{"paper_id":"b3304484-c357-4d2a-8143-b0100e9f5189","body_text":"ARTICLE IN PRESS\nArticle in Press\nThe impact of vaginal bromocriptine on reducing \npain and menstrual bleeding in women with \nadenomyosis: a randomized controlled trial\nScientific Reports\nReceived: 31 December 2025\nAccepted: 12 May 2026\nCite this article as: Hakimi P ., Eghbali E., \nAlborzi M. et al. The impact of vaginal \nbromocriptine on reducing pain and \nmenstrual bleeding in women with \nadenomyosis: a randomized controlled \ntrial. Sci Rep (2026). https://doi.\norg/10.1038/s41598-026-53524-1\nParvin Hakimi, Elham Eghbali, Mahshid Alborzi & Hosein Azizi\nWe are providing an unedited version of this manuscript to give early access to its \nfindings. Before final publication, the manuscript will undergo further editing. Please \nnote there may be errors present which affect the content, and all legal disclaimers \napply.\nIf this paper is publishing under a Transparent Peer Review model then Peer \nReview reports will publish with the final article.\nhttps://doi.org/10.1038/s41598-026-53524-1\n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International \nLicense, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit \nto the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do \nnot have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the \narticle’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain \npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.\n\nThe impact of vaginal Bromocriptine on reducing pain and menstrual \nbleeding in women with adenomyosis: A randomized controlled trial\nParvin Hakimi1, Elham Eghbali2, Mahshid Alborzi3, and Hosein Azizi 4, \n5*\n1. Women's Reproductive Health Research Center, Tabriz University of \nMedical Sciences, Tabriz, Iran. Email: parvin.hakimi56@gmail.com\n2. Women's Reproductive Health Research Center, Tabriz University of \nMedical Sciences, Tabriz, Iran. Email: Eghbelham@gmail.com\n3. Department of Gynecology and Obstetrics, Jhrom University of Medical \nSciences, Jahrom, Iran. Email: alborzimah@gmail.com\n4. Women's Reproductive Health Research Center, Tabriz University of \nMedical Sciences, Tabriz, Iran. Email: aziziepid@gmail.com\n5. Sarab Faculty of Medical Sciences, Sarab, Iran. Email: \naziziepid@gmail.com\n*Correspondence to: Dr. Hosein Azizi, Assistant Professor of Epidemiology, \nWomen's Reproductive Health Research Center, Tabriz University of Medical \nSciences, Tabriz, Iran\nEmail: (aziziepid@gmail.com) Telefax: +984133826512\nAbstract\nBromocriptine, a dopamine receptor agonist that suppresses prolactin \nsecretion from the pituitary gland, is an inexpensive and widely accessible \nmedication with few adverse effects. The study aim was to assesse the efficacy \nof vaginal bromocriptine in reducing pelvic pain, menstrual bleeding, and cycle \nirregularities among patients with adenomyosis. In this randomized controled \ntrial, 64 women diagnosed with adenomyosis were randomly assigned to \neither an intervention group receiving vaginal bromocriptine or a routine-\ntreatment group. The intervention consisted of 5 mg bromocriptine \nadministered vaginally once daily for three months. The control group \nreceived standard treatment comprising oral contraceptive pills (OCPs) and \nmefenamic acid. Primary outcome measures were menstrual bleeding volume, \npain intensity, and menstrual cycle regularity. Linear regression models were \nused to evaluate changes in menstrual bleeding after adjusting for potential \nconfounders. All 64 participants (32 per group) completed the study and were \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nincluded in the analysis. Baseline demographic, obstetric, and \nultrasonographic characteristics were comparable between groups (P > 0.05). \nAfter treatment, the mean pain score was significantly lower in the \nintervention group than in the control group (2.01 vs. 5.10; P = 0.011). Mean \nmenstrual bleeding volume also decreased significantly with vaginal \nbromocriptine (280.8 mL vs. 525.9 mL; P = 0.001). Final analysis indicated \nthat bromocriptine significantly reduced menstruation bleeding after adjusting \nfor potential confounders (Beta= -1.157, P= 0.001). Vaginal bromocriptine \nappears to be an effective and well-tolerated therapeutic option for alleviating \nsymptoms of adenomyosis, particularly pelvic pain, excessive menstrual \nbleeding, and irregular cycles. The beneficial effects may result from reduced \nprolactin levels, inhibition of angiogenesis, and modulation of the \nhypothalamic–pituitary–ovarian axis.\nIRCT registration number: IRCT20240806062668N3\nRegistration date: 2025-03-19\nPatient recruitment date: 2025-04-13\nIntroduction\nOne of the most accepted pathogenetic hypotheses involves disruption or \nabsence of the endometrial–myometrial junctional zone, allowing endometrial \nmucosa to invaginate into the underlying myometrium [6,7]. Although the \npathogenesis is multifactorial, experimental studies have highlighted a \npotential role for prolactin: elevated serum prolactin may promote \nendometrial gland growth and activity [8], and in the presence of ovarian \nsteroids, it can induce myometrial cell injury, facilitating endometrial invasion \n[9].\nThe burden of adenomyosis extends beyond individual symptoms, imposing \nsubstantial long-term healthcare costs comparable to chronic conditions such \nas diabetes and rheumatoid arthritis [10]. Consequently, it represents both a \nclinical and economic challenge in gynecology [11]. Medical therapy remains \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nthe cornerstone of symptom management and disease modulation [12]; \nhowever, no standardized treatment guideline has been established. Current \nmedical options—including gonadotropin-releasing hormone (GnRH) agonists, \noral contraceptives, and progestins—often yield modest efficacy, limited \ntolerability, and considerable expense [1]. For many women, these \nshortcomings culminate in hysterectomy; in the United States, approximately \n82% of patients with adenomyosis undergo hysterectomy for symptom relief, \nresulting in permanent loss of fertility [13]. Given the substantial impact on \nquality of life and the therapeutic limitations of existing modalities, the search \nfor new, effective, and well-tolerated interventions remains imperative [2].\nProlactin synthesis occurs not only in the pituitary gland but also in \nendometrial and myometrial tissues, where it acts as a mitogenic factor for \nsmooth muscle cells under experimental conditions [14]. Evidence suggests a \nstrong correlation between serum prolactin levels and the progression of \nadenomyosis [15], implying that prolactin-lowering agents may represent a \nrational therapeutic approach. Bromocriptine—an ergot-derived, \nsympatholytic dopamine D₂-receptor agonist with potent biological activity—\nhas been used for over three decades to treat hyperprolactinemia, \nprolactinomas, Parkinson’s disease, acromegaly, and other \nhormone-dependent pituitary adenomas, as well as certain metabolic \ndisorders such as diabetes mellitus.\nProlonged bromocriptine therapy is generally safe, with minimal hepatic, \nrenal, cardiac, or hematologic toxicity [16]. The drug is inexpensive, widely \naccessible, and well tolerated, with a favorable side-effect profile [16,17]. \nVaginal administration further improves tolerability by reducing \ngastrointestinal reactions and has been shown to effectively lower serum \nprolactin levels in women with hyperprolactinemia [18]. Recent clinical \nfindings report significant improvements in menstrual bleeding, pain intensity, \nand overall quality of life following vaginal bromocriptine therapy [15].\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nTherefore, this trial was designed to evaluate the impact of vaginal \nbromocriptine on menstrual bleeding and pain among patients diagnosed with \nadenomyosis.\nMethods\nStudy design and setting\nThis pilot parallel randomized controlled clinical trial was conducted to assess \nthe impact of vaginal bromocriptine on reducing pain and menstrual bleeding \nin patients with adenomyosis. Participants were recruited from Al-Zahra \nHospital, affiliated with Tabriz University of Medical Sciences, and the infertility \ncenter of Jahrom University of Medical Sciences. The trial was conducted \nbetween 2024 and 2025, adhering to predefined inclusion and exclusion \ncriteria.\nInclusion Criteria\nEligible participants were premenopausal women aged 25 years or older \npresenting with heavy menstrual bleeding, defined as a Pictorial Blood Loss \nAssessment Chart (PBAC) score exceeding 100. Diagnosis of adenomyosis was \nbased on transvaginal ultrasound criteria, including an irregular endometrial–\nmyometrial junction, asymmetric myometrial wall thickness, presence of \nmyometrial cysts, and fan-shaped acoustic shadowing in the myometrium. \nAdditional inclusion criteria included normal baseline serum prolactin levels, \nuse of adequate contraception (ranging from contraceptive devices and \nsterilization to sexual abstinence), and the ability and willingness to read and \nunderstand study information.\nExclusion Criteria\nExclusion criteria encompassed women actively trying to conceive, those in \nthe postpartum period for less than 6 months, breastfeeding individuals, and \nwomen with a uterine size greater than the level of the umbilicus (equivalent \nto >20 weeks gestation). Furthermore, women with acute pelvic infection, \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nthose using an intrauterine device (IUD), or with contraindications to \nbromocriptine or ergot alkaloids were excluded. Participants exhibiting \nintolerance or adverse reactions to bromocriptine during the evaluation phase, \nrecent use of gonadotropin-releasing hormone (GnRH) agonists or \nantagonists, steroidal oral contraceptives, intrauterine hormonal devices, \nantidepressants, or opioid analgesics were also deemed ineligible. Individuals \nwith transvaginal ultrasound or MRI findings suggestive of endometriosis, a \nhistory of hyperprolactinemia, high-grade cervical intraepithelial lesions, or \nsuspected uterine or ovarian malignancy were excluded. Other \ncontraindicating factors included a history of peptic ulcer disease, syncope, \nseizures, uncontrolled hypertension, cardiovascular or cerebrovascular \ndisease, valvular heart disease, diabetes, Parkinson’s disease, psychosis, \npleural or pericardial effusion, pulmonary fibrosis, Raynaud phenomenon, \nlactose intolerance, and current use of opioid medications.\nSample Size\nBased on a previous study [15], mean blood loss scores (m) and standard \ndeviations (sd) were assumed for the intervention (m₁=349, sd₁=155) and \ncontrol (m₂=233, sd₂=175) groups. With a minimum power of 80% to detect \na significant difference in menstrual blood loss between groups and a \nmaximum type I error rate of less than 5%, the required sample size was \ncalculated to be 32 participants per group, totaling 64 patients.\nRandomization and Blinding\nParticipants were assigned to the intervention and control groups using a \nbalanced block randomization method. This process involved random \nallocation within predetermined blocks to ensure complete randomness. A \ntotal of 16 blocks were used, each containing 4 participants. The sequence \nwithin each block determined individual group placement, thereby \nmaintaining a balanced distribution of participants across groups regarding \npotential confounding variables. Participants in the control group received oral \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\ncontraceptive pills (OCPs) and mefenamic acid (for pain management). \nRandomization was performed by an independent individual who concealed \nthe allocation sequence. Participants were unaware of their group \nassignments (Figure 1). To mitigate assessment bias, research nurses \ncollecting data on pain and bleeding scores were blinded to treatment \nallocation.\nInterventions\nTreatment commenced with one 2.5 mg vaginal tablet inserted once daily for \nthe first week. Subsequently, the dose was increased to twice daily, achieving \na total daily dose of 5 mg (one 2.5 mg vaginal tablet every 12 hours). Day 1 \nof the study was defined as the first day the participant successfully received \nthe full 5 mg daily dose. The medication was continued for a total duration of \nthree months.\nFollow-up\nFollow-up visits were scheduled during the proliferative phase of the menstrual \ncycle in the third month of treatment. The final evaluation occurred at the end \nof a 4-month follow-up period, one month after discontinuation of the study \nmedication. According to the study protocol, any participant experiencing \nadverse effects or intolerance to bromocriptine would lead to treatment \ndiscontinuation and potential withdrawal from the study. No such events were \nobserved.\nOutcomes and Measurements\nThe primary outcomes were: (i) the change in Visual Analogue Scale (VAS) \npain score and (ii) the change in Pictorial Blood Loss Assessment Chart (PBAC) \nscore from baseline to Day 30. Menstrual blood loss was assessed using the \nstandardized PBAC, which estimates menstrual volume by recording the \nnumber of sanitary pads and/or tampons used daily and assigning scores \nbased on saturation levels. This tool is validated for distinguishing between \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nnormal and heavy menstrual bleeding and is suitable for diverse populations, \nincluding Asian women [19]. Average pain intensity was measured using the \nVAS at three intervals following menstruation: within the first 3 days, between \ndays 3 and 7, and more than 7 days after menstruation. VAS scores ranged \nfrom 0 (no pain) to 10 (most severe pain imaginable). Pain scores were \nmeticulously recorded according to the study protocol.\nStatistical Analysis\nAll data were analyzed using SPSS version 24 (Chicago, IL, USA). Descriptive \nstatistics, including mean and standard deviation, were used for normally \ndistributed quantitative data, while frequencies and percentages were used \nfor qualitative or categorical variables. To compare menstrual blood loss and \npain scores between the two groups, the Independent Samples t-test was used \nfor normally distributed variables, and the Mann–Whitney U test was used for \nnon-normally distributed variables. Within-group comparisons (before and \nafter treatment) were conducted using the paired t-test.\nMenstrual bleeding (ml) was considered the primary outcome variable. Linear \nregression analysis was performed for additional adjusted analyses, \ncontrolling for baseline treatment differences and employing change-from-\nbaseline comparisons. This approach aimed to estimate the Standardized \nCoefficients (Beta) for menstrual bleeding after accounting for potential \nconfounders. The study groups and baseline variables were entered as \nindependent variables into the model. The control group (treatment as usual) \nserved as the reference group, allowing for the estimation of the impact of \nbromocriptine (intervention group) in reducing menstrual bleeding compared \nto the control group. A significance level of less than 5% was considered \nstatistically significant for all analyses.\nResults\nObstetric and clinical characteristic of the participants at baseline\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nA total of 64 patients diagnosed with adenomyosis, with 32 patients \nrandomized to each group, were included in the final analysis. All participants \ncompleted the 3-month treatment period and underwent a subsequent 1-\nmonth follow-up. No participants were lost to follow-up throughout the study \nduration.\nThe demographic and baseline characteristics of the study participants are \ndetailed in Table 1. The mean age was 32.5 years in the intervention group \nand 33.8 years in the control group, with no statistically significant difference \nobserved between the groups (P > 0.05). Similarly, mean body weight and \nbody mass index (BMI) did not differ significantly between the groups (P = \n0.561). Other demographic factors, including occupation and educational \nlevel, also exhibited no significant variations (P > 0.05). Concerning obstetric \nhistory, the mean number of cesarean deliveries (1.24 vs. 1.42) and mean \nparity (1.15 vs. 1.24) were comparable at baseline, with no statistically \nsignificant differences (P > 0.05).\nTable 2 presents the transvaginal ultrasound findings at the time of study \nentry, along with selected clinical parameters prior to the intervention. \nUltrasound assessments indicated that both groups were comparable in terms \nof uterine volume, endometrial thickness, and the number of myometrial \ncysts, showing no statistically significant differences at baseline (P > 0.05). \nFurthermore, posterior uterine wall thickening and the presence of an \nasymmetric, heterogeneous myometrium did not differ significantly between \nthe groups (P > 0.05). Pre-intervention measurements of pain intensity and \nmenstrual bleeding volume also revealed no significant differences between \nthe two treatment arms. The menstrual cycle length was likewise comparable \n(P > 0.05).\nClinical outcomes post-intervention\nThe primary clinical outcomes following the intervention period are \nsummarized in Table 3. Mean pain scores demonstrated a statistically \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nsignificant reduction in the intervention group (2.01) compared to the control \ngroup (5.1) (P = 0.011). A significant difference was also observed in \nmenstrual bleeding volume post-treatment, with the intervention group \naveraging 280.8 mL versus 525.9 mL in the control group (P = 0.001). \nMenstrual duration, categorized into three intervals (<3 days, 3–7 days, and \n>7 days), was significantly shorter in the intervention group compared to the \ncontrol group (P = 0.001). Regarding menstrual regularity post-treatment, \n75% (24 patients) in the intervention group reported regular cycles, compared \nto 25% (8 patients) in the control group, a statistically significant difference (P \n= 0.001).\nTable 4 presents the results of the linear regression analysis, which aimed to \nestimate the impact of bromocriptine and to perform change-from-baseline \ncomparisons for menstruation bleeding, adjusted for potential confounders. \nThe final analysis indicated that bromocriptine treatment significantly reduced \nmenstrual bleeding compared to the control group (Beta = -1.157; P = 0.001). \nConversely, the presence of myometrial cysts (Beta = 0.626; P = 0.027) and \nendometrial thickness (Beta = 0.635; P = 0.048) were positively associated \nwith higher menstrual bleeding volumes. Specifically, for each unit increase in \nmyometrial cysts and endometrial thickness, menstrual bleeding increased by \napproximately 0.626 and 0.635 times, respectively. Other variables, including \nage, weight, history of cesarean delivery, uterine volume, posterior uterine \nwall thickening, and heterogeneous myometrium, showed no significant \nassociation with increased menstrual bleeding (P > 0.05).\nDiscussion\nAccording to the findings of this study, vaginal administration of bromocriptine \nresulted in statistically significant and clinically meaningful reductions in pain \nintensity and menstrual bleeding. These improvements were corroborated by \ngynecologic assessments and patient-reported satisfaction. Quantitatively, \nthe study reported significant between-group differences in pain scores (2.01 \nvs. 5.1) and menstrual bleeding volume (280.8 vs. 525.9 mm³).\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nThe pathogenesis of pain in adenomyosis is multifactorial, involving the \nectopic infiltration of endometrial tissue into the myometrium, heightened \nprostaglandin production, stimulation of nociceptive nerve endings, and \nchronic inflammatory processes [11]. Bromocriptine, a dopaminergic agent, \nexerts its effects by inhibiting pituitary prolactin secretion. This action is \nassociated with the modulation of pro-inflammatory pathways and a reduction \nin the excessive production of pro-inflammatory cytokines, such as Tumor \nNecrosis Factor-alpha (TNF-α) and Interleukin-1 beta (IL-1β) [12]. Furthermore, \nprolactin has been implicated in enhancing uterine contractility through \nincreased oxytocin sensitivity [13]. Consequently, bromocriptine-induced \nprolactin suppression may indirectly alleviate painful uterine contractions \nduring menstruation, thereby contributing to pain relief [14, 20].\nA notable secondary finding was the marked reduction in menstrual bleeding \nvolume within the intervention group. This effect is predominantly attributed \nto the diminished growth and activity of adenomyotic tissue. In adenomyosis, \nectopic endometrial tissue within the myometrium promotes angiogenesis, \ninduces uterine hypertrophy, and contributes to the formation of fragile \nvascular networks, all of which are implicated in heavy menstrual bleeding \n[14]. Bromocriptine may mitigate the growth of such tissue by downregulating \nthe expression of angiogenic factors, including Vascular Endothelial Growth \nFactor (VEGF), and by inhibiting cellular proliferation within the endometrium \n[15]. Additionally, a reduction in prolactin levels can attenuate \ncyclooxygenase-2 (COX-2) activity in the uterus, thereby decreasing \ninflammation and subsequent menstrual blood loss [16]. By ameliorating local \ninflammation, bromocriptine may also enhance vascular stability and function, \nthus preventing abnormal uterine bleeding [16, 21].\nThe observed reduction in menstrual duration in the intervention group \nrepresents another significant clinical outcome. Prolonged menstruation in \nadenomyosis is partly attributed to persistent inflammation within the \nheterotopic endometrial tissue and impaired vascular repair mechanisms [18]. \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nBy potentially decreasing vascular permeability and improving endometrial \nfunction, bromocriptine may facilitate the restoration of a more physiological \nmenstrual duration. While molecular mechanisms, such as the regulation of \nthe Phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway and mammalian \nTarget of Rapamycin (mTOR) inhibition, might contribute to enhanced \nendometrial repair post-menstruation, further detailed molecular \ninvestigations are warranted [22].\nImprovements in menstrual cycle regularity were also substantially observed \nin the intervention group. This effect may be attributed to bromocriptine’s \nmodulatory influence on the hypothalamic–pituitary–ovarian (HPO) axis. \nElevated serum prolactin levels are known to suppress HPO axis function, \npotentially leading to anovulation and menstrual irregularities [22]. By \nreducing prolactin concentrations, bromocriptine may help restore the normal \npulsatile release of Gonadotropin-Releasing Hormone (GnRH) from the \nhypothalamus, subsequently normalizing the physiological secretion of \nLuteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) from the \npituitary gland [23]. This normalization of endocrine rhythms is expected to \nre-establish ovulatory cycles and improve menstrual regularity [24].\nFurthermore, bromocriptine may suppress the growth of adenomyotic tissue \nthrough the reduction of steroid hormone levels, such as estrogen, which plays \na critical role in the development and progression of adenomyosis [25]. Prior \nanimal and human studies have suggested that prolactin can increase the \nsensitivity of uterine estrogen receptors, thereby promoting the growth and \nsurvival of adenomyotic tissue. Consequently, prolactin suppression by \nbromocriptine might attenuate estrogen-driven proliferative effects within \nthese tissues [26].\nAn important methodological consideration in this study is the utilization of \nthe vaginal route for bromocriptine administration. This administration \npathway bypasses first-pass hepatic metabolism, thereby increasing drug \nconcentrations within the pelvic region and adjacent uterine tissues [27]. \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nConsequently, higher local drug levels can be achieved at the target site, \npotentially with a reduced incidence of systemic side effects. Previous \nresearch has also indicated that vaginal bromocriptine is generally better \ntolerated than oral formulations, with a lower prevalence of gastrointestinal \nand neurological adverse events [28].\nComparisons with existing literature further substantiate the beneficial effects \nof bromocriptine. For instance, Andersson et al. reported that dopamine \nagonists can inhibit the growth of endometriotic lesions and alleviate chronic \npelvic pain [18]. Similarly, Tang et al. demonstrated that bromocriptine \nreduced the thickness of heterotopic endometrial tissue in mouse models of \nadenomyosis. Although the majority of current literature pertains to \nendometriosis, the shared pathophysiological mechanisms between \nendometriosis and adenomyosis lend support to the applicability of these \nfindings in the context of adenomyosis.\nLimitations\nThe limitations of this study include a relatively short follow-up period. \nAdditionally, the study lacked long-term imaging and comprehensive \nbiochemical assessments to evaluate the drug’s structural and sustained \neffects. The reliance on subjective instruments for measuring pain intensity \nand menstrual regularity could potentially introduce assessment bias. To \nmitigate these concerns, the study employed blocked randomization and \nparticipant blinding, alongside standardized instruments for assessing \nmenstrual blood loss and pain intensity across the study groups.\nAnother methodological consideration is the difference in background therapy: \nthe control group received oral contraceptive pills (OCPs) ± mefenamic acid, \nwhereas the intervention group received bromocriptine monotherapy. While \nthis difference in adjunctive treatment may be minor, it could complicate the \nprecise attribution of observed effects solely to bromocriptine. However, the \nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nuse of balanced block randomization aimed to mitigate this potential \nconfounding factor.\nAlthough the power analysis indicated an 80% power to detect moderate \neffect sizes (with significant P-values), a larger sample size would be beneficial \nfor enhancing the generalizability of the results.\nConclusion\nBased on the findings of this study, vaginal bromocriptine appears to be an \neffective adjunctive therapy for patients diagnosed with adenomyosis. It \ndemonstrates significant efficacy in reducing pain intensity, menstrual blood \nloss, and menstrual duration, while concurrently improving menstrual cycle \nregularity. Considering its favorable tolerability profile, ease of administration, \nand enhanced local efficacy, vaginal bromocriptine presents a promising, low-\nrisk therapeutic option that may complement conventional treatments for the \nmanagement of adenomyosis.\nDeclarations\nEthics approval and consent to participate\nThe study protocol was approved by the ethics committee of Tabriz University \nof Medical Sciences to number IR.TBZMED.REC.1403.795. Written informed \nconsent was obtained before the study. The study was conducted in \naccordance with the Declaration of Helsinki.\nConsent for publication\nNot Applicable.\nAvailability of data and materials\nThe datasets generated and/or analyzed during the current study are available \nfrom the corresponding author on reasonable request.\nCompeting interests\nThe authors have no competing interests to declare.\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nFunding\nThis study was funded by Tabriz University of Medical Sciences, Iran\nAuthors’ contributions:\nHA, PH, EE, and MA contributed to protocol development, data creation and \ncollection, manuscript development, and review. PH supervised the trial. PH \nand MA treated and followed up on the patients. HA analyzed, interpreted, \nreviewed, provided the first draft of the manuscript and edited. All authors \nread, provided comments and approved the final manuscript.\nAcknowledgments\nAuthors would like to thank statistical supports of “Clinical Research \nDevelopment Unit of Al-Zahra Educational, Research and Treatment Center”, \nTabriz University of Medical Sciences, Tabriz, Iran.\nReferences\n1. Che X, Wang J, Sun W, He J, Wang Q, Zhu D, Zhu W, Zhang J, Dong J, Xu J et \nal: Effect of Mifepristone vs Placebo for Treatment of Adenomyosis \nWith Pain Symptoms: A Randomized Clinical Trial. JAMA network open \n2023, 6(6):e2317860.\n2. García-Solares J, Donnez J, Donnez O, Dolmans MM: Pathogenesis of \nuterine adenomyosis: invagination or metaplasia? Fertil Steril 2018, \n109(3):371-379.\n3. Antero MF, Ayhan A, Segars J, Shih IM: Pathology and Pathogenesis of \nAdenomyosis. Seminars in reproductive medicine 2020, 38(2-03):108-118.\n4. Raffone A, Seracchioli R, Raimondo D, Maletta M, Travaglino A, Raimondo I, \nGiaquinto I, Orsini B, Insabato L, Pellicano M  et al : Prevalence of \nadenomyosis in endometrial cancer patients: a systematic review and \nmeta-analysis. Archives of gynecology and obstetrics 2021, 303(1):47-53.\n5. Maheshwari A, Gurunath S, Fatima F, Bhattacharya S: Adenomyosis and \nsubfertility: a systematic review of prevalence, diagnosis, treatment \nand fertility outcomes. Hum Reprod Update 2012, 18(4):374-392.\n6. Schrager S, Yogendran L, Marquez CM, Sadowski EA: Adenomyosis: \nDiagnosis and Management. American family physician 2022, 105(1):33-\n38.\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\n7. Moawad G, Kheil MH, Ayoubi JM, Klebanoff JS, Rahman S, Sharara FI: \nAdenomyosis and infertility. Journal of assisted reproduction and genetics \n2022, 39(5):1027-1031.\n8. Łupicka M, Socha BM, Szczepańska AA, Korzekwa AJ: Prolactin role in the \nbovine uterus during adenomyosis. Domestic animal endocrinology 2017, \n58:1-13.\n9. Sengupta P, Sharma A, Mazumdar G, Banerjee I, Tripathi SK, Bagchi C, Das \nN: The possible role of fluoxetine in adenomyosis: an animal \nexperiment with clinical correlations. Journal of clinical and diagnostic \nresearch : JCDR 2013, 7(7):1530-1534.\n10. Guo SW, Groothuis PG: Is it time for a paradigm shift in drug research \nand development in endometriosis/adenomyosis? Hum Reprod Update \n2018, 24(5):577-598.\n11. Donnez J, Donnez O, Dolmans MM: Introduction: Uterine adenomyosis, \nanother enigmatic disease of our time. Fertil Steril 2018, 109(3):369-370.\n12. Vannuccini S, Luisi S, Tosti C, Sorbi F, Petraglia F: Role of medical \ntherapy in the management of uterine adenomyosis. Fertil Steril 2018, \n109(3):398-405.\n13. Yu O, Schulze-Rath R, Grafton J, Hansen K, Scholes D, Reed SD: \nAdenomyosis incidence, prevalence and treatment: United States \npopulation-based study 2006-2015. Am J Obstet Gynecol 2020, 223(1):94 \ne91-94 e10.\n14. Nowak RA, Mora S, Diehl T, Rhoades AR, Stewart EA: Prolactin is an \nautocrine or paracrine growth factor for human myometrial and \nleiomyoma cells. Gynecologic and obstetric investigation 1999, 48(2):127-\n132.\n15. Andersson JK, Khan Z, Weaver AL, Vaughan LE, Gemzell-Danielsson K, \nStewart EA: Vaginal bromocriptine improves pain, menstrual bleeding \nand quality of life in women with adenomyosis: A pilot study. Acta \nobstetricia et gynecologica Scandinavica 2019, 98(10):1341-1350.\n16. Naz F, Malik A, Riaz M, Mahmood Q, Mehmood MH, Rasool G, Mahmood Z, \nAbbas M: Bromocriptine therapy: Review of mechanism of action, \nsafety and tolerability. Clinical and experimental pharmacology & \nphysiology 2022, 49(8):903-922.\n17. Kletzky OA, Vermesh M: Effectiveness of vaginal bromocriptine in \ntreating women with hyperprolactinemia. Fertil Steril 1989, 51(2):269-\n272.\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\n18. Andersson JK, Pozzi Mucelli R, Epstein E, Stewart EA, Gemzell-Danielsson \nK: Vaginal bromocriptine for treatment of adenomyosis: Impact on \nmagnetic resonance imaging and transvaginal ultrasound. European \njournal of obstetrics, gynecology, and reproductive biology 2020, 254:38-43.\n19. Ko JKY, Lao TT, Cheung VYT: Pictorial Blood Loss Assessment Chart \nfor evaluating heavy menstrual bleeding in Asian women. Hong Kong \nmedical journal = Xianggang yi xue za zhi 2021, 27(6):399-404.\n20. Gellersen B, Bonhoff A, Hunt N, Bohnet HG: Decidual-type prolactin \nexpression by the human myometrium. Endocrinology 1991, 129(1):158-\n168.\n21. Permana MY, Sarwanti S, Fauziah S: Effectivity of Bromocriptine \nAdministration Towards Prolactin Positive Breast Cancer Receiving \nAnthracycline-Based Chemotherapy: A Literature Review. Acta medica \nIndonesiana 2023, 55(4):465-474.\n22. Tang Y, Ponandai-Srinivasan S, Frisendahl C, Andersson JK, Pavone D, \nStewart EA, Lalitkumar PGL, Korsching E, Bogavarappu NR, Gemzell-\nDanielsson K: Bromocriptine inhibits proliferation in the endometrium \nfrom women with adenomyosis. Frontiers in endocrinology 2023, \n14:1026168.\n23. Ma K, Ma L, Huang T, Wang Y, Zhong G, Gao C, Zhou Z, Luo J: The \neffectiveness and safety of aripiprazole, bromocriptine, and \ncabergoline in the treatment of hyperprolactinemia: a systematic \nreview and network meta-analysis. Expert opinion on drug safety 2025, \n24(7):773-786.\n24. Parsanezhad ME, Alborzi S, Namavar Jahromi B: Retraction Note: A \nprospective, double-blind, randomized, placebo-controlled clinical \ntrial of bromocriptin in clomiphene-resistant patients with polycystic \novary syndrome and normal prolactin level. Archives of gynecology and \nobstetrics 2024, 309(2):729.\n25. Snellen M, Power J, Blankley G, Galbally M: Pharmacological lactation \nsuppression with D2 receptor agonists and risk of postpartum \npsychosis: A systematic review. The Australian & New Zealand journal of \nobstetrics & gynaecology 2016, 56(4):336-340.\n26. Nyboe Andersen A, Damm P, Tabor A, Pedersen IM, Harring M: Prevention \nof breast pain and milk secretion with bromocriptine after second-\ntrimester abortion. Acta obstetricia et gynecologica Scandinavica 1990, \n69(3):235-238.\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\n27. Sherwal V, Malik S, Bhatia V: Effect of bromocriptine on the severity \nof ovarian hyperstimulation syndrome and outcome in high \nresponders undergoing assisted reproduction. Journal of human \nreproductive sciences 2010, 3(2):85-90.\n28. Badianyama M, Das PK, Gaddameedi SR, Saukhla S, Nagammagari T, \nBandari V, Mohammed L: A Systematic Review of the Utility of \nBromocriptine in Acute Peripartum Cardiomyopathy. Cureus 2021, \n13(9):e18248.\nTAU: Treatment as usual included OCP and/or Mefenamic acid\nFigure 1. Consort flow diagram\nTable 1. Baseline characteristics of the participants \nGroups (n= 64)\nVariables Intervention (n= \n32)\nMean ± SD\nControl (n= \n32)\nMean ± SD\nP-value\nAge (year)* 32.5 ± 5.6 33.8 ± 5.6 0.574\nWeight (kg)* 71.4 ± 6.0 70.4 ± 7.8 0.561\nCesarean** 1.24 ± .38 1.42 ± 0.25 0.749\nParity** 1.15 ± 0.41 1.24 ± 0.33 0.951\nHistory of infertility (n \n%)* 9 (28.2) 11 (34.4) 0.148\nSingle 12 11Marital \nStatus (n) married 21 20\n0.611\nBMI (Body mass index) 25.5 ± 3.6 25.9 ± 3.3 0.924\nAcademic 23 22Educational \n(n) Non-\nacademic 9 10\n0.803\nEmployed 15 15Occupation\nal (n) Self-\nemployed 10 11\n0.851\nEnrollment\nExcluded (n= 72)\n￿   Not meeting inclusion criteria \n(n=72)\n￿   Declined to participate (n= 0 )\n￿ Other reasons (n= 0 )\nFollow-Up\nAnalysed (n=32) \n￿ Excluded from analysis (give reasons) \n(n= 0)\nAnalysis\nAnalysed (n= 32) \n￿ Excluded from analysis (give reasons) \n(n= 0)\nLost to follow-up (give reasons) (n= 0)\nDiscontinued intervention (give reasons) \n(n=0)\nLost to follow-up (give reasons) (n=0)\nDiscontinued intervention (give reasons) \n(n=0)\nAllocated to control (TAU) (n= 32)\n￿ Received allocated intervention (n= 32 \n)\n￿ Did not receive allocated intervention \n(give reasons) (n=0  )\nAllocation\nAllocated to intervention (Vaginal \nBromocriptine) (n= 32)\n￿ Received allocated intervention (n= 32 \n)\n￿ Did not receive allocated intervention \n(give reasons) (n= 0 )\nRandomized (n= 64)\nAssessed for eligibility (n= \n156\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nUnemploy\ned 7 6\n* T-test\n** Mann-Whitney\nTable 2. Comparison of transvaginal ultrasound results and clinical features between \nthe two study groups at the baseline\nGroups (n= 64)\nVariables Intervention (n= \n32)\nMean ± SD\nControl (n= \n32)\nMean ± SD\nP-value\nUterine volume (cubic \ncentimeters) 150.5 ± 32.6 147.8 ± 30.9 0.681\nEndometrial thickness (mlm) 10.2 ± 1.3 10.5 ± 1.6 0.432\nMyometrial cysts (n) 23 21 0.589\nThickening of the posterior \nwall of the uterus (n) 18 20 0.615\nHeterogeneous \nmyometrium(n) 26 25 0.743\nAsymmetrical thickening of \nthe myometrium (n) 20 19 0.798\nPain (before)\nMean ± SD 7.1 ± 1.3 7.6 ± 1.4 0.618\nBleeding during menstruation \n(before)\nMean ± SD\n616 ± 60.6 601 ± 56.6 0.881\n< 3 5 4\n3-7 22 21Menstruation \nperiod (day) (n)\n> 7 5 7\n0.485\nTable 3. The study outcomes after interventions\nGroups (n= 64)\nVariables Intervention \n(n= 32)\nMean ± SD\nControl (n\n= 32)\nMean ± SD\nMean \ndifference P-value\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS\n\nPain 2.01 ± 1.2 5.1 ± 1.7 3.19 ± 1.03 0.011\nmenstrual bleeding (ml) 280.8 ± 20.6 525.9 ± \n45.7 245.1 ± 27.5 0.001\nMenstrual regularity (n%) 24 (75%) 8 (25%) - 0.001\n< 3 9 3 -\n3-7 21 20 -\nMenstruation \nperiod (day) \n(n)\n> 7 2 9 -\n0.001\nTable 4. Results of linear regression analysis* to estimate the impact of \nbromocriptine and related factors on menstrual bleeding\nVariables\nStandardized \nCoefficient \n(Beta)**\n95% CIs P-value\nControl Ref. Ref. Ref.\nGroups Intervention \n(bromocriptine) - 1.157 -3.19 – -7.61 0.001\nAge (year) 0.067 - 0.96 – 8.01 0.137\nWeight (kg) 0.12 -0.23 – 1.61 0.194\nCesarean history (n) 0.028 - 2.01 – 3.82 0.543\nParity (n) -0.145 -1.63 – 2.21 0.641\nUterine volume (cubic \ncentimeters) 0.012 - 2.34 – 3.08 0.788\nEndometrial thickness \n(mlm) 0.635 0.031 – 2.15 0.048\nMyometrial cysts (n) 0.626 0.14 – 3.32 0.027\nThickening of the posterior \nwall of the uterus (n) 0.116 -1.05 – 4.96 0.135\nHeterogeneous \nmyometrium (n) 0. 374 -0.971 – 2.51 0.269\n* menstrual bleeding was considered as outcome variable\n** Adjusted R square= 0.654; Durbin-Watson= 2.06\nACCEPTED MANUSCRIPT\nARTICLE IN PRESSARTICLE IN PRESS","source_license":"CC0","license_restricted":false}