{"paper_id":"cf9238cf-fa19-4348-b343-2a34a4bc4140","body_text":"Introduction\nEndometrial tissue outside the uterus is a defining feature \nof endometriosis, a persistent gynecological condition. \nIt is associated with infertility and pelvic discomfort (1). \nEctopic endometrial tissue is usually located in the pelvis \nbut can manifest in many other areas of the body. The \nmost common areas of involvement include the ovaries, \nuterosacral and broad ligaments, fallopian tubes, appendix, \nand the sigmoid colon (2). Based on epidemiological data, \nthe incidence of endometriosis in a typical population is \nestimated to be 4-15%, which varies depending on the \nsource of the disease (3). The primary suspicion of its \nexistence is based on clinical symptoms. The symptoms of \nendometriosis include infertility, dyspareunia, dyschezia, \npelvic pain, and dysmenorrhea (4). The gold standard \ndiagnostic method is the observation of endometriotic \nlesions upon surgery with or without biopsy (5). \nEndometriosis is the most common cause of secondary \nEffect of Curcumin Nanomicelle on the Intensity of \nDysmenorrhea in Endometriosis Patients: A Randomized \nTriple-Blind Placebo-Controlled Trial\nMalihe Amirian1 ID\n, Navid Omidkhoda2 ID\n, Leli Hafizi3 ID\n, Maliheh Mahmoudinia4 ID\n, Shabnam Niroumand5 ID\n, Amir \nHooshang Mohammadpour2,6 ID\n, Shima Hatami7* ID\n1Department of Reproductive Medicine and Gynecology, Milad (Mashhad) Infertility Center, Mashhad University of Medical \nSciences, Mashhad, Iran\n2Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran \n3Department of Obstetrics and Gynecology, Women’s Health Research Center, Faculty of Medicine, Mashhad University of \nMedical Sciences, Mashhad, Iran \n4Department of Obstetrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran \n5Department of Community Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran \n6Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran \n7Department of Obstetrics and Gynecology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran \n*Corresponding Author: Shima Hatami, Email: Shimahatami1369@gmail.com\nhttps://jkmu.kmu.ac.ir\n10.34172/jkmu.3820\nJKMU. 2025;32:3820\nOriginal Article\n© 2025 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the \nterms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted \nuse, distribution, and reproduction in any medium, provided the original work is properly cited.\nAbstract\nBackground: Consisting of endometrial tissue outside the uterus, endometriosis is a persistent gynecological illness that causes \ninfertility, pelvic pain, and dysmenorrhea. Curcumin is a bioactive ingredient derived from the spice turmeric and has many \npharmacological properties. This study aimed to determine how curcumin affected the severity of dysmenorrhea in patients with \nendometriosis.\nMethods: This research was a triple-blind, randomized-controlled clinical trial conducted on patients referred to the gynecological \nclinic at the Ghaem and Imam Reza hospitals in Mashhad, Iran. Participants were randomly allocated to the placebo (n = 25) and \ncurcumin nanomicelle (n = 25) groups. Each patient received two capsules daily (intervention: 40 mg of curcumin nanomicelle; \ncontrol: placebo) for three months. Before treatment and at the end of the first, second, and third months, the severity of \ndysmenorrhea, dyspareunia, dyschezia, and chronic pelvic pain was measured using the visual analog scale (VAS). The data were \nanalyzed using SPSS version 26.\nResults: The initial and final dysmenorrhea intensity scores differed by 1.66 ± 2.05 and 4.56 ± 1.66 in the placebo and curcumin \ngroups, respectively (P < 0.001). The placebo and curcumin groups had significantly higher rates of dyspareunia (P < 0.02), dyschezia \n(P < 0.02), and chronic pelvic pain (P < 0.001).\nConclusion: Although we have limitations, such as the small sample size and restricted generalizability of the results to other \npopulations, our findings demonstrate the possible benefits of curcumin in the improvement of dysmenorrhea, dyspareunia, \ndyschezia, and chronic pelvic pain in patients with endometriosis.\nKeywords: Endometriosis, Dysmenorrhea, Complementary therapy, Herbal medicine, Pelvic pain\nReceived: November 17, 2023, Accepted: April 9, 2025, ePublished: October 11, 2025\nCitation: Amirian M, Omidkhoda N, Hafizi L, Mahmoudinia M, Niroumand S, Mohammadpour AH, et al. Effect of curcumin nanomicelle \non the intensity of dysmenorrhea in endometriosis patients: a randomized triple-blind placebo-controlled trial. Journal of Kerman University \nof Medical Sciences. 2025;32:3820. doi:10.34172/jkmu.3820\nJournal of \nKerman University of Medical Sciences\nOpen Access\nPublish Free\n\nAmirian et al\nJournal of Kerman University of Medical Sciences. 2025;32:38202\ndysmenorrhea (6). Endometriosis’ dysmenorrhea usually \nbegins before menstruation and persists during or after \nthis period. This pain is regularly diffused through the \npelvis or spread over the back, and may be accompanied by \npressure in the rectum, nausea, and transient diarrhea (7). \nIt is hypothesized that the mechanism of dysmenorrhea in \nendometriosis patients is related to prostaglandins (PGs) \nbecause of their higher concentration in the menstrual \nblood of these patients (8). A study by Bulletti et al \nrevealed that uterine contractions had higher frequency, \namplitude, and basal pressure tone in women with \nendometriosis (9). Hence, severe dysmenorrhea in women \nwith endometriosis may be a consequence of abnormal \ncontractions of the uterus. Although many chemical \ndrugs are used to reduce the intensity of endometriosis’ \ndysmenorrhea, their consumption has been limited due to \na wide range of adverse effects (10). Hormonal therapy, \nincluding combined estrogen-progestin contraceptives, \nprogestogens, and gonadotropin-releasing hormone \n(GnRH) analogues, seeks to restrict ovarian hormone \nproduction to minimize endometriotic lesion activity. \nHowever, these treatments typically provide temporary \nrelief, with symptoms recurring after therapy is ceased. \nFurthermore, not all patients have adequate pain relief \nthroughout treatment (11). Long-term use of hormonal \ntreatments can lead to side effects such as bone density loss, \nmood changes, weight gain, and vasomotor symptoms. \nFor instance, GnRH analogs induce a hypoestrogenic \nstate, potentially causing menopausal-like symptoms \nand decreasing bone mineral density (12). Given these \nlimitations, there is a compelling need to explore \nalternative treatments that offer effective symptom relief \nwith fewer side effects. Alternatively, herbal medicine \nand complementary products such as ginkgo, magnesium \npyrrolidone, saffron, St. John’s Wort, soy, and vitamin E \nare being administered extensively in many inflammatory \nconditions, such as premenstrual syndrome (PMS) and \ndysmenorrhea (13). Turmeric is the source of curcumin, \na bioactive substance that belongs to the Zingiberaceae \nfamily. Curcumin has many pharmacological properties, \nincluding anti-inflammatory, antineoplastic, antioxidant, \ncardioprotective, immunomodulatory, lipid-lowering, \nantidepressant, and analgesic (14-16). Curcumin’s \ntherapeutic use has been affected by its low bioavailability \ndue to low solubility and rapid metabolism. Curcumin’s \nbioavailability and therapeutic efficacy have been improved \nusing nanotechnology-based delivery technologies, such \nas nanomicelle. Nano-micelles can enhance curcumin’s \nsolubility, stability, and absorption, potentially improving \nits therapeutic efficacy in endometriosis patients \n(17). It is interesting to note that curcumin has been \ndemonstrated to suppress PG formation by inhibiting the \ncyclooxygenase-2 (COX-2) enzyme (18). Additionally, the \nclinical effects of curcumin on endometriosis have not \nbeen previously investigated. This study was thus carried \nout to examine the impact of curcumin nanomicelle \non the severity of dysmenorrhea and other symptoms, \nincluding dyspareunia, dyschezia, and chronic pelvic pain \nin patients with endometriosis, based on the role of PGs in \nendometriosis’ dysmenorrhea. \nMethods \nStudy Design \nThis study was a triple-blind, randomized clinical trial \nwith control and intervention groups, performed from \nDecember 2020 to November 2021, at the gynecology \nclinic of Ghaem and Imam Reza hospitals affiliated with \nthe Mashhad University of Medical Sciences, Mashhad, \nIran. To report this clinical research, we followed the \nCONSORT reporting criteria (19). \nStudy Population \nSixty patients with endometriosis were assessed, and 50 \npatients were included in the study based on inclusion and \nexclusion criteria.\nThe following were the requirements for inclusion: \ndiagnosis of endometriosis based on ultrasound, magnetic \nresonance imaging (MRI), or surgery (based on persistent \ncyst or typical endometriosis profile); complaints of \ndysmenorrhea; and age of 15-45 years. The exclusion \ncriteria were treatment with GnRH agonist or antagonist \ndrugs, other medical treatments such as dinogest and \ncontraceptives, the intention to become pregnant, and any \nmajor allergic reaction related to curcumin. \nStudy Protocol\nPatients who qualified were divided into two groups \nrandomly: the curcumin nanomicelle group and the \nplacebo group. The intervention group received two \noral capsules (red oval soft gel capsules) of curcumin \nnanomicelle (40 mg) (Cinacurcumin, Minoo \nPharmaceutical Company, Tehran, Iran) daily for three \nmonths. The encapsulation percentage of curcumin in the \nformulation was approximately 100%. In addition, it has \nbeen demonstrated that the bioavailability of curcumin \nnanomicelle is significantly higher than that of other \nformulations (20). The control group was concurrently \ntreated with two placebo capsules (red oval soft gel \ncapsules) per day. Patients in both groups only received \nnon-steroidal anti-inflammatory drugs (NSAIDs) as \na standard treatment in cases of extreme pain because \nthey had low stages of endometriosis. We measured \ncharacteristics such as age (year), BMI, marital status, \nparity status, dysmenorrhea, dyspareunia, dyschezia, and \npain severity between periods at baseline. The severity of \ndysmenorrhea, dyspareunia, dyschezia, and pain severity \nbetween periods was measured by the visual analog scale \n(V AS) score. A gynecologist used the V AS score to assess \nthe severity of dysmenorrhea, dyspareunia, dyschezia, \nand pain severity between periods on the first day of \n\nJournal of Kerman University of Medical Sciences. 2025;32:3820 3\nCurcumin and intensity of dysmenorrhea in endometriosis patients\nmenstruation before beginning treatment. The V AS uses \na 10-cm horizontal line with a score range of 0–10. Zero \ntraditionally denotes “no pain at all, ” while 10 implies the \n“worst pain” that is physically possible. The treatment \nbegan on that day (the first day of menstruation). The \ngynecologist was trained to use the V AS scale consistently \nby participating in educational workshops and simulation-\nbased trainings. We conducted workshops that provided \ncomprehensive education on the V AS, including its \npurpose, application, and interpretation. Furthermore, \nsimulation-based training provided an excellent \nopportunity for the gynecologist to improve her skills \nin administering the V AS. By participating in realistic \nscenarios with standardized patients, the practitioner \ndeveloped her communication skills, gained confidence, \nand ensured adherence to standardized procedures, \nresulting in better patient outcomes. \nDuring the three months of treatment, patients were \nevaluated according to the intensity of dysmenorrhea, \ndyspareunia, dyschezia, and pain severity between periods \nat 4-time points, before the treatment, at the end of the \nfirst month, at the end of the second month, and finally, at \nthe end of the third month (the last appointment and the \nend of the treatment). However, detecting the differences \nwithin each study group over time was also important and \nwas assessed. To detect any overall differences within each \ngroup, we calculated the difference between initial and \nfinal measurements.\nOutcome \nThe severity of dysmenorrhea was assessed and compared \nwith the placebo group as a primary endpoint, and the \nseverity of dyspareunia, dyschezia, and chronic pelvic \npain was measured and compared with the placebo group \nas our secondary endpoints.  Additionally, medication \nadherence was assessed at each visit.\nRandomization and Blinding\nThe random allocation sequence was created using \na computer-generated randomized list that was \nobtained from the randomization.com website. The \nMinoo Company packed bottles with a placebo and \nnanocurcumin, then numbered them (a number between \n1 and 50) according to the allocation order. The clinical \npharmacist or physician, depending on which patient \nmet the inclusion criteria, gave the boxes to them. The \nphysician assessed the patients while they were receiving \ntreatment. The clinical pharmacist handled the data \nentry and gathering into the SPSS program. The patients’ \ngroup assignment was undisclosed to the clinicians. \nBefore the clinical pharmacist analysis of the data, \ngrouping data were added to the SPSS file according to \nthe allocation sequence, but only as group 1 or 2, by a \nthird party who was not involved in the investigation. \nAs a result, the clinical pharmacist was unaware of the \npatient’s allocation to treatments or placebos. Following \nthe analysis, the third party defined codes 1 and 2. \nThus, the patient’s group assignment was unknown to \nthe physician, the clinical pharmacist, or the surgery \nspecialist.\nSample Size Calculation and Statistical Analysis\nSince this study was intended to be a pilot study, the \nsample size was determined using the formula below. \nBased on the findings of the Warzecha et al study (5), the \nsample size was determined to be 22 by assuming equal \nvariances and taking into account a two-level reduction \nin dysmenorrhea pain that was substantial in the view \nof our experts. Statistical analysis was performed using \nSPSS version 26. Descriptive statistics (mean and standard \ndeviation) were calculated for age, body mass index \n(BMI), marital status, and parity. Categorical variables \nwere compared with the chi-square test. The Kolmogorov-\nSmirnov test was used to assess the normality of the data. \nTo compare the mean or median between two independent \ngroups, the independent t-test and the Mann-Whitney \nU-test were utilized, respectively. Any discrepancies \nbetween related means or medians were found using the \nFriedman test or repeated measures ANOV A. Statistical \nsignificance was set at P ≤ 0.05, which was considered \nstatistically significant.\n( )\n( )\n2\n22\n12 1 1 2\n12 2\n12\nnn\nSS Z Z\nXX\nαβ −−\n++ \n= =\n−\nResults \nPopulation Study\nThe present study was conducted on 50 patients; 25 were \ntreated with curcumin in the intervention group, and 25 \nwere treated with a placebo. All of these patients fulfilled \nthe trial criteria, were enrolled in the study by protocol, \nand completed the whole three months of trial duration \n(Figure 1). We measured characteristics such as age, BMI, \nmarital status, parity status, dysmenorrhea, dyspareunia, \ndyschezia, and pain severity between periods at baseline \n(Table 1). At baseline, there were no notable variations \namong the patients.\nComparison of Dysmenorrhea Severity Between Placebo \nand Curcumin Nanomicelle\nBefore intervention, we found no discernible difference \nin the severity of dysmenorrhea between the groups \nreceiving curcumin nanomicelle and a placebo. However, \npain levels in the intervention group, as mentioned in \nTable 2, decreased over time. In the placebo group, the \npain severity decreased during the study, but not as much \nas in the patients treated with curcumin nanomicelle. \nNevertheless, the reduction was statistically significant in \nthe placebo group too. In addition, differences between \n\nAmirian et al\nJournal of Kerman University of Medical Sciences. 2025;32:38204\nthe initial and final scores were measured. Interestingly, \nwe found that curcumin nanomicelle  had a significantly \ngreater effect on reducing the severity of dysmenorrhea \nthan the placebo group (P < 0.001) (Table 3, Figure 2).\nComparison of Dyspareunia Severity Between Placebo \nand Curcumin Nanomicelle \nIn examining patients at baseline regarding pain during \nintercourse or dyspareunia, we found no substantial \ndifference between patients in the intervention and placebo \ngroups. After the administration of curcumin, the patient’s \npain level in the intervention group decreased gradually. \nCurcumin significantly decreased dyspareunia at the end \nof the study compared to the initial examination. Also, in \nthe placebo group, we observed a reduction in pain levels \nduring the study ( Table 2). Ultimately, we demonstrated \nthat dyspareunia reduction was substantially superior in \nthe curcumin group than in the placebo group ( P < 0.02) \n(Table 3, Figure 3).\nFigure 1. Flow diagram of the trial\nTable 1. The Baseline characteristics of the participants\nCharacteristics\nGroup\nP valuea\nPlacebo (n = 25)\nMean ± SD\nCurcumin (n = 25)\nMean ± SD\nAge (year) 31.88 ± 6.13 32.36 ± 6.21 1\nBMI (kg/m2) 25.36 ± 3.23 24.76 ± 3.58 0.57\nMarital status\n0.74Married 18 (72%) 19 (76%)\nSingle 7 (28%) 6 (24%)\nParity status\n0.56No child 15 (60%) 13 (52%)\nWith children (1-4) 10 (40%) 12 (48%)\nDysmenorrhea score 7 ± 1.44 6.88 ± 1.48 0.81\nDyspareunia score 5.9 ± 2.62 6.08 ± 1.84 0.36\nDyschezia score 5 ± 3.16 6.08 ± 1.65 0.41\nChronic pelvic pain score 5.11 ± 144 5.38 ± 1.62 0.70\na Calculated by the Mann-Whitney U test; * Significant differences vs. \nplacebo group (*P < 0.05).\nFigure 2.  Dysmenorrhea severity in placebo and curcumin nanomicelle \ngroups\n6.88 7\n5.44\n5.88\n4.08\n5.08\n2.32\n5\n0\n1\n2\n3\n4\n5\n6\n7\n8\nCurcumin Placebo\nVAS score\nDysmenorrhea\nBaseline First Month Second Month Third Month\n\n\nJournal of Kerman University of Medical Sciences. 2025;32:3820 5\nCurcumin and intensity of dysmenorrhea in endometriosis patients\nComparison of Dyschezia Severity Between Placebo and \nCurcumin Nanomicelle \nDyschezia or  pain and difficulty during defecation \nseverity were not statistically different at baseline between \nthe intervention and control groups . Interestingly, pain \nreduction during the study period was statistically \nsignificant in the curcumin group ( P < 0.001). However, \npatients in the placebo group experienced less and \nnon-significant pain reduction during the study period \n(P < 0.43) ( Table 2 ). Furthermore, we compared the \namount of pain reduction between the placebo and the \nintervention groups. Finally, it was demonstrated that \ncurcumin significantly decreased dyschezia compared to \nthe placebo group (P < 0.02) (Table 3, Figure 4).\nComparison of Chronic Pelvic Pain Between Placebo and \nCurcumin Nanomicelle \nThe chronic pelvic pain in the curcumin group and the \nplacebo group at baseline was not considerably different. \nNevertheless, after curcumin treatment, the pain was \nreduced in the intervention group and significantly \nimproved compared to the initial measurements. \nConversely, in the placebo group, we observed a non-\nsignificant increase in pain levels during the study \n(Table 2). In addition, the difference in initial and final \nscores was measured, and the intervention group showed \na significantly greater reduction in chronic pelvic pain \nthan the placebo group (P < 0.001) (Table 3, Figure 5).\nDiscussion \nThis study presents valuable results regarding the effects of \ncurcumin nanomicelle on the intensity of dysmenorrhea \npain in patients with endometriosis. Based on our findings, \npatients with endometriosis and dysmenorrhea after \nthree months of treatment with curcumin nanomicelle  \nshowed significant reductions in the mean scores of \ndysmenorrhea, dyspareunia, dyschezia, and chronic pelvic \npain in comparison with the control group. To the best \nof our knowledge, this is the first study to investigate the \neffect of curcumin on dysmenorrhea intensity in patients \nwith endometriosis. \nRegarding the pathophysiology of endometriosis, some \nideas have been put out; the most commonly recognized \nof them is Sampson’s implantation theory. According to \nthis opinion, retrograde menstruation is the mechanism \nby which some endometrial cells enter the peritoneal \ncavity (21). Therefore, the adhesion and multiplication \nof endometrial cells, cellular invasion, and angiogenesis \nare crucial in the development of endometriosis (22). \nThe pathophysiology of endometriosis involves several \ninflammatory and growth factors, angiogenic stimulants, \nand adhesion molecules, including vascular endothelial \ngrowth factor (VEGF), transforming growth factor-β \n(TGF-β), interleukin-6 (IL-6), IL-8, and tumor necrosis \nfactor-α (TNF-α) (21). Curcumin is an anti-inflammatory \nagent that has recently demonstrated additional properties \nsuch as anti-angiogenic, anti-metastatic, anti-mutagenic, \nand hormonal regulatory (23,24). A study performed \nby Zhang et al analyzed the impact of curcumin on \nendometrial cells in patients with endometriosis. In this \nTable 2. Dysmenorrhea, dyspareunia, dyschezia, and chronic pelvic pain severity in placebo and curcumin nanomicelle groups \nDysmenorrhea Dyspareunia Dyschezia Chronic pelvic pain\nPlacebo (n = 25)\n(Median ± IQR)\nCurcumin \n(n = 25)\n(Median ± IQR)\nPlacebo (n = 18)\n(Median ± IQR)\nCurcumin \n(n = 19)\n(Median ± IQR)\nPlacebo (n = 25)\n(Median ± IQR)\nCurcumin \n(n = 25)\n(Median ± IQR)\nPlacebo (n = 25)\n(Median ± IQR)\nCurcumin \n(n = 25)\n(Median ± IQR)\nFirst month 5.88 ± 1.71 5.44 ± 1.47 4.36 ± 2.20 4.31 ± 1.79 4.38 ± 3.62 4.15 ± 1.86 3.89 ± 1.62 3.67 ± 1.88\nSecond month 5.08 ± 1.86 4.08 ± 1.60 3.18 ± 1.25 2.62 ± 2.10 3.88 ± 1.80 1.92 ± 1.93 4 ± 1.76 1.57 ± 1.53\nThird month 5.38 ± 1.86 2.32 ± 1.40 2.73 ± 1.42 1.38 ± 1.80 3.25 ± 1.48 1.31 ± 1.70 4.11 ± 2.49 1.10 ± 1.44\nP valuea  < 0.001*  < 0.001*  < 0.01*  < 0.001*  < 0.43  < 0.001*  < 0.01*  < 0.001*\na Calculated by the Friedman test; * Significant differences vs. placebo group (*P < 0.05).\nTable 3. Comparison of initial and final difference scores between the \nplacebo and curcumin groups\nInitial and final \ndifference score\nPlacebo \n(Median ± IQR)\nCurcumin \n(Median ± IQR) P valuea\nDysmenorrhea 1.66 ± 2.05 4.56 ± 1.66  < 0.001*\nDyspareunia 2.36 ± 2.78 4.69 ± 1.54  < 0.02*\nDyschezia 1.75 ± 2.43 4.76 ± 2.31  < 0.02*\nChronic pelvic pain 1 ± 1.88 4.28 ± 1.79  < 0.001*\na Calculated by the Mann-Whitney U test; * Significant differences vs. \nplacebo group (P < 0.05).\nFigure 3.  Dysmenorrhea severity in placebo and curcumin nanomicelle \ngroups\n6.08 5.9\n4.31 4.36\n2.62\n3.18\n1.38\n2.3\n0\n1\n2\n3\n4\n5\n6\n7\nCurcumin Placebo\nVAS score\nDyspareunia\nBaseline First month Second month Third month\n\nAmirian et al\nJournal of Kerman University of Medical Sciences. 2025;32:38206\nstudy, endometriotic epithelial cells, normal endometrial \nstromal cells, normal epithelial cells, and endometriotic \nstromal cells were isolated from premenopausal women \nwho had undergone hysterectomy and were fixed in 10% \nformalin. Then, the cells were examined for pathology \nand were excluded from the study in case of malignancy. \nCells estradiol value and the effect of curcumin on cell \nproliferation were assessed. Finally, they found that \ncurcumin inhibited cell proliferation by reducing the \namount of estradiol in endometrial cells (25). Another \nstudy investigated the effect of curcumin on apoptosis \nand the progression of endometriosis in BALB/c mice. \nThey carried out a three-day pretreatment of curcumin \nbefore the induction of peritoneal endometriosis, and \nthen, a five-day treatment with curcumin or celecoxib. \nThey reported that the development of peritoneal \nendometrial glands significantly decreased in the \ncurcumin group. They also reported an increase in the \nratio of  B-cell lymphoma protein 2 (Bcl-2)-associated \nX (Bax), elevation of mitochondrial apoptotic factors \nsuch as caspase-9 and cytochrome-c, and upregulation \nof anti-tumor factors like P53 in the curcumin group \ncompared with controls (26). Furthermore, many other \nstudies have reported similar results in terms of the \neffects of curcumin on the proliferation and apoptosis \nof endometrial cells (27-29). Angiogenesis and a new \nblood supply are important factors in the development \nof endometriosis. Interestingly, it has been reported that \nthe angiogenic activity and concentration of angiogenic \nfactors such as VEGF are substantially higher in women \nwith endometriosis (30,31). Some studies have explored \nthe antiangiogenic effects of curcumin in rodent models \nof endometriosis. It has been stated that curcumin can \nrepress the micro-vessel density (MVD) in the ectopic \nendometrium and reduce VEGF in the serum and ectopic \nendometrium, while it had no substantial impact on MVD \nin the utopic endometrium in another investigation (32-\n34). Inflammatory agents, such as TNF-α, IL-1, IL-6, \nIL-8, and TGF-β, play a crucial role in the pathogenesis \nand progression of endometriosis (35). Curcumin has \nbeen identified as a novel anti-inflammatory agent, and \nits effects have been proven in many studies (36,37). \nIn a previous study, curcumin significantly decreased \nthe secretion of IL-6, IL-8, Monocyte chemoattractant \nprotein-1 (MCP-1), and nuclear factor kappa-light-chain-\nenhancer of activated B cells ( NF-κB) in human ectopic \nendometriotic stromal cells (38). Curcumin mainly \nreduces inflammation by blocking the NF-κB signaling \npathway, which is a major inflammatory regulator. TNF-α \nand IL-6 are two pro-inflammatory cytokines that are \ntranscriptionally triggered by NF-κB activation. By \nblocking the phosphorylation and degradation of IκBα, \ncurcumin inhibits NF-κB activation and prevents NF-κB \nfrom translocating to the nucleus. This results in reduced \nexpression of TNF-α, IL-6, and other inflammatory \nmediators (38- 40). In another study conducted by \nSoetikno et al in rats, curcumin treatment significantly \nreduced the abundance of COX-2, NF-κB, TNF-α, and \nmalondialdehyde (MDA) levels (41). A randomized, \ndouble-blinded clinical trial consisting of 70 patients \ndemonstrated that curcumin has a substantial effect on \nPMS symptoms, probably due to its anti-inflammatory \neffects (42). In another randomized controlled study of 76 \nfemale patients treated with curcumin for three months, \ncurcumin had a brilliant effect on PMS symptoms and \ndysmenorrhea in comparison with the control group (43). \nIn addition, a triple-blind, placebo-controlled clinical \ntrial investigated the effects of curcumin on menstrual \npatterns, PMS, and dysmenorrhea. They enrolled 124 \npatients and divided them into two groups. They treated \npatients in the intervention group with curcumin for \nthree months. Eventually, they reported a significant \nimprovement resulting from curcumin in PMS symptoms \nand dysmenorrhea (44). Furthermore, another clinical \ntrial reported that the co-administration of curcumin \nand mefenamic acid could have a significant effect on \nprimary dysmenorrhea (45). Specifically, many studies \nFigure 4. Dyschezia severity in placebo and curcumin nanomicelle groups Figure 5. Chronic pelvic pain severity in placebo and curcumin nanomicelle \ngroups\n6.08\n5\n4.15 4.38\n1.92\n3.88\n1.31\n3.25\n0\n1\n2\n3\n4\n5\n6\n7\nCurcumin Placebo\nVAS score\nDyschezia \nBaseline First month Second month Third month\n5.38\n5.11\n3.67\n3.89\n1.57\n4\n1.1\n4.11\n0\n1\n2\n3\n4\n5\n6\nCurcumin Placebo\nVAS score\nChronic pelvic pain\nBaseline First month Second month Third month\n\nJournal of Kerman University of Medical Sciences. 2025;32:3820 7\nCurcumin and intensity of dysmenorrhea in endometriosis patients\nhave reported that curcumin represses the synthesis \nof PGs through inhibition of the COX-2 enzyme (18). \nFurthermore, it has been mentioned that the main \nmechanism of dysmenorrhea in endometriosis patients \nis related to PGs because of their higher concentration in \nthe menstrual blood of these patients (46). In this study, \nwe investigated the effect of curcumin on the intensity of \ndysmenorrhea in endometriosis patients, which showed \nsignificant reductions in the mean scores of dysmenorrhea, \ndyspareunia, dyschezia, and chronic pelvic pain compared \nto those in the control group. \nNonetheless, we had some limitations, such as a \nsmall sample size due to the limited number of patients \nwho fulfilled the inclusion criteria and the shortness \nof the follow-up period. A longer follow-up period and \ncombining curcumin with other treatments would reveal \nmore accurate results about the efficacy and adverse \neffects of curcumin nanomicelle on patients. Apart from \nthat, demographic factors such as age, marital status, \nparity, and education level can significantly impact the \nprevalence and severity of dysmenorrhea and other \nendometriosis-related symptoms. These demographic \nvariables can influence both the perception and reporting \nof symptoms, potentially affecting the outcomes of \ninterventions like curcumin nanomicelle (47). Although \nthere were no significant differences between the placebo \nand intervention groups in terms of age, marital status, \nparity, and BMI at baseline, we did not record education \nlevel. Future research should include education level as a \ncompounding component. Finally, our study’s limitations \ninclude the limited generalizability of our findings to \nother populations due to the small sample size and \nrigid inclusion criteria. Our study had several strengths, \nincluding a randomized, triple-blind, and placebo-\ncontrolled design and three months of treatment with \ncurcumin nanomicelle  as an identified and standard \nactive turmeric plant constituent. \nConclusion\nThe results of this randomized, triple-blind, placebo-\ncontrolled clinical trial indicated that patients with \nendometriosis who used two oral capsules (40 mg) of \ncurcumin nanomicelle daily for three months reported \na significant reduction in the severity of dysmenorrhea, \ndyspareunia, dyschezia, and chronic pelvic pain based \non the V AS score. Although the severity reduction was \nsignificant in the placebo groups, the reduction was \nsignificantly greater in the curcumin groups than in \nthe placebo groups. To assess the impact of curcumin \non patients with endometriosis more accurately, more \nclinical trials with larger sample sizes and longer follow-\nups are necessary.\nAcknowledgments\nThe authors appreciate Mashhad University of Medical Sciences for \nfunding this study.\nAuthors’ Contribution \nConceptualization: Shima Hatami, Malihe Amirian.\nData curation: Shima Hatami.\nFormal analysis: Shima Hatami, Malihe Amirian.\nFunding acquisition: Malihe Amirian.\nInvestigation: Malihe Amirian.\nMethodology: Leli Hafizi.\nProject administration: Shima Hatami, Navid Omidkhoda.\nResources: Malihe Amirian.\nSoftware: Shabnam Niroumand.\nSupervision: Malihe Mahmoudinia, Amir Hooshang \nMohammadpour.\nValidation: Malihe Mahmoudinia, Amir Hooshang Mohammadpour, \nMaliheh Amirian.\nVisualization: Navid Omidkhoda, Amir Hooshang Mohammadpour. \nWriting–original draft: Navid Omidkhoda.\nCompeting Interests \nThe authors declare that they have no conflict of interest.\nEthical Approval \nThe Ethics Committee of Mashhad University of Medical Sciences \napproved the study (IR.MUMS.MEDICAL.REC.1400.282) \nand was registered in the Iranian Registry of Clinical Trials \n(IRCT20201121049457N1).\nFunding \nThis work was supported by the Mashhad University of Medical \nSciences.\nReferences\n1. 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Open J Obstet Gynecol. \n2020;10(8):1000-10. doi: 10.4236/ojog.2020.1080095.","source_license":"CC0","license_restricted":false}