{"paper_id":"5fd1a340-15c3-4608-845d-ed93a734fed4","body_text":"Bahoorzahi et al. \nMiddle East Fertility Society Journal           (2024) 29:55  \nhttps://doi.org/10.1186/s43043-024-00213-6\nRESEARCH Open Access\n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nMiddle East Fertility\nSociety Journal\nThe effects of vaginal bromocriptine \nand dienogest on women with adenomyosis: \na clinical study\nParvane Bahoorzahi1, Soheila Aminimoghaddam1, Roya Derakhshan2,3, Neda Hashemi2 and \nSamaneh Rokhgireh1,2* \nAbstract \nObjective Adenomyosis occurs when endometrial glands and stroma develop in the myometrium, leading to symp-\ntoms such as pelvic pain and heavy menstrual bleeding.\nMethod This randomized, double-blinded, controlled trial study was conducted on patients with adenomyosis \nreferred to the Rasul-e-Akram Hospital. Group A received vaginal bromocriptine, and group B received dienogest. \nTransvaginal ultrasonography (TVS), visual analog scale (VAS), and pictorial blood loss assessment chart (PBLAC) evalu-\nation were performed at the beginning and after 3, 6, and 9 months of the study.\nResult The mean blood visual chart 3 and 6 months after intervention in the bromocriptine group was significantly \nlower than the dienogest group (P < 0.001). The mean intensity of menstrual pain 3 months after intervention was sig-\nnificantly lower in the dienogest group compared to the bromocriptine group (P < 0.001). There was a significant \nimprovement in TVS appearance in both groups at the 6-month follow-up.\nConclusion Dienogest and bromocriptine both effectively reduced pain intensity, menstrual bleeding, and sono-\ngraphic characteristics in patients with adenomyosis.\nKeywords Adenomyosis, Dienogest, Bromocriptine, Menstrual bleeding, Pain\nIntroduction\nAdenomyosis is a benign gynecologic disease in which \nstroma and endometrial glands are found in the myo -\nmetrium. Symptoms in women with adenomyosis are \nheavy menstrual bleeding and pelvic pain [3, 7]. The \nprecise etiology of this disease is obscure, but two pri -\nmary hypotheses have been considered, invagination of \nthe endometrial basalis due to the activation of the tis -\nsue injury and repair (TIAR) and metaplasia of displaced \nembryonic multipotent Mullerian remnants or differen -\ntiation of adult stem cells [6]. Diagnosis of adenomyo -\nsis is based on surgery and histopathology, but recently, \ndiagnosis and treatment can be achieved through diag -\nnostic methods such as TVS and magnetic resonance \nimaging (MRI) [2–4, 6, 7, 17, 18]. Prolactin (PRL), being a \nmitogen of uterine muscle cells, is considered a risk fac -\ntor for adenomyosis [2]. Bromocriptine, an ergot alkaloid \nthat suppresses pituitary prolactin synthesis [19], can \nalleviate adenomyosis symptoms. Vaginal bromocrip -\ntine can be as effective as the oral form without gastro -\nintestinal and other side effects [5], and reduces pain and \nsevere menstrual bleeding in women with adenomyosis \n[3]. Bromocriptine might have antiproliferative activity \n*Correspondence:\nSamaneh Rokhgireh\ns.rokhgireh@gmail.com\n1 Department of Obstetrics and Gynecology, School of Medicine, Iran \nUniversity of Medical Sciences, Tehran, Iran\n2 Endometriosis Research Center, Iran University of Medical Sciences, \nTehran, Iran\n3 Department of Artificial Intelligence, Smart University of Medical \nSciences, Tehran, Iran\n\nPage 2 of 8Bahoorzahi et al. Middle East Fertility Society Journal           (2024) 29:55 \nby inhibiting gene expression due to activating several \nmiRNA expressions [10].\nDienogest is a highly selective progesterone with anti -\nproliferative effects, and there is evidence that it is highly \neffective in alleviating adenomyosis pain. However, it can \ncause menorrhagia, and in rare cases of menometrorrha -\ngia, it may cause severe anemia in patients with adeno -\nmyosis, necessitating drug discontinuation [16].\nGiven the significance of adenomyosis in women’s \nhealth and the limited research comparing the effects \nof bromocriptine and vaginal dienogest, this study was \ndesigned and conducted. The main focus of the study \nwas to compare the therapeutic efficacy of vaginal bro -\nmocriptine and dienogest in reducing menstrual bleeding \nand pain associated with adenomyosis and to describe \nrelated TVS characteristics in patients referred to Rasul-\ne-Akram Hospital.\nMaterials and methods\nThis randomized, double-blinded, controlled trial study \nwas performed on 60 women with adenomyosis referred \nto Rasul-e-Akram Hospital of Iran University of Medical \nSciences from 2021 to 2023. The study was explained to \nthe participants, and informed consent was obtained by \na gynecology resident, indicating their voluntary agree -\nment to participate. The regional Ethics Committee of the \nIran University of Medical Sciences approved the study \nwith the Ethical Code IR.IUMS.FMD.REC.1400.361 and \nIRCT20230407057838N1. The patients’ personal infor -\nmation remained confidential and was identified with a \ncode; only the gynecologist had the patients’ informa -\ntion. In case of side effects in the patients after taking \ndienogest or vaginal bromocriptine, the intervention \nwas stopped, and alternative treatments were initiated. \nThe expected sample size (n = (Z1 − α/2 + Z1 − β)2 / \n(δ12 − δ22) / (µ1 − µ2)) was 60 women. Considering the \nprobability of a 10% sample loss, the sample size was cal -\nculated as 30 people in each group. Both groups were \nequivalent in terms of demographic characteristics and \nclinical attributes.\nThe patients were divided into two groups: group A \nreceived vaginal bromocriptine, and group B received \ndienogest. The allocation to each group was done based \non computer-generated admission numbers. For blind -\ning, the drugs (vaginal bromocriptine and dienogest) \nwere packed in separate but similar packages with A and \nB labels attached to them. Gynecology resident who filled \nout the questionnaires and analyst were blinded (Fig. 1).\nInclusion criteria included premenopausal women aged \nbetween 35 and 50 years who exhibited symptoms of \nadenomyosis (menorrhagia with or without pelvic pain), \nconfirmed by a PBAC score (pictorial blood loss assess -\nment score) of > 100 and transvaginal ultrasound (TVS); \nthey needed to have regular menstrual cycle, normal \nserum prolactin (PRL) levels, and used non-hormonal \ncontraceptive methods.\nThe exclusion criteria included the following: women \nwho were less than 6 months postpartum, currently \nbreastfeeding, had a uterus larger than 20 cm, had con -\ntraindications for bromocriptine or ergot alkaloids, were \ncurrently being treated with gonadotropin-releasing \nhormone agonists or antagonists, or were using contra -\nceptive steroids, intrauterine contraceptive devices, anti -\ndepressants, or opioid pain relievers. Women were also \nexcluded if they had MRI or transvaginal ultrasound \n(TVS) findings indicating endometriosis or fibroids \n(myomas), a medical history of prolactinoma, a high-\ngrade squamous intraepithelial lesion on a Pap test, or \nwere suspected of or diagnosed with malignant diseases \nof the uterus, ovary, or cervix.\nAt the beginning of the study, a transvaginal ultrasound \n(TVS) was performed, and adenomyosis was diagnosed \nbased on the Morphological Uterus Sonographic Assess -\nment (MUSA) features [8].\nThe checklist contained questions about the demo -\ngraphic variables including age and marriage. The VAS \nscore questionnaire was used to assess pain, and the pic -\ntorial blood loss assessment (PBAC) score questionnaire \nwas used to evaluate the amount of menstrual bleeding. \nPBAC is a subjective assessment of the amount of blood \nloss in menstruation. This method records the number of \npads and tampons used and the amount of blood on each \npad or tampon; a score of more than 100 indicates the \nvolume of menstrual bleeding is more than 80 cc. PBAC \nsensitivity and specificity are 86% and 88%, respectively \n[9, 11, 24]. The asymmetrical myometrial thickness of the \nanteroposterior wall and irregularity of the endometrial-\nmyometrial junction were measured before and after \nthe study. The participants were provided with identi -\ncal disposable pads for nine menstrual cycles. Group A \nreceived vaginal bromocriptine 5 mg daily, administered \ndeep in the vagina. Group B was administered continu -\nous oral dienogest 2 mg once daily. The duration of the \nintervention was 6 months. Both groups were evaluated \nfor pain and menstrual bleeding in the third, sixth, and \nninth month, and TVS changes included irregularity of \nmyometrial-endometrial junction and the asymmetry of \nmyometrial thickness of the anteroposterior wall [23] at \nthe sixth and ninth month. This study utilized various \ndescriptive statistics, including frequency, percentage, \nmean, and standard deviation (SD). The research com -\nmittee of the Department of Obstetrics and Gynecology \nof Iran University of Medical Sciences monitored and \nvalidated the data.\nWe used the chi-square test to compare the frequency \nof variables between the two groups. Repeated measures \n\nPage 3 of 8\nBahoorzahi et al. Middle East Fertility Society Journal           (2024) 29:55 \n \nanalysis assessed sonographic findings, pain intensity, \nand bleeding rates at different time points. An independ -\nent t-test was conducted to compare the two groups. \nData analysis was performed using SPSS version 23, with \na significance level set at P < 0.05, which was considered \nfor all analyses.\nResults\nA comparison of demographic and clinical variables \nbetween the two groups was conducted. The mean age of \nparticipants in the bromocriptine and dienogest groups \nwas 39.05 ± 4.99 and 38.08 ± 5.68, respectively (P = 0.41). \nTable 1 displays the demographic and clinical variables of \nthe two groups. The results indicated no significant dif -\nferences between the variables in the bromocriptine and \ndienogest groups (P > 0.05).\nFig. 1 Consort flow diagram\nTable 1 Comparison of the demographic and clinical variables \nbetween the two groups\n* P value was calculated using an independent t-test at 95% CI\nVariables Group (mean ± SD) P  value*\nBromocriptine Dienogest\nAge 39.05 ± 4.99 38.08 ± 5.68 0.41\nBMI 25.74 ± 0.51 25.79 ± 0.48 0.71\nNumber of births 2.47 ± 1.51 2.55 ± 1.48 0.824\nNumber of abortions 0.15 ± 0.36 0.10 ± 0.30 0.505\nTime of last birth 5.4 ± 3.42 5.4 ± 3.52 0.998\nMenarche age 13.57 ± 0.81 13.5 ± 0.81 0.682\n\nPage 4 of 8Bahoorzahi et al. Middle East Fertility Society Journal           (2024) 29:55 \nThe comparison of clinical variables related to men -\nstruation between the bromocriptine and dienogest \ngroups is presented in Table  2. There were no signifi -\ncant differences regarding the variables, such as the time \nof starting menstrual pain and the time of relief in each \ncycle (P > 0.05).\nBefore the intervention, myometrial-endometrial junc -\ntion was irregular in all patients. However, it became reg-\nular at 6 and 9 months after the intervention (Table  3). \nThe myometrial thickness of the anteroposterior wall \nwas asymmetric in all patients before the intervention. In \n6 and 9 months after the intervention, 46.8% (n = 29) of \npatients in the bromocriptine group and 53.2% (n = 33) in \nthe dienogest group showed symmetric anterior–poste -\nrior wall thickness (Table 4).\nThe chi-square test demonstrated that in both bro -\nmocriptine and dienogest groups, 9 months after the \nintervention, the state of asymmetry of the myome -\ntrial thickness of the anteroposterior wall, the irregu -\nlar appearance of the myometrial-endometrial junction \nimproved compared to before the intervention. There \nwas no significant difference between the two groups \nin terms of asymmetry of myometrial thickness of the \nanteroposterior wall and irregular appearance of myo -\nmetrial-endometrial junction in 6 and 9 months after \nthe intervention.\nThree months after the intervention, the mean visual \nblood chart score in the bromocriptine group was sig -\nnificantly lower than in the dienogest group. Still, it was \nlower in the dienogest group after 6 months (P  < 0.001). \nIn the ninth month of the study, however, the difference \nbetween the two groups was not statistically significant \n(Table 5).\nTable 2 Comparison of clinical variables related to menstruation frequency between two groups\n* P value was calculated using the chi-2 statistic test at 95% CI\nVariables Group (%) P  value*\nBromocriptine Dienogest\nMenstrual pain\n No 2 (66.7) 1 (33.3) 0.9\n Yes 38 (49.4) 39 (50.6)\nMenstrual pain onset time\n 1 or 2 days before menstruation 4 (57.1) 3 (42.9) 0.924\n 1 or more hours before menstruation 31 (42.2) 32 (50.8)\n After starting menstruation 5 (50.0) 5 (50.0)\nMenstrual pain relief time\n 1st menstrual day 1 (50.0) 1 (50.0) 0.731\n 3rd menstrual day 8 (42.1) 11 (57.9)\n 4th menstrual day and later 31 (52.5) 28 (47.5)\nTable 3 Comparison of irregularity of myometrial-endometrial \njunction between two groups of bromocriptine and dienogest\n* P value was calculated using the chi-2 statistic test at 95% CI\nTime Group P  value*\nBromocriptine Dienogest\nBefore\n Regular 0 (0%) 0 (0%) 1\n Irregular 40 (50%) 40 (50%)\nAfter 6 months\n Regular 31 (47%) 35 (53%) 0.95\n Irregular 0 (0%) 0 (0%)\nAfter 9 months\n Regular 31 (47%) 35 (53%) 0.95\n Irregular 0 (0%) 0 (0%)\nTable 4 Comparison of the anterior–posterior myometrial \nthickness between bromocriptine and dienogest groups\n* P value was calculated using the chi-2 statistic test at 95% CI\nTime Group P  value*\nBromocriptine Dienogest\nBefore\n Symmetric 0 (0%) 0 (0%) 1\n Asymmetric 40 (50%) 40 (50%)\nAfter 6 months\n Symmetric 29 (46.8%) 33 (53.2%) 0.90\n Asymmetric 2 (50%) 2 (50%)\nAfter 9 months\n Symmetric 29 (46.8%) 33 (53.2%) 0.90\n Asymmetric 2 (50%) 2 (50%)\n\nPage 5 of 8\nBahoorzahi et al. Middle East Fertility Society Journal           (2024) 29:55 \n \nFurther investigation using Tukey’s test indicated that \nin both groups, the visual blood chart score consistently \ndecreased over time (P < 0.001) (Fig. 2).\nMoreover, the mean intensity of menstrual pain in the \ndienogest group was significantly lower than in the bro -\nmocriptine group at 3 months and 6 months after the \nintervention (P < 0.001). There was no significant differ -\nence between both groups regarding pain intensity at the \nbeginning of the study and 9 months after the interven -\ntion (Table  6). Tukey’s test showed that in both groups, \nthe mean intensity of menstrual pain progressively \ndecreased over time (P < 0.001) (Fig. 3).\nRegarding drug side effects, three patients in the bro -\nmocriptine group (n = 31) experienced nausea, one \npatient had headache and constipation, and four patients \nhad spotting in the dienogest group (n = 35).\nDiscussion\nMedical treatment for adenomyosis requires a drug \nthat has low side effects and effectively reduces pain \nand the intensity of menstrual bleeding. Bromocriptine, \nwhich is currently used for managing type 2 diabetes \n[22], is also effective in the treatment of hyperprol -\nactinemia [12], acromegaly [1 ], and Parkinson’s disease \n[21]. Research on the mechanism of pain and bleed -\ning of adenomyosis and potential treatment options \nremains sparse, but animal research has suggested \nthat increased uterine prolactin concentration might \nbe a risk factor since prolactin is a smooth muscle cell \nmitogen. If prolactin contributes to the pathogenesis of \nadenomyosis, lowering uterine prolactin may serve as \na beneficial medical treatment. Therefore, bromocrip -\ntine, as a prolactin inhibitor, may be effective in alle -\nviating menstrual bleeding and pain in women with \nadenomyosis [2 ]. However, further studies are needed \nto investigate the role and mechanism of bromocriptine \nin alleviating related symptoms.\nIn this study, bromocriptine was administered vagi -\nnally to achieve higher drug concentrations in the uterus, \nthereby maximizing efficacy while minimizing blood lev -\nels to reduce adverse drug effects. Previous studies have \nshown that vaginal bromocriptine has fewer gastrointes -\ntinal side effects in comparison with the oral form of the \ndrug [1]. In the present study, three patients in the bro -\nmocriptine group experienced nausea after receiving the \nprescribed dose. The side effects noted in this study were \ntemporary, and patients did not report any long-term \nside effects throughout the study.\nTable 5 Comparison of mean blood visual chart between two \ngroups before, 3, 6, and 9 months after the intervention\n* P value was calculated using an independent t-test at 95% CI\nTime Group (mean ± SD) P  value*\nBromocriptine Dienogest\nBefore 302.32 ± 18.43 302.42 ± 18.05 0.920\nAfter 3 months 140.22 ± 14.06 176.0 ± 14.22 < 0.001\nAfter 6 months 85.93 ± 5.17 79.62 ± 3.69 < 0.001\nAfter 9 months 66.96 ± 8.62 66.14 ± 4.35 0.620\nP  value* < 0.001 < 0.001\nFig. 2 Blood visual chart trend in bromocriptine (a) and dienogest (b) group\nTable 6 Comparison of intensity of menstrual pain between two \ngroups before, 3, 6, and 9 months after the intervention\n* P value was calculated using an independent t-test at 95% CI\nTime Group (mean ± SD) P  value*\nBromocriptine Dienogest\nBefore 6.75 ± 0.75 6.72 ± 0.5 0.833\nAfter 3 months 4.2 ± 0.69 3.02 ± 0.71 < 0.001\nAfter 6 months 1.19 ± 0.6 2.04 ± 0.86 < 0.001\nAfter 9 months 0.48 ± 0.35 0.48 ± 0.28 0.958\nP  value* < 0.001 < 0.001\n\nPage 6 of 8Bahoorzahi et al. Middle East Fertility Society Journal           (2024) 29:55 \nThe findings from limited studies in this area sup -\nport our results and highlight the effectiveness of bro -\nmocriptine. Andersson et  al. [2] reported that vaginal \nbromocriptine significantly reduced heavy menstrual \nbleeding and pain intensity in women with diffuse adeno-\nmyosis. Andersson et  al. [1] demonstrated a significant \nreduction in both the myometrial-endometrial junction \nand asymmetric myometrial wall thickness as observed \nthrough transvaginal sonography (TVS), indicating the \nradiologically proven effectiveness of vaginal bromocrip -\ntine on adenomyosis.\nOur research showed a significant impact of dien -\nogest and bromocriptine on the sonographic features of \nadenomyosis. The most significant improvement in the \nendometrial-myometrial junction and anterior–posterior \nmyometrial thickening asymmetry was observed in the \nsixth month, with no further sonographic changes noted \nafter the drug was discontinued.\nIn another study, Andersson et al. [2] found significant \nimprovements in menstrual bleeding, pain, and quality \nof life following vaginal administration of bromocriptine, \nwhich is consistent with our study’s results. It is note -\nworthy, however, that the quality of life was not explic -\nitly investigated in our study. A recent study by Tang et al. \n[21] indicated that bromocriptine had an antiproliferative \neffect on the endometrium of women with adenomyosis \nin both in vivo and laboratory conditions. Bromocriptine \nappears to inhibit the proliferation of endometrial tissue \nin adenomyosis by regulating irregular microRNAs and \nproliferation-related signaling pathways.\nDienogest has been acknowledged in numerous \nsources for its effectiveness in treating adenomyosis [10]. \nSome studies have compared dienogest with other drugs, \nbut none has compared it with bromocriptine. In the pre-\nsent study, dienogest also significantly reduced menstrual \npain and bleeding. Neither vaginal bromocriptine nor \ndienogest caused significant adverse effects. Both drugs \ndemonstrated effectiveness in reducing pain intensity and \nmenstrual bleeding. The mean blood visual chart score \nbefore the intervention in both groups had no significant \ndifference. Three months after the intervention, the mean \nblood visual chart score was significantly lower in the \nbromocriptine group. During the subsequent 6 months, \ndienogest was slightly more effective, possibly due to the \ndecidualization of the endometrium by the progestogenic \nactivity of dienogest. After 3 months of stopping the \nintervention in the 9th month, both medications showed \nsimilar effects,each intervention reduced bleeding to the \nsame extent. After 6 and 9 months of study, the aver -\nage blood visual chart score was below 100. Dienogest \nwas more effective at reducing pain intensity by the 3rd \nmonth, while bromocriptine showed greater effectiveness \nby the 6th month. Although bromocriptine’s effect on \npain intensity began slightly slower, both bromocriptine \nand dienogest produced similar results, making them \neffective options for treating adenomyosis.\nMiao et al. [13] conducted a study to assess the effec -\ntiveness and safety of dienogest in women suffering from \nsymptomatic adenomyosis. The results of this study were \nconsistent with the present study’s findings, indicating \nthat dienogest is an effective and well-tolerated long-\nterm treatment for symptomatic adenomyosis. These \nfindings are also consistent with the results of Zhang \net al. ’s study [25]. Furthermore, Ono et al. [15] study dem-\nonstrated that dienogest was highly effective in pain relief \nin endometriosis and adenomyosis. Similarly, Neriishi \net al. ’s study [14] found that 24 weeks of dienogest treat-\nment significantly reduced pain in patients with sympto -\nmatic adenomyosis.\nStudies indicate that patients with endometriosis \ntreated with dienogest may experience irregular uterine \nbleeding and metrorrhagia. Additionally, women with \nuterine adenomyosis and fibroids are at a higher risk of \nexperiencing moderate-to-severe bleeding. This heavy \nFig. 3 Intensity of menstrual pain trend in bromocriptine (a) and dienogest (b) group\n\nPage 7 of 8\nBahoorzahi et al. Middle East Fertility Society Journal           (2024) 29:55 \n \nbleeding in women with adenomyosis may lead patients \nto discontinue the treatment, but this adverse effect \nhas not been reported with the use of bromocriptine. \nNo such side effect due to bromocriptine was observed \nin our study and Andersson et al. ’s study [2 ]. Therefore, \nin this group of patients with irregular uterine bleeding \nand metrorrhagia due to dienogest use, bromocriptine \ncould be a suitable substitution [20]. Bromocriptine can \nbe effectively prescribed, especially for patients who \nhave contraindications to hormonal treatment.\nOne of the strengths of the current study was its novel \ncomparison between vaginal bromocriptine and dien -\nogest, which are the most commonly prescribed drugs. \nThis comparison was conducted for the first time and \ndemonstrated that both drugs have a favorable effect. \nAnother strength of the study was the follow-up after \ncession of intervention to evaluate the recurrence of \nsymptoms. However, the study also had some limita -\ntions, such as the small sample size.\nIn future studies, evaluating the quality of life is rec -\nommended, which is a more accurate criterion.\nConclusion\nThe results of this study show that both vaginal dien -\nogest and bromocriptine effectively reduce pain inten -\nsity and menstrual bleeding and improve sonographic \ncharacteristics.\nAcknowledgements\nWe are most grateful to Iran University of Medical Sciences for conducting this \nresearch.\nAuthors’ contributions\nP .B. contributed to the writing of the original draft and performed the experi-\nmental technique in the conceptualization of the work. S.R,S.A., N.H., and R.D. \nperformed the collection of data. S.R. contributed to the writing the review, \nand the editing of the paper and contributed to the conceptualization.\nFunding\nNA.\nData availability\nThe underlying data supporting the results of our study can be found in the \nmanuscript.\nDeclarations\nEthics approval and consent to participate\nNA.\nConsent for publication\nAll authors consent to the publication of this study.\nCompeting interests\nThe authors declare no competing interests.\nReceived: 28 August 2024   Accepted: 14 December 2024\nReferences\n 1. Andersson JK, Pozzi Mucelli R, Epstein E, Stewart EA, Gemzell-Danielsson \nK (2020) Vaginal bromocriptine for treatment of adenomyosis: Impact on \nmagnetic resonance imaging and transvaginal ultrasound. Eur J Obstet \nGynecol Reprod Biol 254:38-43\n 2. Andersson JK, Khan Z, Weaver AL, Vaughan LE, Gemzell-Danielsson K, \nStewart EA (2019) Vaginal bromocriptine improves pain, menstrual bleed-\ning and quality of life in women with adenomyosis: a pilot study. 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