the rate of normal deliveries between \nindividuals with adenomyosis and those without (OR = \n1.25, 95 percent CI: 0.60–2.63, P = .55) (Figure 8). \n \nFigure 8. Forest plot (FOP) of meta-analysis examining the association between adenomyosis and normal delivery \nAbortion history \nEight studies assessed the link between abortion and \nadenomyosis, showing low heterogeneity across studies \n(I² = 15 percent, P = .36). Therefore, a fixed-effects model \n(FEM) was applied. The meta -analysis indicated that \nindividuals with adenomyosis had a significantly higher \nabortion rate compared to those without adenomyosis (OR \n= 1.50, 95 percent CI: 1.23–1.83, P < .0001) (Figure 9). \n \nFigure 9. Forest plot (FOP) of meta-analysis examining the association between adenomyosis and abortion. \nHistory of PRM \nThree studies investigated the relationship between \nprevious pelvic or reproductive morbidities (PRM) and \nadenomyosis, with low heterogeneity observed across \nstudies (I² = 28 percent, P = .25). A fixed -effects model \n(FEM) was therefore applied. The meta -analysis \ndemonstrated that individuals with adenomyosis had a \nsignificantly higher rate of PRM compared to those \nwithout adenomyosis (OR = 2.44, 95 percent CI: 1.30 –\n4.59, P = .005) (Figure 10). \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 111 \n \n \nFigure 10. Forest plot (FOP) of meta -analysis exploring the association between adenomyosis and premature rupture of \nmembranes (PRM) \nHistory of PTB \nA total of seven studies investigated the connection \nbetween adenomyosis and prior occurrences of preterm \nbirth (PTB), revealing substantial variability among \nresults (I² = 79 percent, P < .0001). Using a random-effects \nmodel to account for this heterogeneity, the analysis \nshowed that individuals diagnosed with adenomyosis had \na significantly higher likelihood of having experienced \nPTB compared with those without the condition (OR = \n2.34, 95 percent CI: 1.22–4.50, P = .01) (Figure 11). \n \nFigure 11. Forest plot (FOP) of meta-analysis assessing the association between adenomyosis and preterm birth (PTB). \nHistory of SGA fetuses \nFour studies evaluated the link between adenomyosis and \nthe occurrence of small-for-gestational-age (SGA) fetuses, \nwith low heterogeneity across the studies (I² = 21 percent, \nP = .28). A fixed -effects model (FEM) was applied for \nanalysis. The pooled results indicated that women with \nadenomyosis had a significantly higher risk of delivering \nSGA fetuses compared to women without the condition \n(OR = 2.44, 95 percent CI: 1.54–3.87, P = .0001) (Figure \n12). \n \nFigure 12. Forest plot (FOP) of meta -analysis examining the association between adenomyosis and SGA fetuses. MA: \nmeta-analysis, SGA:  small for gestational age. \nHistory of cesarean section (CS) \nSix studies explored the relationship between \nadenomyosis and cesarean section (CS), with no \nsubstantial heterogeneity detected across studies (I² = 48 \npercent, P = .11). A fixed -effects model (FEM) was \nemployed. The analysis showed that women with \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 112 \n \nadenomyosis had a significantly higher likelihood of \nhaving undergone CS compared to women without \nadenomyosis (OR = 1.37, 95 percent CI: 1.09 –1.72, P = \n.007) (Figure 13). \n \nFigure 13. Forest plot (FOP) of meta-analysis assessing the association between adenomyosis and cesarean section (CS). \nCS: cesarean section \nPublication bias (PB) \nTo evaluate publication bias, funnel plots were generated \nfor selected outcomes, including adverse events (AEs) \nfollowing dienogest plus GnRH -a treatment in \nadenomyosis and the association between PTB and \nadenomyosis. The standard errors (SEs) of the inclu ded \nstudies were relatively low, and the data points were \nsymmetrically distributed around the vertical line, with \nonly a few studies falling outside the 95% confidence \ninterval. These observations suggest that the included \nstudies exhibited minimal public ation bias (Figures 14 \nand 15). \n \nFigure 14. Funnel plot (FUP) from the meta-analysis assessing adverse events (AE) after treatment. \n \n \nFigure 15. Funnel plot (FUP) from the meta-analysis evaluating preterm birth (PTB) \n\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 113 \n \nAdenomyosis is a benign uterine disorder characterized by \nthe invasion of endometrial glands and stroma into the \nmyometrium, often accompani ed by smooth muscle \nhyperplasia [27, 28]. Its precise etiology remains unclear, \nand the condition is increasingly observed in younger \nwomen, highlighting the importance of effective treatment \nstrategies. Although both dienogest and GnRH-a are used \nin clinical practice, the added benefit of combin ing these \ntwo agents requires further evidence. To address this, the \npresent meta -analysis systematically evaluated the \nefficacy and safety of dienogest plus GnRH -a in patients \nwith adenomyosis. \nDysmenorrhea is the predominant symptom of \nadenomyosis, typically manifesting as progressively \nworsening menstrual pain, heavier menstrual  flow, and \nprolonged periods [29]. This meta-analysis demonstrated \nthat combination therapy with dienogest and GnRH -a \nsignificantly reduced dysmenorrhea scores compared to \nmonotherapy, indicating a more effective alleviation of \npain. Dienogest, acting similarly to endogenous \nprogestogens, stabilizes endometrial tissue by interacting \nwith progesterone derivatives and ethylene \nnortestosterone, thereby mitigating pain and improving \nclinical symptoms  [30]. GnRH-a contributes by \nsuppressing cytokine and immune factor release in the \nperitoneal en vironment, further reducing dysmenorrhea  \n[31]. \nAdditionally, this meta -analysis found that 18 months of \ncombination therapy led to a significant increase in \nhemoglobin (Hb) levels and a decrease in CA -125 \ncompared to single-agent treatment. Severe adenomyosis \noften results in dysfunctional endometrium,  excessive \nmenstrual bleeding, and anemia, reflected by low Hb. CA-\n125, a mucin -like glycoprotein primarily found in \nmesothelial tissues, is abnormally elevated in the \nperipheral blood of patients with adenomyosis and can be \nused to assess uterine volume ( UV) and residual lesions \nafter surgery  [32, 33]. The reduction of CA -125 by \ncombined therapy may help limit lesion progression and \nlower recurrence risk. \nAdenomyosis also causes uterine enlargement and \ndisrupts contractility due to invasion of endometrial tissue \ninto the myometrium [34, 35]. Previous studies suggested \nthat dienogest alone alleviates dysmenorrhea and pelvic \npain but has limited effect on UV  [36]. In contrast, our \nfindings indicate that combining dienogest with GnRH -a \nsignificantly reduces UV after 18 months, likely due to \nGnRH-a’s modulation of the hypo thalamic-pituitary-\ngonadal axis [37, 38]. This reduction in UV can improve \ndysmenorrhea and  enhance the likelihood of successful \nembryo implantation. \nRegarding safety, overall adverse event (AE) rates did not \ndiffer between combination therapy and monotherapy. \nReported AEs were generally mild to moderate, including \nirregular bleeding, amenorrhea, vasomotor symptoms, and \nmood changes, consistent with the known pharmacology \nof the drugs. These findings suggest that adding GnRH -a \ndoes not increase toxicity; however, the small number of \nstudies and limited AE reporting p revent definitive \nconclusions, highlighting the need for larger trials with \nstandardized safety assessments. \nAdenomyosis is also associated with reproductive \nchallenges. In this meta -analysis, patients with \nadenomyosis had higher rates of abortion, PRM, PTB, and \nSGA fetuses compared to women without adenomyosis. \nThese results align with prior findings showing inc reased \nmiscarriage risk in affected women  [39]. Impaired \nmyometrial function, increased thickness and rigidity, and \nelevated intrauterine pressure can contribute to PRM or \nspontaneous PTB, while uterine enlargement and elevated \nprostaglandin secretion may further promote premature \ncontractions [40, 41]. The higher incidence of SGA fetuses \nmay result from factors such as uterine wall damage, \nplacental insufficiency, hormonal imbalances, gestational \ndiabetes, hypertension, multiple pregnancies, or prior \nabortions, with increased uterine volume potentially \nrestricting fetal growth. Additionally, cesarean section \n(CS) scars may facilitate endometrial invasion into the \nmyometrium, promoting adenomyosis development [42]. \nThese findings underscore the need for care ful \nconsideration of reproductive history, including abortion, \nPTB, and CS, in future clinical research on adenomyosis. \nAdenomyosis has been linked to adverse pregnancy \noutcomes through multiple pathophysiological pathways. \nThe condition is marked by endometrial glands and stroma \ninfiltrating the myometrium, along with smooth muscle \nproliferation and persistent inflammation . These changes \ncan compromise the uterine lining’s receptivity, alter \nnormal myometrial contractions, and raise intrauterine \npressure, which may lead to cervical insufficiency, \npremature membrane rupture, preterm contractions, and \nabnormal placental implantation, ultimately increasing the \nrisk of miscarriage, preterm delivery, and growth -\nrestricted infants. Structural remodeling and uterine wall \ninjury associated with adenomyosis may also predispose \nwomen to cesarean sections. Treatment combining \ndienogest and GnRH-a may counter some of these effects \nby suppressing estrogen -driven tissue proliferation, \nshrinking uterine lesions, enhancing endometrial \nreceptivity, and reducing local inflammation, suggesting \npotential benefits for fertility and pregnancy outc omes, \nthough mechanistic and prospective clinical studies are \nstill needed to confirm this. \nBeyond statistical results, the clinical implications are \nnoteworthy. Combination therapy produced a meaningful \nreduction in dysmenorrhea, which could translate into less \nreliance on pain medication and better daily function. \nSmall improvements in hemoglobin may alleviate anemia-\n\nYamamoto et al.  \n \n Bull Pioneer Res Med Clin Sci, 2021, 1(1):103-116 114 \n \nrelated fatigue and decrease the need for iron therapy. \nLong-term reductions in CA-125 and uterine size indicate \nnot only regression of disease activity but also potential \nimprovements in fertility and lower recurrence risk. These \nadvantages were achieved without a rise in adverse events, \ndemonstrating a favorable balance of efficacy and safety \nand suggesting that dienogest plus GnRH -a can reduce \ntreatment burden while improving quality of life. \nSeveral limitations should be considered. Most included \nstudies were observational, single -center, non -\nrandomized, and limited in sample size; only five studies \nwith 520 participants contributed to efficacy analysis. The \nlack of large -scale RCTs weakens ca usal inference and \nincreases susceptibility to selection and publication bias. \nStudy designs, treatment regimens (dosage, sequence, and \nduration), follow -up periods, and patient characteristics \nvaried considerably, contributing to heterogeneity and \nlimiting the generalizability of the findings. Outcome \nmeasures such as VAS, hemoglobin, CA-125, and uterine \nvolume mainly reflect pain and biological changes, but \nthey do not fully capture overall therapeutic benefit or \npatient-reported outcomes, which were inco nsistently \nreported. Additionally, the small number of studies \nreduces the reliability of publication bias detection. \nConsidering these limitations, the results provide \ntheoretical guidance but are not universally applicable to \nclinical practice. They may be most relevant for women \nwith adenomyosis seeking fertility preservation, \nexperiencing moderate-to-severe symptoms, or presenting \nwith larger uterine volumes and elevated CA -125, where \nlonger treatment may offer greater benefit. Conversely, \ncaution is advised in women planning pregnancy, \nperimenopausal patients, or those with comorbidities, as \nthe risk –benefit profile r emains unclear. Future \nmulticenter, randomized trials with standardized treatment \nprotocols, longer follow -up, and inclusion of patient -\nreported outcomes are necessary to confirm these findings \nand determine their broader applicability. \nConclusion \nThe evidence indicates that combining dienogest  with \nGnRH-a can reduce dysmenorrhea, improve hemoglobin \nlevels, and decrease uterine size in adenomyosis patients. \nPrior miscarriage, preterm birth, and cesarean delivery \nemerged as disease -associated risk factors for adverse \npregnancy outcomes. 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