Plant-Based Complementary Treatments for Menstrual Symptoms in Uterine Fibroids: A Triple-Blind, Randomized, Placebo-Controlled Trial

Plant-Based Complementary Treatments for Menstrual Symptoms in Uterine Fibroids: A Triple-Blind, Randomized, Placebo-Controlled Trial | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 20 March 2025 V1 Latest version Share on Plant-Based Complementary Treatments for Menstrual Symptoms in Uterine Fibroids: A Triple-Blind, Randomized, Placebo-Controlled Trial Authors : Maryam Jafari , Fatemeh Heshmatnia , Santosh Giri , Marzieh Akbarzadeh , Masoumeh Emamghoreishi , Aida Iraji , Fatemeh Najib , and Subash Thapa 0000-0002-1182-8511 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174245783.36569247/v1 1006 views 197 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: The efficacy of traditional plant-based treatments, such as chamomile and sumac, for uterine fibroids-associated menstrual symptoms is not known. In this randomized trial, we evaluated the efficacy and safety of sumac and chamomile in reducing the duration and intensity of menstrual bleeding and pain associated with uterine fibroids. Experimental approach: This triple-blind, three-arm, randomized, placebo-controlled trial was conducted among 154 women with uterine fibroids. Participants were randomly assigned to receive either a placebo (n=52), 500 mg of dried sumac powder (n=50), or 500 mg of dried chamomile powder (n=52) every 8 hours from days 1 to 7 of two consecutive menstrual cycles. Generalized Estimating Equations (GEE) were used to analyze repeated measures while accounting for within-subject correlations. Bonferroni correction was applied for post hoc comparisons to adjust for multiple testing. Key results: In the second menstrual cycle, chamomile reduced vaginal bleeding by 20% and bleeding duration by 20%, while sumac reduced bleeding by 14% and duration by 19%. Chamomile also decreased pain intensity by 46% and pain duration by 42%, whereas sumac reduced pain intensity by 45% and duration by 35%. Post-hoc analyses confirmed significant reductions in menstrual bleeding and pain (both intensity and duration) for participants in both groups, with effects more pronounced by the second cycle. Conclusions and implications: The study suggests that chamomile and sumac may serve as effective natural treatments for managing heavy menstrual bleeding and pain associated with uterine fibroids, offering a complementary non-hormonal, non-surgical therapy. Introduction Uterine fibroids (leiomyomas) are myometrial masses and the most common benign uterine tumors. Between 1990 and 2019, the global age-standardized incidence of uterine fibroids increased by 6.87%, rising from 226 to 241 per 100,000 women, with a consistent upward trend, largely attributed to population aging, increased incidence of metabolic diseases and increased infertility rates 1(). This benign tumor, depending on its size and location, can be symptomatic, with key symptoms such as heavy menstrual bleeding and pain occurring in approximately 30% of cases, often requiring medical or surgical intervention 2-4(). Mechanisms such as increased endometrial thickness, inflamed uterine arteries, impaired uterine contraction, and endometrial ulcer contribute to heavy menstrual bleeding and pain in these patients, adding psychological and financial burdens to individuals, families and the state 5-8(). Conventional treatments such as hormonal therapy and surgical procedures are not accessible to all and have limitations, including side effects, and recurrence 9(). Non-hormonal therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) and tranexamic acid can temporarily minimize the loss of menstrual blood and pain for those who wish to delay surgical intervention 10-12(). The endometrium of women with excessive menstrual bleeding has higher levels of prostaglandins E2 and F2α compared to those with normal menstruation. NSAIDs lower prostaglandin levels and help control bleeding by inhibiting the Cyclooxygenase (COX) enzyme 13(). Even though NSAIDs possess a range of therapeutic benefits for these women, they are also infamous for several severe side effects, including cardiovascular risks, gastrointestinal toxicities, renal injuries, and hepatotoxicity, and other minor conditions 1415(, ). Given these constraints, there is growing interest in exploring alternative, plant-based therapies with potential therapeutic benefits and fewer adverse effects. The use of medicinal herbs containing phenolics and flavonoids, are commonly used to prevent undesirable inflammatory processes as they possess anti-inflammatory properties. One of the mechanisms of actions is that certain enzymes, factors, and proteins may promote anti-inflammatory pathways or interfere with those involved in inflammatory pathways, including lipoxygenases, cyclooxygenases, and prostaglandins 16(). Chamomile, scientifically named Matricaria recutita L., is an herbal supplement that is similar to NSAIDs in reducing menstrual bleeding via blocking COX and lipoxygenase by stopping the production of prostaglandins 1718(, ). Another famous plant in the Middle East is sumac with the scientific name of Rhus coriaria L. Sumac is a rich plant in tannin, which induce anti-inflammatory and homeostatic effects, reducing menstrual bleeding by contracting capillary endothelium 19-22(). Sumac and chamomile are rich source of flavonoid and phenolic content and commonly used by women as complementary and alternative medications (CAM) for inflammation, and menstrual disorders 2324(, ). The use of these alternative treatments among women with fibroid-associated menstrual problems will help reduce the use of hormone therapy and analgesics, improving the quality of life for women with the least complicated drugs. However, their efficacy is not well-documented specifically for the symptomatic treatment of uterine fibroids. Such evidence is important for the use of traditional herbal medicines, such as sumac and chamomile, as alternative prescription medicines in clinical guidelines. Therefore, the aim of this study was to evaluate the efficacy and safety of sumac and chamomile in reducing the duration and intensity of menstrual bleeding and pain associated with uterine fibroids among women aged 20–45 years. We hypothesized that use of sumac and chamomile would be more effective than placebo in reducing duration and intensity of menstrual bleeding and pain. Study design This was a three arm, triple-blind, randomized, placebo-controlled trial conducted at the gynecology clinics of Motahari Hospital and Hazrat Zainab Hospital in Shiraz, Iran from August 1, 2020, to September 31, 2021. The participants were assigned to chamomile treatment or sumac treatment or placebo and were follow up for two consecutive menstrual cycles after treatment. The trial was registered at the Iranian Registry of Clinical Trails (IRCT20200113046115N1). The article conforms with the CONSORT guideline. Participants A total of 183 women were confirmed to have uterine fibroid (Leiomyoma) and were eligible in this trial. Women were eligible in the trial if they were aged 20-44 years who presented with complaints of heavy vaginal bleeding (a score ≥ 100 based on the Pictorial Blood Loss Assessment Chart) and with moderate-to-severe uterine fibroid-associated pain moderate to severe menstrual pain (e.g., lower abdominal, low back pain with Visual analog scale score of ≥4 for a minimum of two days during a menstrual cycle. Women were confirmed by checking their recent (<2-month) ultrasound test report showing at least one fibroid measured ≥ 2.5 cm. Only women who were literate, not working as a professional athlete, not taking vitamin supplements, those who had regular menstrual cycles, those who were not consuming any hormonal or herbal medicines were included. Not included were women with known diseases, such as thyroid disease, endometriosis, adenomyosis, malignancies, etc. based on their medical files or ultrasound report. Those who were pregnant or lactating, reported of having allergies to sumac, chamomile, and mefenamic acid, those with a medical history of gastrointestinal, hepatic, cerebral, or renal diseases or coagulation disorders or had intra uterine device inserted or using benzodiazepines were not included in the trial. During the intervention, participants were excluded from the trail if they developed allergic reactions to medications, had asthmatic attacks, had to use anticoagulants, those drinking alcoholic drinks regularly, who became pregnant, had exacerbation of the disease during the trial, or women who self-reported of having lactose intolerance, or dry and recurrent constipation, women who reported of currently having changes in the menstrual period (10 days). Randomization and masking Based on randomly permuted blocks of three, participants were assigned into three groups: chamomile, sumac capsules, and control. Initially, the blocks were divided into three groups labeled A, B, and C. Each letter was then randomly assigned to one of the three groups: sumac, chamomile, or control. The letters were arranged into six possible sequences (1: ABC, 2: ACB, 3: BAC, 4: BCA, 5: CBA, 6: CAB), and a number from 1 to 6 was randomly selected to determine the order of allocation for the first three individuals in the groups. This randomization process was repeated, with a number from 1 to 6 being randomly selected each time. An independent researcher, who was not involved in any other aspect of the trial, conducted the randomization. The participants, the researchers and the statistician were masked for allocation. The capsules of the same size and color in dark color packages was prepared by the pharmacology unit of Shiraz University of Medical Sciences. Only the pharmacist was aware of the content of the capsules based on specific codes assigned to them. Procedures The participants were asked to complete an online survey questionnaire at the end of 7 th day of first menstrual period (baseline), and then at the end of 7 th day of two consecutive menstrual periods from the baseline. All women were prescribed 250 mg capsules of mefenamic acid as a baseline treatment, to be taken three times a day for seven days during all three cycles. Among the two intervention groups, one received a 500 mg Sumac Rus Coriaria capsule, and another received a 500 mg Matricaria chamomile capsule. The control group received a 500mg placebo capsule containing cellulose powder. All the three treatments were administered at the first and second menstrual cycles from the baseline orally three times daily during two consecutive menstrual cycles for the first seven days of menstruation. The participants were instructed to contact the lead researcher (MJ) or the Manager of the Ethics Committee via email or telephone to report any adverse effects, such as severe allergic reactions, bleeding, gastrointestinal distress or low blood pressure. A pharmacist at the Pharmaceutical Unit of Shiraz University of Medical Sciences packaged chamomile flowers, sumac, and lactose into 500 mg capsules of the same color and size in a dark environment, ensuring that the drugs and dosages were standardized according to their phenol content 25(). Chamomile consumption of 500 mg three times a day was recommended by the book, ‘Herbal Therapy and Supplements’ 26(). The consumption of sumac was determined to be 500 mg taken three times a day based on Sabzghabaee et al.’s (2014) recommendation 27(). The plant names were verified with http://www.worldfloraonline.org on March 20, 2020. To ensure the quality and efficacy of these botanical products, chromatographic analysis was used to characterize their phenolic and flavonoid profiles. For chamomile, High-Performance Liquid Chromatography (HPLC) identified and quantified key flavonoids such as apigenin, quercetin, and luteolin, along with their glycosides. The total flavonoid content in chamomile was 2.5% (w/w) as quercetin equivalents. The method used a C18 reversed-phase column with a water (0.1% formic acid) and acetonitrile gradient, detecting at 340 nm. Additionally, Gas Chromatography-Mass Spectrometry (GC-MS) analyzed essential oils like chamazulene and α-bisabolol using a non-polar capillary column (e.g., DB-5) and helium. For sumac, HPLC analyzed its phenolic and flavonoid content, including gallotannins, quercetin, and myricetin, with a total tannin content of 4.2% (w/w) as tannic acid equivalents. The method used a C18 reversed-phase column with a water (0.1% formic acid) and methanol gradient. Detection was at 280 nm for phenolics and 340 nm for flavonoids. To standardize the treatments, the initial concentrations of reagents were selected based on their absorbance close to 1.0 at measured wavelengths. As a result, a freshly prepared methanolic solution of DPPH (2,2-diphenyl-1-picrylhydrazyl) reagent with the concentration of 0.110 mM was used to assess the radical scavenging activity of sumac and chamomile. Briefly, 20 μL of each sample of different were mixed with 180 μL of DPPH reagent in 96-well plate at 25°C temperature 28(). After 30 minutes of incubation in the dark, absorbance measurements were carried out in a Perkin-Elmer Spectrometer at the wavelength of 517 nm. All determinations were performed in triplicate. Based on the DPPH assay, sumac demonstrated superior antioxidant activity with IC 50 of 2.06 (± 0.18) µgr/ml, compared to chamomile with an IC 50 value of 494.92 (± 8.86 µgr/ml). This could be due to the high content of phenolic and flavonoid compounds. The IC 50 value of quercetin as a positive control was 9.43 (± 2.26 µM). Study outcomes Prespecified primary outcomes were reduced duration and amount of menstrual bleeding and pain from baseline to second menstrual cycle. Duration and amount of menstrual bleeding was measured using the Pictorial Blood Loss Assessment Chart (PBLAC), which is a chart that shows menstrual days on the horizontal axis and blood-soaked pads on the vertical axis in three degrees of mild, moderate, and severe. After each pad change, the participants were required to mark the chart according to the amount of blood on the pad, with mild, moderate, and severe degrees of bleeding assigned 1, 5, and 20 scores, respectively. Additionally, one and five points were assigned to small and large clots, respectively. At the end of menstruation, each mark was multiplied by the corresponding coefficient, the obtained numbers were summed up, and the total score was calculated. Scores > 100 represented bleeding greater than 80 ml 2930(, ). Sanitary pads of the same shape and size produced by Golpar Co. without plastic mesh covers were provided to all the participants in all the three menstrual cycles for a more accurate evaluation of the bleeding amount. Researchers ensured that the participants used only the sanitary pads provided to them by the researchers. Intensity of pain symptoms was measured using Visual analog scale (VAS). The participants were instructed to record their subjective feeling of the intensity of pain according to the VAS scale, which is ranged 0 to 10 (0=no pain, 10=worst pain imaginable) 31(). The duration of menstrual pain was measured by asking women to score the number of hours they experienced pain during each day of their menstrual cycle. Statistical analysis Before initiating the trial, a sample size calculation was performed. The power analysis, based on a relative effect size of approximately 0.55, α = 0.05, power = 0.80, and an assumed correlation of 0.5 among repeated measures, indicated that a total of 18 participants (6 per group) is the minimum adequate sample size to detect the treatment effect for this study. Accounting for loss to follow-up, the study recruited 183 participants. Descriptive statistics, including mean and standard deviation (SD), were used for continuous variables, while categorical variables were summarized using frequencies and percentages. The chi-square test was used to compare categorical variables across treatment groups, and one-way analysis of variance (ANOVA) was used for continuous variables. Missing data accounted for <1% of the dataset which were imputed using the most frequent category. To analyze repeated measures data, we used Generalized Estimating Equations (GEE) to account for within-subject correlations over time. GEE was preferred over traditional parametric methods (e.g., linear mixed models and repeated measures ANOVA) because the assumptions of normality and homogeneity of variance were violated. Unlike mixed models, which estimate subject-specific effects, GEE provides population-averaged estimates 3233(, ). Additionally, GEE is robust to deviations from normality and misspecification of the correlation structure, making it suitable for non-normally distributed and non-continuous data. Given the nature of the outcome variables, different distributions and link functions were applied. Vaginal bleeding volume was analyzed using a Gamma family with a log link, as the data was right-skewed and strictly positive. Vaginal bleeding duration, pain intensity, and pain duration were analyzed using Poisson regression with robust standard errors, which is appropriate for count data and avoids the assumption of normality. An exchangeable correlation structure was used, assuming a constant correlation between repeated measures within individuals. Model fit was assessed using Wald Chi-Square tests, and exponentiated coefficients (exp(β)) and 95% confidence interval (CI) were reported to facilitate interpretation in terms of relative change. Post hoc comparisons were conducted using Bonferroni-corrected pairwise comparisons to adjust for multiple testing. The significance level was set at p < 0.05 for all analyses. Statistical analyses were performed using Stata version 18 (StataCorp, USA). Result Study participants Between August 1, 2020, to September 31, 2021, we recruited 183 patients and 61 each were assigned to two interventions and one control groups. We excluded 29 women from the intervention and control groups for the following reasons: unwillingness to continue the trial (n=8), use of other medical treatments (n=7), incorrect completion of the VAS (n=7) and undergoing surgery (n=6). The sumac group had 50 patients, the chamomile and control groups each had 52 patients (Figure 1). The participants’ ages ranged from 28 to 45 years, with a mean age of 36.5 (±4.4) years. Most participants (n=70, 45.5%) were homemakers, with a mean BMI of 24.2 (±1.8) kg/m². The results showed no statistically significant differences among the three groups in terms of demographic characteristics and BMI (p>0.05). Additionally, 31.8% of participants reported a history of myoma in their first-degree relatives. The three groups were well balanced in most socio-demographic and disease, and symptoms related characteristics at baseline. At baseline, the mean duration of menstruation was 7.5 (±1.2) days (Table 1). The results revealed no statistically significant difference among the three groups in terms of the duration of diagnosis of uterine fibroid (p=0.052) and duration of menstruation (p=0.518). At baseline, a total of 98.7% (n=152) reported pelvic pain, with 46.8% (n=72) reporting lower back pain (p=0.116). There was no statistically significant difference between the three groups in terms of the onset of menstrual pain (p=0.984). At baseline, there was no major difference observed between the three groups in terms of the amount and duration of menstrual bleeding, and the intensity and duration of menstrual pain at baseline (Figure 2). Effect on amount and duration of menstrual bleeding After adjusting for the confounders, the GEE model showed a significant effect of treatment on reducing the amount (Wald χ²(12) = 219.72, p < 0.001) and duration of vaginal bleeding (Wald χ²(12) = 416.88, p < 0.001). Compared to baseline and the control group, in the second menstrual cycle, chamomile led to a 20% reduction in the amount of vaginal bleeding (exp(β) = 0.80, 95% CI: 0.74–0.85, p < 0.001), while sumac led to a 14% reduction (exp(β) = 0.86, 95% CI: 0.81–0.92, p < 0.001). Similarly, in the second cycle, chamomile reduced bleeding duration by 20% (exp(β) = 0.80, 95% CI: 0.74–0.86, p < 0.001), and sumac reduced it by 19% (exp(β) = 0.81, 95% CI: 0.76–0.87, p < 0.001) (Table 2, Figure 2). Post-hoc analyses comparing the amount of menstrual bleeding and duration of menstrual bleeding days (Supplementary file 1) indicated that participants in both the chamomile and sumac groups significantly reduced amount and duration of menstrual bleeding, with effects more pronounced by the second cycle. Effect on intensity and duration of menstrual pain The GEE model showed a significant effect of treatments on reducing pain intensity (Wald χ² (12) = 560.99, p < 0.001) and pain duration (Wald χ² (12) = 174.09, p < 0.001). Compared to baseline and the control group, in the second cycle, chamomile resulted in a 46% reduction in pain intensity (exp(β) = 0.54, 95% CI: 0.49–0.61, p < 0.001) and sumac reduced pain intensity by 45% (exp(β) = 0.55, 95% CI: 0.49–0.62, p < 0.001). Similarly, in the second cycle, chamomile led to a 42% reduction in pain duration in the second cycle (exp(β) = 0.58, 95% CI: 0.47–0.72, p < 0.001), while Sumac reduced it by 35% (exp(β) = 0.65, 95% CI: 0.48–0.90, p = 0.009) (Table 2, Figure 2). Post-hoc analyses comparing the amount of menstrual bleeding and duration of menstrual bleeding days (Supplementary file 1) indicated that participants in both the chamomile and sumac groups significantly reduced intensity and duration of menstrual pain, with effects more pronounced by the second cycle. Discussion To our knowledge, this is the first RCT to compare the efficacy of sumac and chamomile on menstrual bleeding and pain associated with uterine fibroids. The trial showed that the use of both chamomile and sumac capsules reduced the severity and duration of menstrual bleeding and pain in patients with fibroids, with the effect being highest at the second menstrual cycle of use. The overall effect of chamomile was slightly superior to that of sumac in reducing intensity and duration of both menstrual bleeding and pain. No serious adverse effects were reported by the participants. The study suggests that chamomile and sumac may serve as effective natural treatments for managing heavy menstrual bleeding and pain associated with uterine fibroids, offering a complementary or alternative non-hormonal, non-surgical therapy. Since excessive menstrual bleeding and pain can severely impact daily life, work productivity, and emotional well-being, these natural treatments may provide relief and enhance the quality of life for individuals with uterine fibroids. The significant reductions in bleeding and pain suggest potential anti-inflammatory, antispasmodic, or hemostatic properties of chamomile and sumac. One of the most important mechanisms that have been proposed to increase menstrual bleeding in women with uterine fibroids is the increased production of prostaglandins F2α and E2 from arachidonic acid by the COX pathway 3435(, ). Chamomile’s chemical compounds including chamazulene, apigenin, flavonoids, and alpha-bisabol provide antioxidant and anti-inflammatory properties 3637(, ), by selectively inhibiting the COX-2 enzyme, and the production of prostaglandins 38(). Previous studies have also reported the benefits of taking chamomile in capsules or other forms in reducing the amount of menstrual bleeding 1839-41(, ). We noted that chamomile’s effect on menstrual bleeding and pain among women with uterine fibroids was superior to sumac, likely due to its stronger anti-inflammatory, antispasmodic, and analgesic properties, mediated by compounds like apigenin, luteolin, and bisabolol 17243738(, ). Additionally, its hemostatic activity, better bioavailability, and mild sedative effects may further enhance its effectiveness in managing uterine fibroid symptoms 24(). Probably due to sumac lacking certain bioactive compounds, such as apigenin and bisabolol, which are abundant in chamomile, sumac’s astringent and hemostatic effects may not be as potent in regulating blood flow and muscle relaxation 23(). Yet, sumac still performed relatively well in this trial, showing significant reductions in menstrual bleeding, pain intensity, and pain duration, making it a promising natural treatment option. Previous studies have noted that sumac capsules were more effective than tranexamic acid (a fibrinolysis inhibitor) in preventing blood loss among women with menorrhagia 4243(, ). The antioxidant and anti-inflammatory effects of sumac have been confirmed in several studies for controlling and reducing internal bleeding (such as gastrointestinal inflammation, dysentery and menorrhagia) and topically for external bleeding 192244-46(, ). This effect is likely due to the organic acids and tannins in sumac fruit, which inhibit the migration of vascular smooth muscle cells responsible for regulating arterial tone and bleeding 2347(, ). Future pharmacological research could help elucidate the mechanisms underlying their effects, potentially leading to the development of novel therapeutic agents for patients who prefer or require non-invasive approaches 48(). Future studies may also evaluate the combined synergistic effects of sumac and chamomile in reducing uterine fibroid-associated menstrual symptoms, although evidence on their complementary effects has so far been limited to pilot studies on managing gastrointestinal inflammation 46(). To date, there is no data about the contraindication of herbal medicines, such as chamomile, in uterine tumors, nor is there any data on whether chamomile could affect the size of tumors 24(). While considering chamomile or any other herbal remedy for managing symptoms related to uterine fibroids, it is still crucial to consult with a healthcare professional for guidance based on specific medical condition and overall health. Important to note that herbal medicines, including chamomile and sumac, may not have any effect on the size of the tumor. Clinical guidelines should be developed based on more extensive Phase 3 clinical trials that confirm the efficacy, safety, and long-term effects of a treatment in a diverse population. Given their traditional use across various cultures, chamomile and sumac could offer affordable and accessible treatment options for uterine fibroids, particularly in low-resource settings where conventional treatments are limited. Study limitations Limitations of this RCT include the relatively small sample size of 154 women, which may limit the generalizability of the findings to broader populations. Additionally, the use of self-reported measures for menstrual pain and bleeding to compare the effectiveness of sumac and chamomile at two consecutive periods post-intervention introduces the potential for recall bias and subjectivity in responses. The use of baseline treatment 250 mg capsules of mefenamic acid (three times a day for seven days) at the two consecutive cycles of follow up might have influenced the true effect of chamomile or sumac on pain reduction. Furthermore, the short follow-up period of 2 consecutive menstrual cycles may not capture longer-term effects of the treatments on the outcomes. Future studies with larger, more diverse samples recruited from multiple settings and longer follow-up periods are warranted to assess the sustained effects of chamomile and sumac. Conclusions This RCT has shown that chamomile and sumac capsules reduced the severity and duration of menstrual bleeding and pain in patients with fibroids, with the effect being highest at the second menstrual cycle of use. The overall effect of chamomile was slightly superior to that of sumac in reducing intensity and duration of both menstrual bleeding and pain. No serious adverse effects were reported by the participants. Chamomile and sumac may serve as effective natural treatments for managing heavy menstrual bleeding and pain associated with uterine fibroids, offering a complementary non-hormonal, non-surgical therapy. Future Phase 3 trials are recommended to further confirm the effects of chamomile and sumac, either individually or synergistically, on menstrual symptoms associated with uterine fibroids. Abbreviations ANOVA: One-Way Analysis of Variance CAM: Complementary and Alternative Medications CI: Confidence Interval CONSORT: Consolidated Standards of Reporting Trials COX: Cyclooxygenase DPPH: 2,2-Diphenyl-1-Picrylhydrazyl Exp(Β): Exponentiated Coefficients GC-MS: Gas Chromatography-Mass Spectrometry GEE: Generalized Estimating Equations HPLC: High-Performance Liquid Chromatography NSAIDs: Non-Steroidal Anti-Inflammatory Drugs PBLAC: Pictorial Blood Loss Assessment Chart RCT: Randomized Controlled Trial SD: Standard Deviation VAS: Visual Analog Scale Declarations Ethics approval and consent to participate The Ethics Committee of Shiraz University of Medical Sciences provided the ethical approval for this trial (IR.SUMS.REC.1398.1199). Written informed consent was taken from all the study participants before enrollment in the trial. The participants were instructed to contact the lead researchers (MJ) or the Manager of the Ethics Committee of Shiraz University of Medical Sciences via email or telephone to report adverse events. No serious adverse effects were reported throughout the study duration. The study followed guidelines of the Declaration of Helsinki and Tokyo for humans and was approved by the institutional human experimentation committee or equivalent, and that informed consent was obtained. Consent for publication Not applicable Availability of data and material The datasets analysed during the current study are not publicly available due the security of the participants but are available from the corresponding author on reasonable request. Competing interest The authors declare that they have no competing interests. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors contribution Maryam Jafari: Conceptualization, Methodology, Investigation, Writing - Original Draft. Fatemeh Heshmatnia: Investigation, Writing- Reviewing and Editing. Santosh Giri: Software, Validation, Formal analysis, Writing- Reviewing and Editing; Masoumeh Emamghoreishi: Investigation, Writing- Reviewing and Editing. Aida Iraji: Investigation, Writing- Reviewing and Editing. Sedigheh Forouhari: Investigation, Writing- Reviewing and Editing. Fatemeh Sadat Najib: Investigation, Writing- Reviewing and Editing. Subash Thapa: Conceptualization, Methodology, Investigation, Software, Validation, Formal analysis, Writing- Reviewing and Editing, Supervision. All authors read and approved the final manuscript. Acknowledgements We would like to acknowledge the gynecology clinics of Motahari Hospital and Hazrat Zainab Hospital in Shiraz, Iran for their invaluable support in this project. References 1. Li B, Wang F, Chen L, Tong H. Global epidemiological characteristics of uterine fibroids. Arch Med Sci. 2023;19(6):1802-10.2. Giuliani E, As-Sanie S, Marsh EE. Epidemiology and management of uterine fibroids. Int J Gynaecol Obstet. 2020;149(1):3-9.3. Ekanem E, Talaulikar V. Medical therapy for fibroids: what next for ulipristal acetate? Advances in Therapy. 2020:1-12.4. Go VAA, Thomas MC, Singh B, Prenatt S, Sims H, Blanck JF, et al. A systematic review of the psychosocial impact of fibroids before and after treatment. Am J Obstet Gynecol. 2020;223(5):674-708 e8.5. Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: findings from a cross-sectional survey analysis. Int J Womens Health. 2017;9:403-11.6. Soliman AM, Margolis MK, Castelli-Haley J, Fuldeore MJ, Owens CD, Coyne KS. Impact of uterine fibroid symptoms on health-related quality of life of US women: evidence from a cross-sectional survey. Curr Med Res Opin. 2017;33(11):1971-8.7. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health. 2012;12:6.8. Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: findings from a cross-sectional survey analysis. International journal of women’s health. 2017:403-11.9. Taylor DK, Leppert PC. Treatment for Uterine Fibroids: Searching for Effective Drug Therapies. Drug Discov Today Ther Strateg. 2012;9(1):e41-e9.10. Kashani BN, Centini G, Morelli SS, Weiss G, Petraglia F. Role of Medical Management for Uterine Leiomyomas. Best Pract Res Clin Obstet Gynaecol. 2016;34:85-103.11. Sinai Talaulikar V. Medical therapy for fibroids: An overview. Best Pract Res Clin Obstet Gynaecol. 2018;46:48-56.12. De La Cruz MS, Buchanan EM. Uterine Fibroids: Diagnosis and Treatment. American family physician. 2017;95(2):100-7.13. Bofill Rodriguez M, Lethaby A, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. The Cochrane database of systematic reviews. 2019;9(9):CD000400.14. Ghosh S. Metabolomic Studies for Metabolic Alterations Induced by Non-Steroidal Anti-Inflammatory Drugs: Mini Review. Biomolecules. 2021;11(10).15. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147.16. Yatoo MI, Gopalakrishnan A, Saxena A, Parray OR, Tufani NA, Chakraborty S, et al. Anti-Inflammatory Drugs and Herbs with Special Emphasis on Herbal Medicines for Countering Inflammatory Diseases and Disorders - A Review. Recent Pat Inflamm Allergy Drug Discov. 2018;12(1):39-58.17. Miraj S, Alesaeidi S. A systematic review study of therapeutic effects of Matricaria recuitta chamomile (chamomile). Electronic physician. 2016;8(9):3024-31.18. Niazi A, Moradi M. The Effect of Chamomile on Pain and Menstrual Bleeding in Primary Dysmenorrhea: A Systematic Review. Int J Community Based Nurs Midwifery. 2021;9(3):174-86.19. Alsamri H, Athamneh K, Pintus G, Eid AH, Iratni R. Pharmacological and Antioxidant Activities of Rhus coriaria L. (Sumac). Antioxidants (Basel). 2021;10(1).20. Nozza E, Melzi G, Marabini L, Marinovich M, Piazza S, Khalilpour S, et al. Rhus coriaria L. Fruit Extract Prevents UV-A-Induced Genotoxicity and Oxidative Injury in Human Microvascular Endothelial Cells. Antioxidants (Basel). 2020;9(4).21. Tansaz M, Memarzadehzavareh H, Qaraaty M, Eftekhar T, Tabarrai M, Kamalinejad M. Menorrhagia Management in Iranian Traditional Medicine. J Evid Based Complementary Altern Med. 2016;21(1):71-6.22. Martinelli G, Angarano M, Piazza S, Fumagalli M, Magnavacca A, Pozzoli C, et al. The Nutraceutical Properties of Sumac (Rhus coriaria L.) against Gastritis: Antibacterial and Anti-Inflammatory Activities in Gastric Epithelial Cells Infected with H. pylori. Nutrients. 2022;14(9).23. Fereidoonfar H, Salehi-Arjmand H, Khadivi A, Akramian M, Safdari WL. Chemical variation and antioxidant capacity of sumac. Industrial Crops and Products. 2019;139:111518.24. Srivastava JK, Shankar E, Gupta S. Chamomile: A herbal medicine of the past with bright future. Mol Med Rep. 2010;3(6):895-901.25. Waterman PG, Mole S. Analysis of phenolic plant metabolites: Blackwell Scientific Oxford; 1994.26. Kuhn MA, Winston D. Herbal therapy and supplements: a scientific and traditional approach: Lippincott Williams & Wilkins; 2000.27. Sabzghabaee AM, Kelishadi R, Golshiri K, Ghannadi A, Badri S. Clinical Effects of Rhus coriaria Fruits on Dyslipidemia308 in Adolescents: a Triple-blinded Randomized Placebo-controlled Trial. Medical archives (Sarajevo, Bosnia and Herzegovina). 2014;68(5):308-12.28. Iraji A, Firuzi O, Khoshneviszadeh M, Nadri H, Edraki N, Miri R. Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer’s disease. Bioorg Chem. 2018;77:223-35.29. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990;97(8):734-9.30. Donnez J, Hudecek R, Donnez O, Matule D, Arhendt HJ, Zatik J, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril. 2015;103(2):519-27 e3.31. Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Breivik Hals EK, et al. Assessment of pain. British Journal of Anaesthesia. 2008;101(1):17-24.32. Ballinger GA. Using Generalized Estimating Equations for Longitudinal Data Analysis. Organizational Research Methods. 2004;7(2):127-50.33. Paquette CE, Reese ED, Yi JY, Maccarone JM, Stewart ZJ, Daughters SB. Group behavioral activation with and without a smartphone app in intensive outpatient treatment for substance use disorder: A three-arm randomized controlled trial. Drug and Alcohol Dependence. 2023;243:109758.34. Ikhena DE, Bulun SE. Literature Review on the Role of Uterine Fibroids in Endometrial Function. Reprod Sci. 2018;25(5):635-43.35. Rodwell VW, Bender DA, Botham KM, Kennelly PJ, Weil PA. Harper’s illustrated biochemistry: McGraw-Hill Education New York (NY); 2018.36. Al-Dabbagh B, Elhaty IA, Elhaw M, Murali C, Al Mansoori A, Awad B, et al. Antioxidant and anticancer activities of chamomile (Matricaria recutita L.). BMC Res Notes. 2019;12(1):3.37. Matic IZ, Juranic Z, Savikin K, Zdunic G, Nadvinski N, Godevac D. Chamomile and marigold tea: chemical characterization and evaluation of anticancer activity. Phytother Res. 2013;27(6):852-8.38. Srivastava JK, Pandey M, Gupta S. Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity. Life Sci. 2009;85(19-20):663-9.39. Karimian Z SZ, Bahrami N, Kafaie M. Comparison of Chamomile and Mefenamic acid capsules in hemorrhage of menstruation. The Iranian Journal of Obstetrics, Gynecology and Infertility. 2015;18(157):11-7.40. Mollabashi EN, Ziaie T, Bekhradi R, Khalesi ZB. Do Chamomile effect on duration, amount of bleeding, and interval of menstrual cycles? Journal of pharmacopuncture. 2020;23(1):25-9.41. Shabani F, Chabra A, Vakilian K, Bioos S, Bozorgi M, Ayati MH, et al. The Effect of Ginger-chamomile Sachet with Honey on Primary Dysmenorrhea and Associated Symptoms: A Randomized, Double-Blind, Controlled Trial. Current Womens Health Reviews. 2020;16(4):348-58.42. Borazjanizadeh N. The effect of rhus coriaria capsule on hemorrhage in women with menorrhagia referring to selected hospitals of Shiraz University of Medical Sciences 2017. Shiraz: Shiraz University of Medical Sciences; 2019.43. Zakeri S, Enayati A, Kolangi F. Sumac Can Be Offered as an Alternative Treatment for Controlling Abnormal Bleedings Based on Persian Medicine. Traditional and Integrative Medicine. 2021;5(4):180-2.44. Khoshkharam M, Shahrajabian M, Sun W, Cheng Q. Sumac (Rhus coriaria L.) a spice and medicinal plant-a mini review. Amazonian Journal of Plant Research. 2020;4(2):517-23.45. Khalilpour S, Behnammanesh G, Suede F, Ezzat MO, Muniandy J, Tabana Y, et al. Neuroprotective and Anti-Inflammatory Effects of Rhus coriaria Extract in a Mouse Model of Ischemic Optic Neuropathy. Biomedicines. 2018;6(2):48.46. Mahernia S, Bagherzadeh K, Mojab F, Amanlou M. Urease Inhibitory Activities of some Commonly Consumed Herbal Medicines. Iran J Pharm Res. 2015;14(3):943-7.47. Wang S, Zhu F. Chemical composition and biological activity of staghorn sumac (Rhus typhina). Food Chem. 2017;237:431-43.48. Bouabdallah S, Al-Maktoum A, Amin A. Steroidal Saponins: Naturally Occurring Compounds as Inhibitors of the Hallmarks of Cancer. Cancers (Basel). 2023;15(15). Figure captions Figure 1. CONSORT flow diagram Figure 2. Average amount and duration of menstrual bleeding, as well as intensity and duration of menstrual pain, at baseline, first, and second menstrual cycle. (Figure legend: The endpoints of the upper and lower whiskers represent the maximum and minimum values, respectively; The upper edge, center horizontal line, and lower edge of the box correspond to the 75 th percentile, 50 th percentile (median), and 25 th percentile, respectively.) Table 1. Study participants and baseline characteristics Age in years, mean (±SD) 35.6(±4.4) 36.7(±4.4) 35.7(±4.4) 0.356\RL a Body mass index 24.5(±1.6) 24.2(±1.9) 24.1(±1.9) 0.520\RL a Occupation, n (%) Homemaker \RL (9 .51)27 23(44.2) \RL (40.0)20 0.189ᵇ Governmental employee \RL (1 .23)12 \RL (11.5)6 \RL (24.0)12 Self-employed \RL (25.0)13 \RL (44.2)23 \RL (36.0)18 Education level, n (%) Elementary school 14 (26.9) \RL (25.0)13 \RL (34.0)17 0.351ᵇ Secondary school \RL (34.6)18 \RL (36.5)19 \RL (30.0)15 Diploma \RL (38.5)20 \RL (30.8)16 \RL (34.0)17 Academic \RL (0)0 \RL (7.7)4 \RL (2.0)1 History of uterine fibroids in the family, n(%) 15(28.5) 18(34.6) 16(32) 0.819 \RL a Duration of diagnosis in years, mean (±SD) 3.6 (±1.4) 3.6 (±1.1) 3.2 (±1.5) 0.052 \RL a Menstruation duration in days, mean (±SD) 7.7 (±1.2) 7.7 (±1.1) 7.1 (±2.1) \RL0.518 a Menstruation interval, n (%) Every 21 days \RL (28.8)15 \RL (38.5)20 \RL (30.0)15 \RL 0.522ᵇ Every 22-35 days \RL (71.2)37 \RL (61.5)32 35(70.0) Pain area, n (%) Lower abdomen 19(36.5) 16(30.8) 17(34.0) 0.116ᵇ Lower abdomen to thigh 1(1.9) 5(9.6) 5(10.0) Lower abdomen to Waist 29(55.8) 20(38.5) 23(46.0) Waist 3(5.8) 11(21.2) 5(10.0) Start of menstrual pain, n (%) Days before menstruation 15(28.8) 16(30.8) 14(28.0) 0.984ᵇ Hours before menstruation 24(46.2) 24(46.2) 22(44.0) Start of menstruation 11(21.2) 10(19.2) 10(20.0) 24 hours after menstruation 2(3.8) 2(3.8) 4(8.0) a p-values based on one-way Anova test. b p-values based on the chi-square test. Table 2. Generalized estimating equations predicting amount of menstrual bleeding, duration of menstrual bleeding (days), pain intensity and duration of pain (hours per day). Age in years 0.00 (-0.01, 0.01) 1 (0.99, 1.01) 0.01 0.993 BMI 0.01 (-0.02, 0.04) 1.01 (0.98, 1.04) 0.02 0.598 History of uterine fibrosis (Ref = No) Yes -0.07 (-0.21, 0.07) 0.94 (0.81, 1.07) 0.07 0.344 Duration of diagnosis -0.02 (-0.06, 0.02) 0.98 (0.94, 1.02) 0.02 0.353 Treatment group (Ref = Control) Chamomile 0.02 (-0.15, 0.19) 1.02 (0.86, 1.21) 0.09 0.831 Sumac 0.02 (-0.14, 0.18) 1.02 (0.87, 1.19) 0.08 0.820 Follow-up (Ref = Baseline) First cycle -0.06 (-0.12, -0.01) 0.94 (0.89, 0.99) 0.03 0.018 Second cycle -0.05 (-0.1, -0.01) 0.95 (0.91, 0.99) 0.02 0.013 Treatment group*Follow-up Chamomile*First cycle -0.03 (-0.09, 0.04) 0.97 (0.91, 1.04) 0.03 0.423 Chamomile*Second cycle -0.23 (-0.3, -0.16) 0.80 (0.74, 0.85) 0.03 <0.001 Sumac*First cycle -0.02 (-0.08, 0.04) 0.98 (0.92, 1.04) 0.03 0.453 Sumac*Second cycle -0.15 (-0.21, -0.09) 0.86 (0.81, 0.92) 0.03 <0.001 Wald χ² (12) = 219.72, p <0.001 Duration of menstrual bleeding in days Age in years 0.00 (-0.01, 0.01) 1.00 (0.99, 1.01) 0.00 0.893 BMI -0.01 (-0.03, 0.01) 0.99 (0.97, 1.01) 0.01 0.377 History of uterine fibrosis (Ref = No) Yes 0.02 (-0.05, 0.08) 1.02 (0.95, 1.08) 0.03 0.636 Duration of diagnosis 0.00 (-0.02, 0.03) 1.00 (0.98, 1.03) 0.01 0.930 Treatment group (Ref = Control) Chamomile 0.20 (0.12, 0.28) 1.22 (1.13, 1.33) 0.04 <0.001 Sumac 0.12 (0.03, 0.21) 1.13 (1.03, 1.24) 0.05 0.009 Follow-up (Ref = Baseline) First cycle -0.08 (-0.13, -0.04) 0.92 (0.88, 0.97) 0.02 0.001 Second cycle -0.04 (-0.1, 0.01) 0.96 (0.91, 1.01) 0.03 0.110 Treatment group*Follow-up Chamomile*First cycle -0.1 (-0.15, -0.04) 0.91 (0.86, 0.96) 0.03 0.001 Chamomile*Second cycle -0.23 (-0.3, -0.16) 0.8 (0.74, 0.86) 0.04 <0.001 Sumac*First cycle -0.08 (-0.14, -0.02) 0.92 (0.87, 0.98) 0.03 0.013 Sumac*Second cycle -0.21 (-0.28, -0.14) 0.81 (0.76, 0.87) 0.04 <0.001 Wald χ² (12) = 416.88, p <0.001 Pain intensity (VAS score) Age in years 0.00 (-0.01, 0.01) 1 (0.99, 1.01) 0.00 0.908 BMI 0.02 (0, 0.03) 1.02 (1, 1.03) 0.01 0.021 History of uterine fibrosis (Ref = No) Yes 0.05 (-0.01, 0.1) 1.05 (0.99, 1.11) 0.03 0.116 Duration of diagnosis -0.01 (-0.03, 0.01) 0.99 (0.97, 1.01) 0.01 0.452 Treatment group (Ref = Control) Chamomile -0.08 (-0.16, 0.01) 0.93 (0.85, 1.01) 0.04 0.071 Sumac -0.04 (-0.11, 0.04) 0.97 (0.89, 1.04) 0.04 0.382 Follow-up (Ref = Baseline) First cycle 0.00 (0.00, 0.00) 1.00 (1.00, 1.00) 0.00 0.317 Second cycle -0.02 (-0.1, 0.05) 0.98 (0.91, 1.05) 0.04 0.506 Treatment group*Follow-up Chamomile*First cycle 0.00 (-0.01, 0.00) 1.00 (0.99, 1.00) 0.00 0.524 Chamomile*Second cycle -0.61 (-0.72, -0.5) 0.54 (0.49, 0.61) 0.06 <0.001 Sumac*First cycle 0.00 (-0.01, 0.00) 1.00 (0.99, 1.00) 0.00 0.277 Sumac*Second cycle -0.6 (-0.71, -0.48) 0.55 (0.49, 0.62) 0.06 <0.001 Wald χ² (12) = 560.99, p <0.001 Duration of pain in hours per day Age in years -0.01 (-0.01, 0.00) 0.99 (0.99, 1.00) 0.00 0.028 BMI -0.01 (-0.03, 0.01) 0.99 (0.97, 1.01) 0.01 0.21 History of uterine fibrosis (Ref = No) Yes 0.04 (-0.06, 0.15) 1.04 (0.94, 1.16) 0.05 0.419 Duration of diagnosis 0.04 (0.00, 0.08) 1.04 (1.00, 1.08) 0.02 0.028 Treatment group (Ref = Control) Chamomile 0.07 (-0.11, 0.24) 1.07 (0.89, 1.27) 0.09 0.471 Sumac 0.11 (-0.18, 0.39) 1.11 (0.83, 1.48) 0.15 0.472 Follow-up (Ref = Baseline) First cycle 0.07 (-0.13, 0.27) 1.07 (0.88, 1.32) 0.10 0.495 Second cycle 0.15 (-0.01, 0.31) 1.16 (0.99, 1.37) 0.08 0.063 Treatment group*Follow-up Chamomile*First cycle -0.06 (-0.31, 0.18) 0.94 (0.74, 1.2) 0.12 0.605 Chamomile*Second cycle -0.55 (-0.77, -0.33) 0.58 (0.47, 0.72) 0.11 <0.001 Sumac*First cycle -0.12 (-0.45, 0.21) 0.89 (0.64, 1.24) 0.17 0.481 Sumac*Second cycle -0.42 (-0.74, -0.11) 0.65 (0.48, 0.9) 0.16 0.009 Wald χ² (12) = 174.092, p 100 represents excessive bleeding. Pain intensity was measured using Visual analogue scale (VAS). Supplementary Material File (consort flowdiagram.docx) Download 74.29 KB Information & Authors Information Version history V1 Version 1 20 March 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords behavioural pharmacology cancer and carcinogenesis reproduction pharmacology Authors Affiliations Maryam Jafari Shiraz University View all articles by this author Fatemeh Heshmatnia Shiraz University View all articles by this author Santosh Giri Charles Sturt University View all articles by this author Marzieh Akbarzadeh Shiraz University View all articles by this author Masoumeh Emamghoreishi Shiraz University View all articles by this author Aida Iraji Shiraz University of Medical Sciences View all articles by this author Fatemeh Najib Shiraz University of Medical Sciences View all articles by this author Subash Thapa 0000-0002-1182-8511 [email protected] Charles Sturt University View all articles by this author Metrics & Citations Metrics Article Usage 1006 views 197 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Maryam Jafari, Fatemeh Heshmatnia, Santosh Giri, et al. 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