{"paper_id":"78d173d5-2e8b-4424-9dc7-fd5b808d2f9d","body_text":"Effect of silymarin on Interleukin-6 level and size of endometrioma lesions in women with ovarian endometriosis: a randomized, double-blind placebo-controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effect of silymarin on Interleukin-6 level and size of endometrioma lesions in women with ovarian endometriosis: a randomized, double-blind placebo-controlled trial negin mirzaei, shahideh Jahanian Sadatmahalleh, Safoura Rouholamin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1632161/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective: To study the effect of silymarin on interleukin-6 (IL-6) level, size of endometrioma lesion, pain, sexual function, and quality of life (QoL) in women diagnosed with endometriosis. Materials and methods: This randomized, double-blind placebo-controlled clinical trial was performed on 70 women with endometriosis which was divided into two groups of intervention and control. The intervention was 140 mg silymarin (or matching placebo) administered twice daily for 12 weeks. The volume of endometrioma lesions, IL-6, pain, sexual function, and QoL were analyzed before and after the intervention. Results: The means of endometrioma volume (P =0.04), interleukin-6 (P = 0.002), and pain (P<0.001) were reduced significantly in the silymarin group after intervention. However, the QoL, FSFI did not improve substantially in the two groups (P > 0.05). Conclusion: Silymarin significantly reduced interleukin-6 levels, sizes of endometrioma lesions, and pain-related symptoms. The trial has been registered in the Iranian Registry of Clinical Trials (IRCT20150905023897N5) on 4 th February 2020 (04/02/2020) (https://en.irct.ir/trial/42215) and the date of initial participant enrollment was 2 nd March 2020 (02/03/2020). Endometrioma Endometriosis-Associated Pain Silymarin IL-6 Sexual function Figures Figure 1 Introduction Endometriosis is a debilitating recurrent gynecological disease that is classified based on its location outside the uterus into peritoneal implants, ovarian endometrioma (OMA), and Deep Infiltrating Endometriosis (DIE) ( 1 ). The most common site of endometriosis is ovarian, and OMA is described as an ovarian cyst lined with endometrial tissue with internal thick brown fluid (hence the term chocolate cyst) arising from the accumulation of menstrual debris ( 2 ). The prevalence of endometriosis has been reported in approximately 10% of reproductive-aged women, up to 50% of the infertile population, and 60% of women with pelvic pain ( 3 , 4 ). In addition, approximately 17–44% of patients with endometriosis have an endometrioma ( 5 ). OMA might be accompanied by several pain-related manifestations such as chronic pelvic pain, dysmenorrhea, dyspareunia, and subfertility ( 6 ). Not only do these discomfort symptoms pose devastating impacts on the psychological, social, sexual life, and Quality of Life (QoL) of afflicted women, also these can represent a massive economic burden on patients and the health care system ( 7 , 8 ). Although the accurate pathogenesis of endometriosis remains elusive, recent studies have addressed the roles of oxidative stress and inflammatory factors in the development of OMA ( 2 ). Hence, an endometrioma contains free iron, Reactive Oxygen Species (ROS), and inflammatory molecules such as Interleukin (IL)-8, IL-6, Tumor Necrosis Factor-a (TNF-a) are higher compared with those present in peripheral blood or other types of benign cysts ( 9 , 10 ). All available therapeutic modalities of endometriosis, including medical treatment (such as androgens, Oral Contraceptive Pills (OCPs), progestogens, anti-progestogens, and Gonadotrophin-Releasing Hormone analogues (GnRH-a)) and surgical therapy, alone or in combination treatments, have several limitations that include the risk of recurrence, side effects, contraceptive action for those are disastrous to become pregnant, and their costs ( 11 ). Not only has the recurrence of endometriosis’s symptoms after surgical and medical treatments been estimated approximately 21.5% at two years and some 40–50% after five years, but also several reports have indicated laparoscopic management of OMA can decrease ovarian reserve ( 12 , 13 ). Therefore, the development of new strategies and novel agents from herbal medicine with minor side effects, costs, and enhanced efficacy and availability has become a new area of research in the last decades ( 14 ). Silymarin, a flavonolignan derived from the milk thistle plant (Silybum marianum), has been widely used for the treatment of various disorders, and it is the mixture of six isomeric flavonoids such as silybins A and B (major bioactive compounds), isosilybins A and B, silychristin, and silydianin ( 15 ). Numerous studies have demonstrated that silymarin has potent antioxidant, anti-inflammatory, and anti-fibrotic properties ( 16 , 17 ). Moreover, silymarin is one of the highly potent anti-cancer agents since it could diminish the secretion level of vascular endothelial growth factors in human breast and prostate cancer cells, induce apoptosis in human hepatic cancer cells, suppress cell proliferation, modulate cell cycle progression, and imped epithelial-to-mesenchymal transition in lung carcinoma, ( 18 – 20 ). In addition, several in vitro and animal studies have verified the effects of silymarin in decreasing the size and histopathologic grade of the endometrial lesions ( 21 – 23 ). Thus, in light of previous studies on silymarin in other chronic disease and endometrial cells, we hypothesized that silymarin might be an effective candidate for the treatment of endometrioma. Therefore, to test this hypothesis, this randomized double-blinded clinical trial was conducted to evaluate the efficacy of silymarin on endometrioma. Material And Method Trial Design and Overview This study was a phase II, double-blind, randomized, placebo-controlled trial conducted in gynecological clinics affiliated with Tehran University of Medical Sciences, Tehran, Iran, from 2nd March 2020 (02/03/2020) to 18th May 2021 (18/05/2021). This clinical trial comprised a 12-week treatment period, after which some of the endometriosis-related manifestations were evaluated. This trial conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and ethical approval was obtained from the Ethics Committee of Tarbiat Modares University, Tehran, Iran, before the commencement of the study on 22nd October 2019 (IR.MODARES.REC.1398.143). In addition to that, it has been registered in the Iranian Registry of Clinical Trials in 4th February 2020 (04/02/2020) (IRCT20150905023897N5). All potential study subjects provided written informed consent and were informed about the aims and possible risks of the trial before the study. Not only can all authors attest to the completeness and accuracy of the data and analyses and adherence to the trial protocol, but also they have reviewed and approved the final manuscript. Participants Eligible subjects were women of reproductive age (15–49 years), married, and non-pregnant with a confirmed diagnosis of OMA via transvaginal ultrasonography performed by a single sonologist at the three-dimensional level in the previous five years and currently experiencing moderate to severe pain and receiving 2mg dienogest daily in last six months. The pattern recognition using subjective evaluation of Gray-scale and Doppler-ultrasound characteristics based on IOTA rules “an adnexal mass with ground glass echogenicity of the cyst fluid, one to four locules and no papillations with detectable blood flow” and volume (L×D×W×0.5235) was achieved through the Orsini formula ( 24 ). Women would have been excluded if they had suffered from chronic diseases such as hypertension, diabetes, coronary, renal, and hepatic disorders or liver enzyme anomalies. Also, suppose they had taken specific medications like oral contraceptives, anti-depressant and GnRH analogues, or systemic glucocorticoids, with a specified wash-out period for each one based on the period. In that case, they might have a continued effect. In addition, using silymarin or other milk thistle preparations and anti-inflammatory supplements (e.g., vitamin, vitamin E, ...) and even non-prescribed complementary alternative drugs must have been stopped for at least 30 days before the study. All subjects were instructed to use non-hormonal, double-barrier contraception such as a condom or diaphragm, each combined with a spermicide. Interventions Eligible subjects were randomized into placebo and treatment groups based on the computer-generated list. All participants received a dose of 280 mg silymarin including two tablets of Livergol 140 mg, Goldaru Pharma Co. Isfahan-Iran) or placebo (Goldaru Pharma Co. Isfahan-Iran) daily in two meals (after breakfast and dinner) for 12 weeks along with standard treatment of endometrioma (dienogest 2mg/day). This dosage was chosen because it is safe and effective in treating liver diseases ( 25 ). The therapeutic doses of silymarin have been considered safe and well-tolerated in humans. Some slight gastrointestinal discomforts like nausea and diarrhea might be accrued ( 26 ). Randomization and blinding Simple randomization was done according to a computer-generated list of random number groups prepared using Statistical Analysis System Software Version 9.2 (SAS Institute Inc., Cary, NC, USA). All participants were randomly allocated to each arm and given the tablets based on a computer-generated randomization list by the investigator. Treatment and placebo allocations were blinded to subjects, the investigator, and the attending doctor. Trial Procedures and Assessments At the first and follow-up visit that was planned after 12-week treatment, participants were referred to the lab and sonography single-center (based on routine standard protocols) to measure IL-6 (Roche Instr Kit, Germany) and record the sizes of the endometrioma lesions via three-dimensional transvaginal ultrasonography (by the same physician in blind), respectively. In addition, they were asked to fill out several self-report questionnaires as follows: Firstly, demographic data that consists of address, phone number, date of birth, weight, height, Body Mass Index (BMI), education level, occupation, education level of husband, and a history of the disease was gathered. Because the observation suggests that IL-6 may be a good marker of disease prediction and progression and may serve as biomarkers for the diagnosis of endometriosis ( 27 – 29 ), subjects were supplied ibuprofen and paracetamol/acetaminophen tablets and requested to use these for rescue analgesia if required, for endometriosis pain. Participants did not report any side effects related to silymarin. Female Sexual Function (FSFI): FSFI investigates the sexual function and consists of 19 Likert-scale questions in six domains of desire, arousal, lubrication, satisfaction, orgasm, and pain. The lower score is, the more sexual function impaired ( 30 ). The Iranian version of FSFI has been evaluated for both reliability and validity ( 31 ). Short Form Health Survey (SF-12): SF-12 is designed to evaluate the physical and mental components of health-related QoL by 12 questions. Lower scores indicate inferior health-related QoL ( 32 ). The validity and reliability of this questionnaire have been confirmed in Iran ( 33 ). Visual Analog Scale (VAS): VAS has been used most often to assess the intensity of endometriosis-related pain (dysmenorrhea, deep dyspareunia, chronic pelvic pain, and menstrual and non-menstrual dysphasia). It is an 11-point scale in which 0 represented the absence of pain, while 10 meant unbearable pain ( 34 ). Outcome One of the primary endpoints was a significant reduction in the mean pelvic pain assessed after 12-week treatment on a VAS. Other primary efficacy endpoints at weeks 12 included a significant decrease in the volume of endometrioma lesions diagnosed via transvaginal ultra-sonography and any change from baseline in the level of IL-6. Secondary efficacy endpoints were improvement of individuals’ QoL and sexual function assessed on mentioned questionnaires. Statistical analysis Based on the study results of Almassinokiani et al. ( 35 ), who assessed the effects of vitamin D on endometriosis-associated pain, with a 99% confidence interval and 90% power of the test, the sample size was determined as 35 individuals for each group. By counting 20% sample loss, the minimum sample size was estimated at 40 individuals in each group, meaning that 80 women diagnosed with endometrioma who had the inclusion criteria (40 persons in each group) were recruited for the present study. Where, α is the probability of type I errors (α = 0.05), and βindicates the probability of type Ⅱ errors (β = 0.20). In addition, (μ 1 -μ 2 )/σ represents the size effect observed that is equal 0.7. $$\\mathbf{n}=2{\\left(1.96+0.85\\right)}^{2}{\\left(\\frac{1}{0.65}\\right)}^{2}=33$$ All statistical analyses were performed by the SPSS software (ver. 22.0) (SPSS Inc., Chicago, IL, USA). The data of normality in distribution were examined by one sample K-S. Group comparisons were carried out with Student’s t-test and Chi-square test. P < 0.05 was considered statistically significant. Result Overall, 10 out of the 90 potentially eligible women refused to participate in the study because of time consuming completing of questionnaires and longtime treatment process, so the response rate was approximately 88%. A total of 80 individuals, (40 women in each group) were enrolled into the study, 10 were excluded due to the unwillingness to peruse recommended treatment (n = 8), surgery (n = 3), the rate of sample loss was 12% (Fig. 1 ). Finally, 35 women were enrolled in each group. Patients reported a mean of 3.4 years since the first diagnosis of endometriosis. Table 1 describes the characteristics of women in the intervention and control groups. There was no statistically significant difference in women’s age, Body Mass Index (BMI), parity, educational level, and occupation status between the two groups (p > 0.05). Table 1 Comparison of demographic characteristics between intervention and control groups Variable Intervention group n = 35 Control group n = 35 P-value Age of female* 36.49 ± 8.11 33.94 ± 7.00 0.16 Number of children** 0.29 0 11 (31.4) 18 (51.4) 1 13 (37.1) 9 (25.7) 2 10 (28.6) 6 (17.1) 3 and more 1 (2.9) 2 (5.7) Education of female** 0.47 Undergraduate 17 (48.6) 14 (40.0) Postgraduate 18 (51.4) 21 (60.0) Occupation ** 0.46 Housewife 19 (54.3) 22 (62.9) Employee 16 (45.7) 13 (37.1) BMI (kg/ m²) * 24.25 ± 4.02 24.54 ± 4.02 0.75 BMI: Body Mass Index, *Values are given as mean ± SD using t-test ** Values are given as a number (%) using Chi-squared test As can be seen in Table 2 , evaluation of the two groups with regard to FSFI before and after treatment did not show any significant differences. The total score of FSFI was significantly lower in control group after treatment (25.54 ± 2.74 vs 24.64 ± 2.74, P = 0.03). Table 2 :Comparison of FSFI scores between intervention and control groups Variable Intervention group n = 35 Mean ± SD Control group n = 35 Mean ± SD P-value* Desire Pre-assessment 3.58 ± 0.71 3.45 ± 0.66 0.42 Post-assessment 3.90 ± 0.75 3.50 ± 0.82 0.06 P-value** 0.01 0.72 Arousal Pre-assessment 3.86 ± 1.18 4.01 ± 0.78 0.56 Post-assessment 4.21 ± 1.01 3.85 ± 0.78 0.15 P-value** 0.40 0.23 Lubrication Pre-assessment 4.37 ± 1.22 4.87 ± 0.97 0.87 Post-assessment 4.53 ± 1.04 4.69 ± 0.83 0.54 P-value** 0.44 0.29 Orgasm Pre-assessment 4.43 ± 1.25 4.68 ± 0.81 0.37 Post-assessment 4.45 ± 1.25 4.15 ± 0.91 0.31 P-value** 0.40 0.01 Satisfaction Pre-assessment 4.50 ± 1.23 4.61 ± 0.88 0.90 Post-assessment 4.40 ± 1.04 4.36 ± 0.90 0.69 P-value** 0.54 0.06 Pain Pre-assessment 3.73 ± 1.23 3.94 ± 1.35 0.44 Post-assessment 4.07 ± 0.76 4.05 ± 0.79 0.97 P-value** 0.18 0.50 Total score Pre-assessment 24.39 ± 4.66 25.54 ± 2.74 0.03 Post-assessment 25.76 ± 4.33 24.64 ± 2.74 0.09 P-value** 0.28 0.03 FSFI: Female Sexual Function Index *T-test was carried out for comparison of the groups **Paired T-test was carried out for comparison of changes between the groups The comparison of SF-12 scores between the intervention and control groups is shown in Table 3 . The mean total scores of SF-12 were not significantly different between groups before treatment compared with after intervention (p > 0.05). Table 3 Comparison of the scores of subgroups of QoL between intervention and control groups Variable Intervention group n = 35 Mean ± SD Control group n = 35 Mean ± SD P-value* Sum score of physical components (PCS-12) Pre-assessment 76.23 ± 13.59 72.03 ± 18.95 0.31 Post-assessment 78.25 ± 11.51 71.45 ± 20.52 0.13 P-value** 0.91 0.71 Sum score of mental components (MCS-12) Pre-assessment 69.79 ± 14.50 70.72 ± 13.80 0.79 Post-assessment 73.20 ± 14.33 72.43 ± 12.20 0.83 P-value** 0.47 0.36 Total score Pre-assessment 73.01 ± 11.73 71.51 ± 14.34 0.65 Post-assessment 75.73 ± 11.56 72.19 ± 15.35 0.34 P-value** 0.58 0.37 QoL: Quality of Life *T-test was carried out for comparison of the groups **Paired T-test was carried out for comparison of changes between the groups It can be seen from the data in Table 4 that there was significant difference in intervention group for the pelvic pain mean changes from baseline to treatment end (7.29 ± 2.49 vs 4.88 ± 2.00, p < 0.001). In addition, IL-6 levels decreased significantly during the 90-day study period (2.40 ± 0.52 vs 2.12 ± 0.20, P = 0.002). Table 4 Comparison of the IL-6 levels and pelvic pain between intervention and control groups Variable Intervention group n = 35 Mean ± SD Control group n = 35 Mean ± SD P-value* IL-6 Pre-assessment 2.40 ± 0.52 2.57 ± 0.78 0.29 Post-assessment 2.12 ± 0.20 2.42 ± 0.73 0.03 P-value** 0.002 0.30 Pelvic pain Pre-assessment 7.29 ± 2.49 6.73 ± 2.97 0.41 Post-assessment 4.88 ± 2.00 6.61 ± 2.64 0.01 P-value** < 0.001 0.64 QoL: Quality of Life *T-test was carried out for comparison of the groups **Paired T-test was carried out for comparison of changes between the groups Table 5 shows a comparison between the 2 groups for the endometrioma lesions volumes at before and after treatment. There were significant differences between the volumes of endometrioma lesions in right ovary intervention group. Table 5 Comparison of the ovaries’ volume between intervention and control groups Variable Intervention group n = 35 Mean ± SD Control group n = 35 Mean ± SD P-value* Right ovary Pre-assessment 58863.51 ± 83820.56 75848.03 ± 135023.70 0.59 Post-assessment 33694.85 ± 53124.60 81963.81 ± 150300.15 0.24 P-value** 0.04 0.16 Left ovary Pre-assessment 65773.67 ± 76725.35 54857.73 ± 57983.99 0.60 Post-assessment 58079.16 ± 73622.66 70801.58 ± 93146.68 0.66 P-value** 0.23 0.26 *T-test was carried out for comparison of the groups **Paired T-test was carried out for comparison of changes between the groups Discussion To the best of our knowledge, this is the first double-blind, randomized clinical trial conducted to investigate the effect of silymarin on IL-6, endometrioma volume, QoL, pain, and sexual function in women diagnosed with OMA. Ovarian endometriotic cyst affects 17–44% of women suffering of endometriosis and it per se and its surgical treatment could impair ovarian function, ovarian reserve by significant reduction in serum Anti-Mullerian Hormone (AMH) and in Antral Follicle Count (AFC), pregnancy outcomes, and on IVF/ICSI outcomes ( 36 ). The exact physiopathology of endometriosis is not clarified. Inflammation, however, is known as a main factor in initiation and progression of endometriosis. Hence, inflammatory mediators such as IL-1β, IL‐6, IL‐8 increase in the peritoneal, serum, and endometrium of endometriosis patients, leading to enhancing proliferation and decreasing apoptotic rate in endometriotic cells ( 37 , 38 ). In addition, the expression of Cyclooxygenase‐2 (COX‐2), Vascular Endothelial Growth Factor (VEGF), IL‐6, Tumor Necrosis Factor‐α (TNF‐α), IL‐8, C‐C Motif Chemokine 2 (MCP‐1), and IL‐10 have increased in endometriosis cases ( 39 , 40 ). Several papers have investigated that oxidative stress plays a vital role in endometriosis pathophysiology as iron overload and inflammation can have impacts on the mechanism of oxidative stress ( 41 , 42 ). ROS concentration promotes fibrogenic response, collagen matrix remodeling, and fibrosis ( 36 ). Sanchez et al. showed that endometrioma cysts contain ROS, free iron, inflammatory molecules, and proteolytic enzymes in concentrations hundred times higher than those present in peripheral blood or in other types of benign cysts ( 2 ). Additionally, dysregulations in angiogenesis and apoptosis pathways might be contributed in endometriosis pathophysiology ( 43 ). Furthermore, the advanced endometriosis may lead to gynecological malignancies and infertility ( 43 ). For instance, the increased risk of developing ovarian cancer is proved by somatic mutations of PIK3CA, PTEN, and ARID1A in endometriosis patients especially in younger ones, however the absolute higher risk is not completely clear ( 44 ). Ideally, therapeutic strategies to conquer endometriosis should be done regarding theses pathogeneses. Silymarin is one of the highly potent antioxidant agents that inhibits lipid peroxidation and exerts antioxidant ( 45 , 46 ). In addition, its anti-inflammatory, antifibrotic, immunomodulatory, and membrane-stabilizing effects have broadly confirmed through numerous studies ( 47 , 48 ). This study was conducted to investigate the effect of Silymarin on IL-6, endometrioma volume, quality of life, pain, and sexual function in women diagnosed with endometriosis. Endometrioma volume This study confirms that silymarin can be effective in reducing endometrioma lesions is consistent with previous observations in animal models. Jouhari et al. compared the effects of silymarin, Cabergoline, and Letrozole on induced endometrial lesions in rats for about 6 months. Silymarin, Letrozole, and Cabergoline administration could decrease size and histopathologic grade of the induced endometrial lesions significantly and those who were received silymarin had significantly higher serum total antioxidant activity compared to control after 21 days ( 21 ). Nahari et al. evaluating legions establishment and growth in experimentally-induced endometriosis in 12 rats after 28 days of oral administration of silymarin showed that the combination of enhancing ERK1/2 expression and suppressing the Bcl-2 expression by silymarin accompanying with down-regulating the angiogenesis ratio led to promote the apoptosis pathway, consequently induced severe fibrosis in endometriotic-like legions ( 22 ). A recent prospective study showed that not only could silibinin induce oxidative stress and lipid peroxidation in human endometriotic cells, but also it exerted antiproliferative and apoptotic impacts on human endometriotic cell lines VK2/E6E7 and End1/E6E7. Moreover, the effects of silibinin on reducing endometriotic lesions by inhibiting the expression of inflammatory cytokines was verified by using an animal model mimicking the retrograde menstruation hypothesis in mice and they proved the possibility of effectiveness of silibinin as a novel therapeutic agent or supplement in inhibiting progression of endometriosis in vitro and in vivo ( 23 ). Interleukin 6 The present results showed that oral administration of silymarin 280 mg/day decreased the IL-6 levels significantly during the study period within the intervention group. Arafa Keshk et al. evaluating the potential protective effects of silymarin against indomethacin-induced gastric injury in rats, have demonstrated that suppression in gastric inflammation by decreasing myeloperoxidase activity, TNF- α, and IL-6 levels along with Nuclear Factor Kappa B p65 (NF-κB) expression was observed. Meanwhile, silymarin prevent gastric oxidative stress via inhibition of lipid peroxides formation, enhancement of glutathione peroxidase, superoxide dismutase activities and up-regulation of Nuclear Factor-Erythroid-2-Related Factor 2 (Nrf2), the redox-sensitive master regulator of oxidative stress signaling ( 49 ). Additionally, Wei Zhang et al. showed that silymarin could protect against the liver injury caused by ethanol administration as it markedly downregulated the expression of NF-κB p65, ICAM-1 and IL-6 in liver tissue ( 50 ). Rongjuan Zheng et al. evaluated the chemo-preventive effect of silibinin (major component of silymarin) on a Colitis-Associated Cancer (CAC) mouse model and determined its impact on IL-6/STAT3 signaling. Silibinin decreased the amount and size of tumors in mice accompanying with inhibition of colonic tumor cell proliferation and promotion of cellular apoptosis. Furthermore, they showed that silibinin could reduce the production of inflammatory cytokines and can protect against colitis-associated tumorigenesis in mice via inhibiting IL-6/STAT3 ( 51 ). In addition, it is revealed that silymarin attenuate the expression of NF-kB and the subsequent inflammatory cascade by suppressing IκB, effectively can down-regulate the expressions of TPA-induced IL-1β, IL-6, TNF-α, and COX-2 in a dose-dependent manner ( 52 , 53 ). Pain- related symptoms Numerous mechanisms are involved in endometriosis-related pain such as various algogens (pain-producing agents), cytokines (such as IL-1b, IL-6, and TNF-a), growth factors (such as b-nerve growth factor and vascular endothelial growth factor), and several chemokines, such as CCL2 ( 54 , 55 ). Several papers have investigated that different kind of antioxidant such as vitamin E and vitamin C can reduce peritoneal inflammatory markers and decrease chronic pelvic pain in endometriosis women ( 56 – 58 ). It might be speculated silymarin could be effective in reducing pain as it can suppress nitric oxide, prostaglandin E2 (PGE2), leukotrienes, cytokines production, and neutrophils infiltration ( 59 , 60 ). This study supports evidence from previous observations about the analgesic effects of silymarin. Vahdati Hassani et al. investigating the effects of silymarin in both chemical nociception and neuropathic pain in rats, showed that silymarin administer was significantly effective in preventing the formalin-induced nociceptive behavior, while it did not have significant effects in reducing sciatic neuropathic pain ( 61 ). Quality of life and sexual function Endometriosis is a very complex condition with wide range of clinical features including pelvic pain, dyspareunia, infertility, and menstrual irregularities that might compromise QoL, psychological wellbeing, sexual function, and interpersonal relationships of affected women ( 62 , 63 ). Caruso et al. evaluating the effects of dienogest on QoL and sexual function in endometriosis women, reported that progressive reduction of the pain could contribute in improving the QoL and sexual life ( 64 ). Very little was found in the literature on the question of the effectiveness of silymarin on QoL and sexual function. Gillessen et al. investigating the effect of silymarin on liver function and QoL in a non-interventional study, reported that improvement in liver-related symptoms and increased QoL after 2 months ( 65 ). Previous researches had proved that silymarin and other anti-oxidants agents can enhance QoL in patients because of their positive effects on pain reduction ( 66 , 67 ). However, the present study found inconsistent results and there was neither a significant difference in SF-12 between treatment and placebo groups nor within groups pre/post treatment The strengths of the study are the RCT design and novelty. In addition, as maintaining endometriosis associated women on a placebo is unethical, the intervention was recommended along with routine treatment. However, the principal limitation of the study is the 8% loss to follow-up and the short duration of follow-up; therefore, results probably cannot be extrapolated for long-term treatment. Additionally, these data warrant further investigations for the potential use of silymarin in the management of endometriosis features to assess long-term effects of this treatment by larger sample. Conclusion In conclusion, silymarin can be considered as a feasible option for treatment women with endometrioma-associated symptoms that has few side effects. Abbreviations AMH: Anti-Mullerian Hormone AFC: Antral Follicle Count IL: Interleukin COX‐2: Cyclooxygenase‐2 VEGF: Vascular Endothelial Growth Factor TNF‐α: Tumor Necrosis Factor‐α MCP‐2: C‐C Motif Chemokine 2 QoL: Quality of Life OMA: Ovarian Endometrioma DIE: Deep Infiltrating Endometriosis ROS: Reactive Oxygen Species OCPs: Oral Contraceptive Pills GnRH-a: Releasing Hormone analogues NF-κB: Nuclear Factor Kappa B p65 Nrf2: Nuclear factor-erythroid-2-related factor 2 CAC: Colitis-Associated Cancer Declarations Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of Tarbiat Modares university (code: IR.MODARES.REC.1398.143). All procedures were in accordance with the ethical standards of the Regional Research Committee and with the Declaration of Helsinki 1964 and its later amendments. After explaining the study's purposes, informed written consent and verbal assent were obtained from all participants. They were informed that their participation was voluntary, confidential and anonymous, and that they had the right to withdraw from the research at any time. Consent for publication Not applicable. Availability of data and materials The data sets used and analyzed for the current study are available upon reasonable request of the corresponding author Dr. Shahideh Jahanian ( [email protected] ). Competing interests The authors declare no conflicts of interest. Funding None. Authors' contributions N.M and Sh.JS contributed to the conception and design of the study; N.M did the literature search; N.M, and M.N performed the statistical analysis; M.N, N.M, Sh.JS, and S.R, wrote the first draft of the manuscript. All authors contributed to the manuscript revision, and read and approved the submitted version. Acknowledgments This study was carried out with the kind collaboration of the participants. We would also like to appreciate the staff of the Tarbiat Modares University and the participating health care centers for their valuable contributions. Trial registration IRCT, IRCT20150905023897N5. Registered 4 th February 2020, https://en.irct.ir/trial/42215 . References Eisenberg V, Weil C, Chodick G, Shalev V. Epidemiology of endometriosis: a large population‐based database study from a healthcare provider with 2 million members. BJOG: An International Journal of Obstetrics & Gynaecology. 2018;125(1):55-62. Sanchez AM, Viganò P, Somigliana E, Panina-Bordignon P, Vercellini P, Candiani M. The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum Reprod Update. 2014;20(2):217-30. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. 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Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression. J Reprod Immunol. 2010;84(2):199-205. Vercellini P, Crosignani P, Somigliana E, Viganò P, Buggio L, Bolis G, et al. The 'incessant menstruation' hypothesis: a mechanistic ovarian cancer model with implications for prevention. Hum Reprod. 2011;26(9):2262-73. Ozkan S, Arici A. Advances in treatment options of endometriosis. Gynecol Obstet Invest. 2009;67(2):81-91. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441-61. Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(9):3146-54. Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-12. Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. The Indian journal of medical research. 2006;124(5):491-504. Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. Journal of hepatology. 2009;50(6):1102-11. Saliou C, Valacchi G, Rimbach G. Assessing bioflavonoids as regulators of NF-kappa B activity and inflammatory gene expression in mammalian cells. Methods in enzymology. 2001;335:380-7. Ramakrishnan G, Lo Muzio L, Elinos-Báez CM, Jagan S, Augustine TA, Kamaraj S, et al. Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells. Cell proliferation. 2009;42(2):229-40. Jiang C, Agarwal R, Lü J. Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun. 2000;276(1):371-8. Cufí S, Bonavia R, Vazquez-Martin A, Corominas-Faja B, Oliveras-Ferraros C, Cuyàs E, et al. Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2013;60:360-8. Jouhari S, Mohammadzadeh A, Soltanghoraee H, Mohammadi Z, Khazali S, Mirzadegan E, et al. Effects of silymarin, cabergoline and letrozole on rat model of endometriosis. Taiwan J Obstet Gynecol. 2018;57(6):830-5. Nahari E, Razi M. Silymarin amplifies apoptosis in ectopic endometrial tissue in rats with endometriosis; implication on growth factor GDNF, ERK1/2 and Bcl-6b expression. Acta Histochem. 2018;120(8):757-67. Ham J, Kim J, Bazer FW, Lim W, Song G. Silibinin-induced endoplasmic reticulum stress and mitochondrial dysfunction suppress growth of endometriotic lesions. Journal of cellular physiology. 2019;234(4):4327-41. Van Holsbeke C, Van Calster B, Guerriero S, Savelli L, Paladini D, Lissoni AA, et al. Endometriomas: their ultrasound characteristics. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2010;35(6):730-40. Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytotherapy Research. 2010;24(10):1423-32. Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytotherapy research : PTR. 2019;33(6):1627-38. Malutan AM, Drugan T, Costin N, Ciortea R, Bucuri C, Rada MP, et al. Pro-inflammatory cytokines for evaluation of inflammatory status in endometriosis. Central-European journal of immunology. 2015;40(1):96. Jiang J, Jiang Z, Xue M. Serum and peritoneal fluid levels of interleukin-6 and interleukin-37 as biomarkers for endometriosis. Gynecological Endocrinology. 2019;35(7):571-5. Kokot I, Piwowar A, Jędryka M, Sołkiewicz K, Kratz EM. Diagnostic significance of selected serum inflammatory markers in women with advanced endometriosis. International journal of molecular sciences. 2021;22(5):2295. Rosen CB, J. Heiman, S. Leiblum, C. Meston, R. Shabsigh, D. Ferguson, R. D'Agostino, R. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. Journal of sex & marital therapy. 2000;26(2):191-208. Mohammadi K, HEYDARI M, Faghihzadeh S. The female sexual function index (FSFI): validation of the Iranian version. 2008. Ware Jr JE, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Medical care. 1996:220-33. Montazeri A, Vahdaninia M, Mousavi SJ, Omidvari S. The Iranian version of 12-item Short Form Health Survey (SF-12): factor structure, internal consistency and construct validity. BMC public health. 2009;9(1):1-10. Gerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz H, Seitz C. Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyses of two placebo-controlled, randomized trials. Health and quality of life outcomes. 2010;8(1):1-7. Almassinokiani F, Khodaverdi S, Solaymani-Dodaran M, Akbari P, Pazouki A. Effects of Vitamin D on Endometriosis-Related Pain: A Double-Blind Clinical Trial. Med Sci Monit. 2016;22:4960-6. Leone Roberti Maggiore U, Gupta JK, Ferrero S. Treatment of endometrioma for improving fertility. Eur J Obstet Gynecol Reprod Biol. 2017;209:81-5. Bersinger NA, Günthert AR, McKinnon B, Johann S, Mueller MD. Dose-response effect of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, and interferon-γ on the in vitro production of epithelial neutrophil activating peptide-78 (ENA-78), IL-8, and IL-6 by human endometrial stromal cells. Arch Gynecol Obstet. 2011;283(6):1291-6. Vetvicka V, Laganà AS, Salmeri FM, Triolo O, Palmara VI, Vitale SG, et al. Regulation of apoptotic pathways during endometriosis: from the molecular basis to the future perspectives. Arch Gynecol Obstet. 2016;294(5):897-904. Sikora J, Smycz-Kubańska M, Mielczarek-Palacz A, Kondera-Anasz Z. Abnormal peritoneal regulation of chemokine activation-The role of IL-8 in pathogenesis of endometriosis. Am J Reprod Immunol. 2017;77(4). Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Association of the Precursor of Interleukin-1β and Peritoneal Inflammation-Role in Pathogenesis of Endometriosis. Journal of clinical laboratory analysis. 2016;30(6):831-7. Defrère S, González-Ramos R, Lousse JC, Colette S, Donnez O, Donnez J, et al. Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis. Histol Histopathol. 2011;26(8):1083-92. Patel BG, Lenk EE, Lebovic DI, Shu Y, Yu J, Taylor RN. Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways. Best practice & research Clinical obstetrics & gynaecology. 2018;50:50-60. Samimi M, Pourhanifeh MH, Mehdizadehkashi A, Eftekhar T, Asemi Z. The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression. Journal of cellular physiology. 2019;234(11):19384-92. Králíčková M, Laganà AS, Ghezzi F, Vetvicka V. Endometriosis and risk of ovarian cancer: what do we know? Arch Gynecol Obstet. 2020;301(1):1-10. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005;12(6):559-67. Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett. 2008;269(2):352-62. Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum). Integr Cancer Ther. 2007;6(2):104-9. Hosseinabadi T, Lorigooini Z, Tabarzad M, Salehi B, Rodrigues CF, Martins N, et al. Silymarin antiproliferative and apoptotic effects: Insights into its clinical impact in various types of cancer. Phytotherapy research : PTR. 2019;33(11):2849-61. Arafa Keshk W, Zahran SM, Katary MA, Abd-Elaziz Ali D. Modulatory effect of silymarin on nuclear factor-erythroid-2-related factor 2 regulated redox status, nuclear factor-κB mediated inflammation and apoptosis in experimental gastric ulcer. Chemico-biological interactions. 2017;273:266-72. Zhang W, Hong R, Tian T. Silymarin's Protective Effects and Possible Mechanisms on Alcoholic Fatty Liver for Rats. Biomol Ther (Seoul). 2013;21(4):264-9. Zheng R, Ma J, Wang D, Dong W, Wang S, Liu T, et al. Chemopreventive Effects of Silibinin on Colitis-Associated Tumorigenesis by Inhibiting IL-6/STAT3 Signaling Pathway. Mediators of inflammation. 2018;2018:1562010. Atawia RT, Mosli HH, Tadros MG, Khalifa AE, Mosli HA, Abdel-Naim AB. Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: emphasis on PTEN, HIF-1α, and NF-κB. Naunyn-Schmiedeberg's archives of pharmacology. 2014;387(12):1131-40. Liu W, Li Y, Zheng X, Zhang K, Du Z. Potent inhibitory effect of silibinin from milk thistle on skin inflammation stimuli by 12-O-tetradecanoylphorbol-13-acetate. Food & function. 2015;6(12):3712-9. Rocha MG, e Silva JC, Ribeiro da Silva A, Candido Dos Reis FJ, Nogueira AA, Poli-Neto OB. TRPV1 expression on peritoneal endometriosis foci is associated with chronic pelvic pain. Reproductive sciences (Thousand Oaks, Calif). 2011;18(6):511-5. McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends in endocrinology and metabolism: TEM. 2015;26(1):1-10. Amini L, Chekini R, Nateghi MR, Haghani H, Jamialahmadi T, Sathyapalan T, et al. The Effect of Combined Vitamin C and Vitamin E Supplementation on Oxidative Stress Markers in Women with Endometriosis: A Randomized, Triple-Blind Placebo-Controlled Clinical Trial. Pain research & management. 2021;2021:5529741. East-Powell M, Reid R. Medical synopsis: Antioxidant supplementation may support reduction in pelvic pain in endometriosis. Advances in Integrative Medicine. 2019;6(4):181-2. Lete I, Mendoza N, de la Viuda E, Carmona F. Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2018;228:221-4. Gupta OP, Sing S, Bani S, Sharma N, Malhotra S, Gupta BD, et al. Anti-inflammatory and anti-arthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2000;7(1):21-4. Kang JS, Jeon YJ, Park SK, Yang KH, Kim HM. Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1beta and prostaglandin E2 synthesis by silymarin. Biochem Pharmacol. 2004;67(1):175-81. Hassani FV, Rezaee R, Sazegara H, Hashemzaei M, Shirani K, Karimi G. Effects of silymarin on neuropathic pain and formalin-induced nociception in mice. Iran J Basic Med Sci. 2015;18(7):715-20. Friedl F, Riedl D, Fessler S, Wildt L, Walter M, Richter R, et al. Impact of endometriosis on quality of life, anxiety, and depression: an Austrian perspective. Arch Gynecol Obstet. 2015;292(6):1393-9. La Rosa VL, De Franciscis P, Barra F, Schiattarella A, Tropea A, Tesarik J, et al. Sexuality in women with endometriosis: a critical narrative review. Minerva medica. 2020;111(1):79-89. Caruso S, Iraci M, Cianci S, Casella E, Fava V, Cianci A. Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest. Journal of endocrinological investigation. 2015;38(11):1211-8. Gillessen A, Herrmann WA, Kemper M, Morath H, Mann K. [Effect of silymarin on liver health and quality of life. Results of a non-interventional study]. MMW Fortschr Med. 2014;156 Suppl 4:120-6. Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. Jama. 2012;308(3):274-82. Salmond SJ, George J, Strasser S, Byth K, Rawlinson B, Mori T, et al. Hep573 study: A randomised, double-blind, placebocontrolled trial of silymarin alone and combined with antioxidants to improve liver function and quality of life in people with chronic hepatitis C. Australian Journal of Herbal and Naturopathic Medicine. 2019;31(2):64-76. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 15 Jul, 2022 Reviews received at journal 30 Jun, 2022 Reviewers agreed at journal 21 Jun, 2022 Reviewers agreed at journal 20 Jun, 2022 Reviewers invited by journal 20 Jun, 2022 Editor assigned by journal 20 Jun, 2022 Editor invited by journal 17 May, 2022 Submission checks completed at journal 17 May, 2022 First submitted to journal 07 May, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-1632161\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":106559447,\"identity\":\"4c0a2b4f-911a-4f14-a332-2e137d2f249c\",\"order_by\":0,\"name\":\"negin mirzaei\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tarbiat Modares University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"negin\",\"middleName\":\"\",\"lastName\":\"mirzaei\",\"suffix\":\"\"},{\"id\":106559448,\"identity\":\"38837e81-fa5d-4500-8f81-70d6993d1fd5\",\"order_by\":1,\"name\":\"shahideh Jahanian Sadatmahalleh\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"\",\"institution\":\"Tarbiat Modares University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"shahideh\",\"middleName\":\"Jahanian\",\"lastName\":\"Sadatmahalleh\",\"suffix\":\"\"},{\"id\":106559449,\"identity\":\"7b6294ba-b46f-4eeb-84aa-35cebfcece15\",\"order_by\":2,\"name\":\"Safoura Rouholamin\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Isfahan University of Medical Sciences and Health Services\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Safoura\",\"middleName\":\"\",\"lastName\":\"Rouholamin\",\"suffix\":\"\"},{\"id\":106559450,\"identity\":\"29038088-5f7a-4fb4-a7ed-dea49d03e0fa\",\"order_by\":3,\"name\":\"Malihe Nasiri\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shahid Beheshti University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Malihe\",\"middleName\":\"\",\"lastName\":\"Nasiri\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2022-05-07 07:14:06\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-1632161/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-1632161/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":21675360,\"identity\":\"822cece3-df1d-4b8f-b388-a6b77e34487b\",\"added_by\":\"auto\",\"created_at\":\"2022-05-19 17:18:27\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":28874,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlowchart of participants: women screened for eligibility, admitted to and randomized in the study on the use of the silymarin\\u0026nbsp;\\u003c/p\\u003e\\u003cp\\u003e\\u003cbr\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1632161/v1/afe9c8304b5e3b5a3c048960.png\"},{\"id\":21675361,\"identity\":\"45667be4-8fe1-43ed-a08c-98650b8ccfb2\",\"added_by\":\"auto\",\"created_at\":\"2022-05-19 17:18:30\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":496546,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1632161/v1/99345de3-4f6a-4ac8-a5c5-6ff59a107efa.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Effect of silymarin on Interleukin-6 level and size of endometrioma lesions in women with ovarian endometriosis: a randomized, double-blind placebo-controlled trial\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eEndometriosis is a debilitating recurrent gynecological disease that is classified based on its location outside the uterus into peritoneal implants, ovarian endometrioma (OMA), and Deep Infiltrating Endometriosis (DIE) (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e). The most common site of endometriosis is ovarian, and OMA is described as an ovarian cyst lined with endometrial tissue with internal thick brown fluid (hence the term chocolate cyst) arising from the accumulation of menstrual debris (\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e). The prevalence of endometriosis has been reported in approximately 10% of reproductive-aged women, up to 50% of the infertile population, and 60% of women with pelvic pain (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e). In addition, approximately 17\\u0026ndash;44% of patients with endometriosis have an endometrioma (\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eOMA might be accompanied by several pain-related manifestations such as chronic pelvic pain, dysmenorrhea, dyspareunia, and subfertility (\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e). Not only do these discomfort symptoms pose devastating impacts on the psychological, social, sexual life, and Quality of Life (QoL) of afflicted women, also these can represent a massive economic burden on patients and the health care system (\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eAlthough the accurate pathogenesis of endometriosis remains elusive, recent studies have addressed the roles of oxidative stress and inflammatory factors in the development of OMA (\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e). Hence, an endometrioma contains free iron, Reactive Oxygen Species (ROS), and inflammatory molecules such as Interleukin (IL)-8, IL-6, Tumor Necrosis Factor-a (TNF-a) are higher compared with those present in peripheral blood or other types of benign cysts (\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eAll available therapeutic modalities of endometriosis, including medical treatment (such as androgens, Oral Contraceptive Pills (OCPs), progestogens, anti-progestogens, and Gonadotrophin-Releasing Hormone analogues (GnRH-a)) and surgical therapy, alone or in combination treatments, have several limitations that include the risk of recurrence, side effects, contraceptive action for those are disastrous to become pregnant, and their costs (\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e). Not only has the recurrence of endometriosis\\u0026rsquo;s symptoms after surgical and medical treatments been estimated approximately 21.5% at two years and some 40\\u0026ndash;50% after five years, but also several reports have indicated laparoscopic management of OMA can decrease ovarian reserve (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e). Therefore, the development of new strategies and novel agents from herbal medicine with minor side effects, costs, and enhanced efficacy and availability has become a new area of research in the last decades (\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eSilymarin, a flavonolignan derived from the milk thistle plant (Silybum marianum), has been widely used for the treatment of various disorders, and it is the mixture of six isomeric flavonoids such as silybins A and B (major bioactive compounds), isosilybins A and B, silychristin, and silydianin (\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e). Numerous studies have demonstrated that silymarin has potent antioxidant, anti-inflammatory, and anti-fibrotic properties (\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e). Moreover, silymarin is one of the highly potent anti-cancer agents since it could diminish the secretion level of vascular endothelial growth factors in human breast and prostate cancer cells, induce apoptosis in human hepatic cancer cells, suppress cell proliferation, modulate cell cycle progression, and imped epithelial-to-mesenchymal transition in lung carcinoma, (\\u003cspan additionalcitationids=\\\"CR19\\\" citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e). In addition, several in vitro and animal studies have verified the effects of silymarin in decreasing the size and histopathologic grade of the endometrial lesions (\\u003cspan additionalcitationids=\\\"CR22\\\" citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThus, in light of previous studies on silymarin in other chronic disease and endometrial cells, we hypothesized that silymarin might be an effective candidate for the treatment of endometrioma. Therefore, to test this hypothesis, this randomized double-blinded clinical trial was conducted to evaluate the efficacy of silymarin on endometrioma.\\u003c/p\\u003e\"},{\"header\":\"Material And Method\",\"content\":\"\\u003ch2\\u003e\\u003cstrong\\u003eTrial Design and Overview\\u003c/strong\\u003e\\u003c/h2\\u003e\\n\\u003cp\\u003eThis study was a phase II, double-blind, randomized, placebo-controlled trial conducted in gynecological clinics affiliated with Tehran University of Medical Sciences, Tehran, Iran, from 2nd March 2020 (02/03/2020) to 18th May 2021 (18/05/2021). This clinical trial comprised a 12-week treatment period, after which some of the endometriosis-related manifestations were evaluated. This trial conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and ethical approval was obtained from the Ethics Committee of Tarbiat Modares University, Tehran, Iran, before the commencement of the study on 22nd October 2019 (IR.MODARES.REC.1398.143). In addition to that, it has been registered in the Iranian Registry of Clinical Trials in 4th February 2020 (04/02/2020) (IRCT20150905023897N5). All potential study subjects provided written informed consent and were informed about the aims and possible risks of the trial before the study. Not only can all authors attest to the completeness and accuracy of the data and analyses and adherence to the trial protocol, but also they have reviewed and approved the final manuscript.\\u003c/p\\u003e\\n\\u003ch2\\u003e\\u003cstrong\\u003eParticipants\\u003c/strong\\u003e\\u003c/h2\\u003e\\n\\u003cp\\u003eEligible subjects were women of reproductive age (15\\u0026ndash;49 years), married, and non-pregnant with a confirmed diagnosis of OMA via transvaginal ultrasonography performed by a single sonologist at the three-dimensional level in the previous five years and currently experiencing moderate to severe pain and receiving 2mg dienogest daily in last six months. The pattern recognition using subjective evaluation of Gray-scale and Doppler-ultrasound characteristics based on IOTA rules \\u0026ldquo;an adnexal mass with ground glass echogenicity of the cyst fluid, one to four locules and no papillations with detectable blood flow\\u0026rdquo; and volume (L\\u0026times;D\\u0026times;W\\u0026times;0.5235) was achieved through the Orsini formula (\\u003cspan class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eWomen would have been excluded if they had suffered from chronic diseases such as hypertension, diabetes, coronary, renal, and hepatic disorders or liver enzyme anomalies. Also, suppose they had taken specific medications like oral contraceptives, anti-depressant and GnRH analogues, or systemic glucocorticoids, with a specified wash-out period for each one based on the period. In that case, they might have a continued effect. In addition, using silymarin or other milk thistle preparations and anti-inflammatory supplements (e.g., vitamin, vitamin E, ...) and even non-prescribed complementary alternative drugs must have been stopped for at least 30 days before the study. All subjects were instructed to use non-hormonal, double-barrier contraception such as a condom or diaphragm, each combined with a spermicide.\\u003c/p\\u003e\\n\\u003ch2\\u003e\\u003cstrong\\u003eInterventions\\u003c/strong\\u003e\\u003c/h2\\u003e\\n\\u003cp\\u003eEligible subjects were randomized into placebo and treatment groups based on the computer-generated list. All participants received a dose of 280 mg silymarin including two tablets of Livergol 140 mg, Goldaru Pharma Co. Isfahan-Iran) or placebo (Goldaru Pharma Co. Isfahan-Iran) daily in two meals (after breakfast and dinner) for 12 weeks along with standard treatment of endometrioma (dienogest 2mg/day). This dosage was chosen because it is safe and effective in treating liver diseases (\\u003cspan class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e). The therapeutic doses of silymarin have been considered safe and well-tolerated in humans. Some slight gastrointestinal discomforts like nausea and diarrhea might be accrued (\\u003cspan class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003ch2\\u003e\\u003cstrong\\u003eRandomization and blinding\\u003c/strong\\u003e\\u003c/h2\\u003e\\n\\u003cp\\u003eSimple randomization was done according to a computer-generated list of random number groups prepared using Statistical Analysis System Software Version 9.2 (SAS Institute Inc., Cary, NC, USA). All participants were randomly allocated to each arm and given the tablets based on a computer-generated randomization list by the investigator. Treatment and placebo allocations were blinded to subjects, the investigator, and the attending doctor.\\u003c/p\\u003e\\n\\u003ch2\\u003e\\u003cstrong\\u003eTrial Procedures and Assessments\\u003c/strong\\u003e\\u003c/h2\\u003e\\n\\u003cp\\u003eAt the first and follow-up visit that was planned after 12-week treatment, participants were referred to the lab and sonography single-center (based on routine standard protocols) to measure IL-6 (Roche Instr Kit, Germany) and record the sizes of the endometrioma lesions via three-dimensional transvaginal ultrasonography (by the same physician in blind), respectively. In addition, they were asked to fill out several self-report questionnaires as follows:\\u003c/p\\u003e\\n\\u003cp\\u003eFirstly, demographic data that consists of address, phone number, date of birth, weight, height, Body Mass Index (BMI), education level, occupation, education level of husband, and a history of the disease was gathered.\\u003c/p\\u003e\\n\\u003cp\\u003eBecause the observation suggests that IL-6 may be a good marker of disease prediction and progression and may serve as biomarkers for the diagnosis of endometriosis (\\u003cspan class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e), subjects were supplied ibuprofen and paracetamol/acetaminophen tablets and requested to use these for rescue analgesia if required, for endometriosis pain. Participants did not report any side effects related to silymarin.\\u003c/p\\u003e\\n\\u003cdiv class=\\\"Section2\\\" id=\\\"Sec3\\\"\\u003e\\n \\u003ch2\\u003eFemale Sexual Function (FSFI):\\u003c/h2\\u003e\\n \\u003cp\\u003eFSFI investigates the sexual function and consists of 19 Likert-scale questions in six domains of desire, arousal, lubrication, satisfaction, orgasm, and pain. The lower score is, the more sexual function impaired (\\u003cspan class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e). The Iranian version of FSFI has been evaluated for both reliability and validity (\\u003cspan class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv class=\\\"Section2\\\" id=\\\"Sec4\\\"\\u003e\\n \\u003ch2\\u003eShort Form Health Survey (SF-12):\\u003c/h2\\u003e\\n \\u003cp\\u003eSF-12 is designed to evaluate the physical and mental components of health-related QoL by 12 questions. Lower scores indicate inferior health-related QoL (\\u003cspan class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e). The validity and reliability of this questionnaire have been confirmed in Iran (\\u003cspan class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv class=\\\"Section2\\\" id=\\\"Sec5\\\"\\u003e\\n \\u003ch2\\u003eVisual Analog Scale (VAS):\\u003c/h2\\u003e\\n \\u003cp\\u003eVAS has been used most often to assess the intensity of endometriosis-related pain (dysmenorrhea, deep dyspareunia, chronic pelvic pain, and menstrual and non-menstrual dysphasia). It is an 11-point scale in which 0 represented the absence of pain, while 10 meant unbearable pain (\\u003cspan class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e).\\u003c/p\\u003e\\n \\u003ch2\\u003e\\u003cstrong\\u003eOutcome\\u003c/strong\\u003e\\u003c/h2\\u003e\\n \\u003cp\\u003eOne of the primary endpoints was a significant reduction in the mean pelvic pain assessed after 12-week treatment on a VAS. Other primary efficacy endpoints at weeks 12 included a significant decrease in the volume of endometrioma lesions diagnosed via transvaginal ultra-sonography and any change from baseline in the level of IL-6.\\u003c/p\\u003e\\n \\u003cp\\u003eSecondary efficacy endpoints were improvement of individuals\\u0026rsquo; QoL and sexual function assessed on mentioned questionnaires.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv class=\\\"Section2\\\" id=\\\"Sec6\\\"\\u003e\\n \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e\\n \\u003cp\\u003eBased on the study results of Almassinokiani et al. (\\u003cspan class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e), who assessed the effects of vitamin D on endometriosis-associated pain, with a 99% confidence interval and 90% power of the test, the sample size was determined as 35 individuals for each group. By counting 20% sample loss, the minimum sample size was estimated at 40 individuals in each group, meaning that 80 women diagnosed with endometrioma who had the inclusion criteria (40 persons in each group) were recruited for the present study.\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cimg src=\\\"data:image/png;base64,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\\\"\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003eWhere, \\u0026alpha; is the probability of type I errors (\\u0026alpha;\\u0026thinsp;=\\u0026thinsp;0.05), and \\u0026beta;indicates the probability of type Ⅱ errors (\\u0026beta;\\u0026thinsp;=\\u0026thinsp;0.20). In addition, (\\u0026mu;\\u003csub\\u003e1\\u003c/sub\\u003e-\\u0026mu;\\u003csub\\u003e2\\u003c/sub\\u003e)/\\u0026sigma; \\u0026nbsp;represents the size effect observed that is equal 0.7.\\u003c/p\\u003e\\n \\u003cdiv class=\\\"Equation\\\" id=\\\"Equa\\\"\\u003e\\n \\u003cdiv class=\\\"mathdisplay\\\" id=\\\"FileID_Equa\\\" name=\\\"EquationSource\\\"\\u003e$$\\\\mathbf{n}=2{\\\\left(1.96+0.85\\\\right)}^{2}{\\\\left(\\\\frac{1}{0.65}\\\\right)}^{2}=33$$\\u003c/div\\u003e\\n \\u003c/div\\u003e\\n \\u003cp\\u003e\\u003cbr\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003eAll statistical analyses were performed by the SPSS software (ver. 22.0) (SPSS Inc., Chicago, IL, USA). The data of normality in distribution were examined by one sample K-S. Group comparisons were carried out with Student\\u0026rsquo;s t-test and Chi-square test. P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered statistically significant.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Result\",\"content\":\"\\u003cp\\u003eOverall, 10 out of the 90 potentially eligible women refused to participate in the study because of time consuming completing of questionnaires and longtime treatment process, so the response rate was approximately 88%. A total of 80 individuals, (40 women in each group) were enrolled into the study, 10 were excluded due to the unwillingness to peruse recommended treatment (n\\u0026thinsp;=\\u0026thinsp;8), surgery (n\\u0026thinsp;=\\u0026thinsp;3), the rate of sample loss was 12% (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Finally, 35 women were enrolled in each group.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003ePatients reported a mean of 3.4 years since the first diagnosis of endometriosis. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e describes the characteristics of women in the intervention and control groups. There was no statistically significant difference in women\\u0026rsquo;s age, Body Mass Index (BMI), parity, educational level, and occupation status between the two groups (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eComparison of demographic characteristics between intervention and control groups\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eIntervention group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eControl group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eP-value\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge of female*\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e36.49\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e33.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7.00\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNumber of children**\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\" morerows=\\\"4\\\" rowspan=\\\"5\\\"\\u003e \\u003cp\\u003e0.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11 (31.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18 (51.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e13 (37.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9 (25.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10 (28.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6 (17.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3 and more\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1 (2.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (5.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEducation of female**\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e \\u003cp\\u003e0.47\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eUndergraduate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e17 (48.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e14 (40.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePostgraduate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e18 (51.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e21 (60.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOccupation **\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e \\u003cp\\u003e0.46\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHousewife\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e19 (54.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e22 (62.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEmployee\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e16 (45.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e13 (37.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBMI (kg/ m\\u0026sup2;) *\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e24.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e24.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.75\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eBMI: Body Mass Index,\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003e*Values are given as mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD using t-test\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003e** Values are given as a number (%) using Chi-squared test\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eAs can be seen in Table \\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e, evaluation of the two groups with regard to FSFI before and after treatment did not show any significant differences. The total score of FSFI was significantly lower in control group after treatment (25.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.74 vs 24.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.74, P\\u0026thinsp;=\\u0026thinsp;0.03).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003e:Comparison of FSFI scores between intervention and control groups\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIntervention group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eControl group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eP-value*\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eDesire\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.58\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.90\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3.50\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.06\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.72\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eArousal\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.86\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.18\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.01\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.78\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.56\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.21\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.78\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.40\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eLubrication\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.37\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.22\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.87\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.97\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.87\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.53\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.04\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.69\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.83\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.54\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.44\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eOrgasm\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.68\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.81\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.37\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.15\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.91\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.40\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSatisfaction\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.50\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.61\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.88\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.90\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.40\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.04\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.69\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.54\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.06\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePain\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.44\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.07\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.76\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4.05\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.79\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.97\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.18\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTotal score\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e24.39\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e25.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.74\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e25.76\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.33\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e24.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.74\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.09\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003eFSFI: Female Sexual Function Index\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003e*T-test was carried out for comparison of the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003e**Paired T-test was carried out for comparison of changes between the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe comparison of SF-12 scores between the intervention and control groups is shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e. The mean total scores of SF-12 were not significantly different between groups before treatment compared with after intervention (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eComparison of the scores of subgroups of QoL between intervention and control groups\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntervention group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eP-value*\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eSum score of physical components (PCS-12)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e76.23\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;13.59\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e72.03\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;18.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e78.25\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.51\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e71.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;20.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.13\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eP-value**\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.91\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eSum score of mental components (MCS-12)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e69.79\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;14.50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e70.72\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;13.80\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.79\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e73.20\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;14.33\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e72.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12.20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.83\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eP-value**\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.47\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eTotal score\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e73.01\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.73\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e71.51\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;14.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e75.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.56\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e72.19\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;15.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.34\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eP-value**\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.58\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.37\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003eQoL: Quality of Life\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e*T-test was carried out for comparison of the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e**Paired T-test was carried out for comparison of changes between the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eIt can be seen from the data in Table \\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e that there was significant difference in intervention group for the pelvic pain mean changes from baseline to treatment end (7.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.49 vs 4.88\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.00, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). In addition, IL-6 levels decreased significantly during the 90-day study period (2.40\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.52 vs 2.12\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.20, P\\u0026thinsp;=\\u0026thinsp;0.002).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eComparison of the IL-6 levels and pelvic pain between intervention and control groups\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntervention group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eP-value*\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIL-6\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.40\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2.57\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.78\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.29\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.12\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.73\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.03\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.002\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.30\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePelvic pain\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.29\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.49\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.97\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.41\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4.88\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.00\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6.61\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003eQoL: Quality of Life\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e*T-test was carried out for comparison of the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e**Paired T-test was carried out for comparison of changes between the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e shows a comparison between the 2 groups for the endometrioma lesions volumes at before and after treatment. There were significant differences between the volumes of endometrioma lesions in right ovary intervention group.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab5\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 5\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eComparison of the ovaries\\u0026rsquo; volume between intervention and control groups\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIntervention group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eControl group\\u003c/p\\u003e \\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;35\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eP-value*\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eRight ovary\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e58863.51\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;83820.56\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e75848.03\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;135023.70\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.59\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e33694.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;53124.60\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e81963.81\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;150300.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.24\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.04\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eLeft ovary\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePre-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e65773.67\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;76725.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e54857.73\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;57983.99\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.60\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePost-assessment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e58079.16\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;73622.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e70801.58\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;93146.68\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.66\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eP-value**\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e*T-test was carried out for comparison of the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e**Paired T-test was carried out for comparison of changes between the groups\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eTo the best of our knowledge, this is the first double-blind, randomized clinical trial conducted to investigate the effect of silymarin on IL-6, endometrioma volume, QoL, pain, and sexual function in women diagnosed with OMA.\\u003c/p\\u003e\\n\\u003cp\\u003eOvarian endometriotic cyst affects 17\\u0026ndash;44% of women suffering of endometriosis and it per se and its surgical treatment could impair ovarian function, ovarian reserve by significant reduction in serum Anti-Mullerian Hormone (AMH) and in Antral Follicle Count (AFC), pregnancy outcomes, and on IVF/ICSI outcomes (\\u003cspan class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eThe exact physiopathology of endometriosis is not clarified. Inflammation, however, is known as a main factor in initiation and progression of endometriosis. Hence, inflammatory mediators such as IL-1\\u0026beta;, IL‐6, IL‐8 increase in the peritoneal, serum, and endometrium of endometriosis patients, leading to enhancing proliferation and decreasing apoptotic rate in endometriotic cells (\\u003cspan class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e). In addition, the expression of Cyclooxygenase‐2 (COX‐2), Vascular Endothelial Growth Factor (VEGF), IL‐6, Tumor Necrosis Factor‐\\u0026alpha; (TNF‐\\u0026alpha;), IL‐8, C‐C Motif Chemokine 2 (MCP‐1), and IL‐10 have increased in endometriosis cases (\\u003cspan class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eSeveral papers have investigated that oxidative stress plays a vital role in endometriosis pathophysiology as iron overload and inflammation can have impacts on the mechanism of oxidative stress (\\u003cspan class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e). ROS concentration promotes fibrogenic response, collagen matrix remodeling, and fibrosis (\\u003cspan class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e). Sanchez et al. showed that endometrioma cysts contain ROS, free iron, inflammatory molecules, and proteolytic enzymes in concentrations hundred times higher than those present in peripheral blood or in other types of benign cysts (\\u003cspan class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eAdditionally, dysregulations in angiogenesis and apoptosis pathways might be contributed in endometriosis pathophysiology (\\u003cspan class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e). Furthermore, the advanced endometriosis may lead to gynecological malignancies and infertility (\\u003cspan class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e). For instance, the increased risk of developing ovarian cancer is proved by somatic mutations of PIK3CA, PTEN, and ARID1A in endometriosis patients especially in younger ones, however the absolute higher risk is not completely clear (\\u003cspan class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e). Ideally, therapeutic strategies to conquer endometriosis should be done regarding theses pathogeneses.\\u003c/p\\u003e\\n\\u003cp\\u003eSilymarin is one of the highly potent antioxidant agents that inhibits lipid peroxidation and exerts antioxidant (\\u003cspan class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e). In addition, its anti-inflammatory, antifibrotic, immunomodulatory, and membrane-stabilizing effects have broadly confirmed through numerous studies (\\u003cspan class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e). This study was conducted to investigate the effect of Silymarin on IL-6, endometrioma volume, quality of life, pain, and sexual function in women diagnosed with endometriosis.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEndometrioma volume\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study confirms that silymarin can be effective in reducing endometrioma lesions is consistent with previous observations in animal models.\\u003c/p\\u003e\\n\\u003cp\\u003eJouhari et al. compared the effects of silymarin, Cabergoline, and Letrozole on induced endometrial lesions in rats for about 6 months. Silymarin, Letrozole, and Cabergoline administration could decrease size and histopathologic grade of the induced endometrial lesions significantly and those who were received silymarin had significantly higher serum total antioxidant activity compared to control after 21 days (\\u003cspan class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eNahari et al. evaluating legions establishment and growth in experimentally-induced endometriosis in 12 rats after 28 days of oral administration of silymarin showed that the combination of enhancing ERK1/2 expression and suppressing the Bcl-2 expression by silymarin accompanying with down-regulating the angiogenesis ratio led to promote the apoptosis pathway, consequently induced severe fibrosis in endometriotic-like legions (\\u003cspan class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eA recent prospective study showed that not only could silibinin induce oxidative stress and lipid peroxidation in human endometriotic cells, but also it exerted antiproliferative and apoptotic impacts on human endometriotic cell lines VK2/E6E7 and End1/E6E7. Moreover, the effects of silibinin on reducing endometriotic lesions by inhibiting the expression of inflammatory cytokines was verified by using an animal model mimicking the retrograde menstruation hypothesis in mice and they proved the possibility of effectiveness of silibinin as a novel therapeutic agent or supplement in inhibiting progression of endometriosis in vitro and in vivo (\\u003cspan class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInterleukin 6\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe present results showed that oral administration of silymarin 280 mg/day decreased the IL-6 levels significantly during the study period within the intervention group. Arafa Keshk et al. evaluating the potential protective effects of silymarin against indomethacin-induced gastric injury in rats, have demonstrated that suppression in gastric inflammation by decreasing myeloperoxidase activity, TNF- \\u0026alpha;, and IL-6 levels along with Nuclear Factor Kappa B p65 (NF-\\u0026kappa;B) expression was observed. Meanwhile, silymarin prevent gastric oxidative stress via inhibition of lipid peroxides formation, enhancement of glutathione peroxidase, superoxide dismutase activities and up-regulation of Nuclear Factor-Erythroid-2-Related Factor 2 (Nrf2), the redox-sensitive master regulator of oxidative stress signaling (\\u003cspan class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eAdditionally, Wei Zhang et al. showed that silymarin could protect against the liver injury caused by ethanol administration as it markedly downregulated the expression of NF-\\u0026kappa;B p65, ICAM-1 and IL-6 in liver tissue (\\u003cspan class=\\\"CitationRef\\\"\\u003e50\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eRongjuan Zheng et al. evaluated the chemo-preventive effect of silibinin (major component of silymarin) on a Colitis-Associated Cancer (CAC) mouse model and determined its impact on IL-6/STAT3 signaling. Silibinin decreased the amount and size of tumors in mice accompanying with inhibition of colonic tumor cell proliferation and promotion of cellular apoptosis. Furthermore, they showed that silibinin could reduce the production of inflammatory cytokines and can protect against colitis-associated tumorigenesis in mice via inhibiting IL-6/STAT3 (\\u003cspan class=\\\"CitationRef\\\"\\u003e51\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eIn addition, it is revealed that silymarin attenuate the expression of NF-kB and the subsequent inflammatory cascade by suppressing I\\u0026kappa;B, effectively can down-regulate the expressions of TPA-induced IL-1\\u0026beta;, IL-6, TNF-\\u0026alpha;, and COX-2 in a dose-dependent manner (\\u003cspan class=\\\"CitationRef\\\"\\u003e52\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e53\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePain- related symptoms\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNumerous mechanisms are involved in endometriosis-related pain such as various algogens (pain-producing agents), cytokines (such as IL-1b, IL-6, and TNF-a), growth factors (such as b-nerve growth factor and vascular endothelial growth factor), and several chemokines, such as CCL2 (\\u003cspan class=\\\"CitationRef\\\"\\u003e54\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e55\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eSeveral papers have investigated that different kind of antioxidant such as vitamin E and vitamin C can reduce peritoneal inflammatory markers and decrease chronic pelvic pain in endometriosis women (\\u003cspan class=\\\"CitationRef\\\"\\u003e56\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e58\\u003c/span\\u003e). It might be speculated silymarin could be effective in reducing pain as it can suppress nitric oxide, prostaglandin E2 (PGE2), leukotrienes, cytokines production, and neutrophils infiltration (\\u003cspan class=\\\"CitationRef\\\"\\u003e59\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e60\\u003c/span\\u003e). This study supports evidence from previous observations about the analgesic effects of silymarin.\\u003c/p\\u003e\\n\\u003cp\\u003eVahdati Hassani et al. investigating the effects of silymarin in both chemical nociception and neuropathic pain in rats, showed that silymarin administer was significantly effective in preventing the formalin-induced nociceptive behavior, while it did not have significant effects in reducing sciatic neuropathic pain (\\u003cspan class=\\\"CitationRef\\\"\\u003e61\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eQuality of life and sexual function\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eEndometriosis is a very complex condition with wide range of clinical features including pelvic pain, dyspareunia, infertility, and menstrual irregularities that might compromise QoL, psychological wellbeing, sexual function, and interpersonal relationships of affected women (\\u003cspan class=\\\"CitationRef\\\"\\u003e62\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e63\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eCaruso et al. evaluating the effects of dienogest on QoL and sexual function in endometriosis women, reported that progressive reduction of the pain could contribute in improving the QoL and sexual life (\\u003cspan class=\\\"CitationRef\\\"\\u003e64\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eVery little was found in the literature on the question of the effectiveness of silymarin on QoL and sexual function. Gillessen et al. investigating the effect of silymarin on liver function and QoL in a non-interventional study, reported that improvement in liver-related symptoms and increased QoL after 2 months (\\u003cspan class=\\\"CitationRef\\\"\\u003e65\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003ePrevious researches had proved that silymarin and other anti-oxidants agents can enhance QoL in patients because of their positive effects on pain reduction (\\u003cspan class=\\\"CitationRef\\\"\\u003e66\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e67\\u003c/span\\u003e). However, the present study found inconsistent results and there was neither a significant difference in SF-12 between treatment and placebo groups nor within groups pre/post treatment\\u003c/p\\u003e\\n\\u003cp\\u003eThe strengths of the study are the RCT design and novelty. In addition, as maintaining endometriosis associated women on a placebo is unethical, the intervention was recommended along with routine treatment. However, the principal limitation of the study is the 8% loss to follow-up and the short duration of follow-up; therefore, results probably cannot be extrapolated for long-term treatment. Additionally, these data warrant further investigations for the potential use of silymarin in the management of endometriosis features to assess long-term effects of this treatment by larger sample.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eIn conclusion, silymarin can be considered as a feasible option for treatment women with endometrioma-associated symptoms that has few side effects.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eAMH: Anti-Mullerian Hormone\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAFC: Antral Follicle Count\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eIL: Interleukin\\u003c/p\\u003e\\n\\u003cp\\u003eCOX‐2: Cyclooxygenase‐2\\u003c/p\\u003e\\n\\u003cp\\u003eVEGF: Vascular Endothelial Growth Factor\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTNF‐\\u0026alpha;: Tumor Necrosis Factor‐\\u0026alpha;\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eMCP‐2: C‐C Motif Chemokine 2\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eQoL: Quality of Life\\u003c/p\\u003e\\n\\u003cp\\u003eOMA: Ovarian Endometrioma\\u003c/p\\u003e\\n\\u003cp\\u003eDIE: Deep Infiltrating Endometriosis\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eROS: Reactive Oxygen Species\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eOCPs: Oral Contraceptive Pills\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eGnRH-a: Releasing Hormone analogues\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eNF-\\u0026kappa;B: Nuclear Factor Kappa B p65\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eNrf2: Nuclear factor-erythroid-2-related factor 2\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eCAC: Colitis-Associated Cancer\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study protocol was approved by the Ethics Committee of Tarbiat Modares university (code: IR.MODARES.REC.1398.143). All procedures were in accordance with the ethical standards of the Regional Research Committee and with the Declaration of Helsinki 1964 and its later amendments. After explaining the study\\u0026apos;s purposes, informed written consent and verbal assent were obtained from all participants. They were informed that their participation was voluntary, confidential and anonymous, and that they had the right to withdraw from the research at any time. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data sets used and analyzed for the current study are available upon reasonable request of the corresponding author Dr. Shahideh Jahanian (shahideh.jahanian@modares.ac.ir).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no conflicts of interest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNone.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026apos; contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eN.M and Sh.JS contributed to the conception and design of the study; N.M did the literature search; N.M, and M.N performed the statistical analysis; M.N, N.M, Sh.JS, and S.R, wrote the first draft of the manuscript. All authors contributed to the manuscript revision, and read and approved the submitted version.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was carried out with the kind collaboration of the participants. We would also like to appreciate the staff of the Tarbiat Modares University and the participating health care centers for their valuable contributions.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTrial registration\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIRCT, IRCT20150905023897N5. Registered 4\\u003csup\\u003eth\\u003c/sup\\u003e February 2020, \\u003ca href=\\\"https://en.irct.ir/trial/42215\\\"\\u003ehttps://en.irct.ir/trial/42215\\u003c/a\\u003e.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eEisenberg V, Weil C, Chodick G, Shalev V. Epidemiology of endometriosis: a large population‐based database study from a healthcare provider with 2 million members. BJOG: An International Journal of Obstetrics \\u0026amp; Gynaecology. 2018;125(1):55-62.\\u003c/li\\u003e\\n\\u003cli\\u003eSanchez AM, Vigan\\u0026ograve; P, Somigliana E, Panina-Bordignon P, Vercellini P, Candiani M. The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum Reprod Update. 2014;20(2):217-30.\\u003c/li\\u003e\\n\\u003cli\\u003eMeuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D\\u0026apos;Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertility and sterility. 2009;92(1):68-74.\\u003c/li\\u003e\\n\\u003cli\\u003eGuo S-W, Wang Y. The prevalence of endometriosis in women with chronic pelvic pain. Gynecologic and obstetric investigation. 2006;62(3):121-30.\\u003c/li\\u003e\\n\\u003cli\\u003eBusacca M, Vignali M. Ovarian endometriosis: from pathogenesis to surgical treatment. Curr Opin Obstet Gynecol. 2003;15(4):321-6.\\u003c/li\\u003e\\n\\u003cli\\u003eGiudice LC. Endometriosis. New England Journal of Medicine. 2010;362(25):2389-98.\\u003c/li\\u003e\\n\\u003cli\\u003eCulley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, et al. The social and psychological impact of endometriosis on women\\u0026apos;s lives: a critical narrative review. Hum Reprod Update. 2013;19(6):625-39.\\u003c/li\\u003e\\n\\u003cli\\u003eSoliman AM, Surrey ES, Bonafede M, Nelson JK, Vora JB, Agarwal SK. Health Care Utilization and Costs Associated with Endometriosis Among Women with Medicaid Insurance. Journal of managed care \\u0026amp; specialty pharmacy. 2019;25(5):566-72.\\u003c/li\\u003e\\n\\u003cli\\u003eVelasco I, Aci\\u0026eacute;n P, Campos A, Aci\\u0026eacute;n MI, Ruiz-Maci\\u0026aacute; E. Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression. J Reprod Immunol. 2010;84(2):199-205.\\u003c/li\\u003e\\n\\u003cli\\u003eVercellini P, Crosignani P, Somigliana E, Vigan\\u0026ograve; P, Buggio L, Bolis G, et al. The \\u0026apos;incessant menstruation\\u0026apos; hypothesis: a mechanistic ovarian cancer model with implications for prevention. Hum Reprod. 2011;26(9):2262-73.\\u003c/li\\u003e\\n\\u003cli\\u003eOzkan S, Arici A. Advances in treatment options of endometriosis. Gynecol Obstet Invest. 2009;67(2):81-91.\\u003c/li\\u003e\\n\\u003cli\\u003eGuo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441-61.\\u003c/li\\u003e\\n\\u003cli\\u003eRaffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(9):3146-54.\\u003c/li\\u003e\\n\\u003cli\\u003eDunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D\\u0026apos;Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-12.\\u003c/li\\u003e\\n\\u003cli\\u003ePradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. The Indian journal of medical research. 2006;124(5):491-504.\\u003c/li\\u003e\\n\\u003cli\\u003eTrappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. Journal of hepatology. 2009;50(6):1102-11.\\u003c/li\\u003e\\n\\u003cli\\u003eSaliou C, Valacchi G, Rimbach G. 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The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression. Journal of cellular physiology. 2019;234(11):19384-92.\\u003c/li\\u003e\\n\\u003cli\\u003eKr\\u0026aacute;l\\u0026iacute;čkov\\u0026aacute; M, Lagan\\u0026agrave; AS, Ghezzi F, Vetvicka V. Endometriosis and risk of ovarian cancer: what do we know? Arch Gynecol Obstet. 2020;301(1):1-10.\\u003c/li\\u003e\\n\\u003cli\\u003eMayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005;12(6):559-67.\\u003c/li\\u003e\\n\\u003cli\\u003eRamasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett. 2008;269(2):352-62.\\u003c/li\\u003e\\n\\u003cli\\u003ePost-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum). 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Chemopreventive Effects of Silibinin on Colitis-Associated Tumorigenesis by Inhibiting IL-6/STAT3 Signaling Pathway. Mediators of inflammation. 2018;2018:1562010.\\u003c/li\\u003e\\n\\u003cli\\u003eAtawia RT, Mosli HH, Tadros MG, Khalifa AE, Mosli HA, Abdel-Naim AB. Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: emphasis on PTEN, HIF-1\\u0026alpha;, and NF-\\u0026kappa;B. Naunyn-Schmiedeberg\\u0026apos;s archives of pharmacology. 2014;387(12):1131-40.\\u003c/li\\u003e\\n\\u003cli\\u003eLiu W, Li Y, Zheng X, Zhang K, Du Z. Potent inhibitory effect of silibinin from milk thistle on skin inflammation stimuli by 12-O-tetradecanoylphorbol-13-acetate. Food \\u0026amp; function. 2015;6(12):3712-9.\\u003c/li\\u003e\\n\\u003cli\\u003eRocha MG, e Silva JC, Ribeiro da Silva A, Candido Dos Reis FJ, Nogueira AA, Poli-Neto OB. TRPV1 expression on peritoneal endometriosis foci is associated with chronic pelvic pain. Reproductive sciences (Thousand Oaks, Calif). 2011;18(6):511-5.\\u003c/li\\u003e\\n\\u003cli\\u003eMcKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends in endocrinology and metabolism: TEM. 2015;26(1):1-10.\\u003c/li\\u003e\\n\\u003cli\\u003eAmini L, Chekini R, Nateghi MR, Haghani H, Jamialahmadi T, Sathyapalan T, et al. The Effect of Combined Vitamin C and Vitamin E Supplementation on Oxidative Stress Markers in Women with Endometriosis: A Randomized, Triple-Blind Placebo-Controlled Clinical Trial. Pain research \\u0026amp; management. 2021;2021:5529741.\\u003c/li\\u003e\\n\\u003cli\\u003eEast-Powell M, Reid R. Medical synopsis: Antioxidant supplementation may support reduction in pelvic pain in endometriosis. Advances in Integrative Medicine. 2019;6(4):181-2.\\u003c/li\\u003e\\n\\u003cli\\u003eLete I, Mendoza N, de la Viuda E, Carmona F. Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. European Journal of Obstetrics \\u0026amp; Gynecology and Reproductive Biology. 2018;228:221-4.\\u003c/li\\u003e\\n\\u003cli\\u003eGupta OP, Sing S, Bani S, Sharma N, Malhotra S, Gupta BD, et al. Anti-inflammatory and anti-arthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2000;7(1):21-4.\\u003c/li\\u003e\\n\\u003cli\\u003eKang JS, Jeon YJ, Park SK, Yang KH, Kim HM. Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1beta and prostaglandin E2 synthesis by silymarin. Biochem Pharmacol. 2004;67(1):175-81.\\u003c/li\\u003e\\n\\u003cli\\u003eHassani FV, Rezaee R, Sazegara H, Hashemzaei M, Shirani K, Karimi G. Effects of silymarin on neuropathic pain and formalin-induced nociception in mice. Iran J Basic Med Sci. 2015;18(7):715-20.\\u003c/li\\u003e\\n\\u003cli\\u003eFriedl F, Riedl D, Fessler S, Wildt L, Walter M, Richter R, et al. Impact of endometriosis on quality of life, anxiety, and depression: an Austrian perspective. Arch Gynecol Obstet. 2015;292(6):1393-9.\\u003c/li\\u003e\\n\\u003cli\\u003eLa Rosa VL, De Franciscis P, Barra F, Schiattarella A, Tropea A, Tesarik J, et al. Sexuality in women with endometriosis: a critical narrative review. Minerva medica. 2020;111(1):79-89.\\u003c/li\\u003e\\n\\u003cli\\u003eCaruso S, Iraci M, Cianci S, Casella E, Fava V, Cianci A. Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest. Journal of endocrinological investigation. 2015;38(11):1211-8.\\u003c/li\\u003e\\n\\u003cli\\u003eGillessen A, Herrmann WA, Kemper M, Morath H, Mann K. [Effect of silymarin on liver health and quality of life. Results of a non-interventional study]. MMW Fortschr Med. 2014;156 Suppl 4:120-6.\\u003c/li\\u003e\\n\\u003cli\\u003eFried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. Jama. 2012;308(3):274-82.\\u003c/li\\u003e\\n\\u003cli\\u003eSalmond SJ, George J, Strasser S, Byth K, Rawlinson B, Mori T, et al. Hep573 study: A randomised, double-blind, placebocontrolled trial of silymarin alone and combined with antioxidants to improve liver function and quality of life in people with chronic hepatitis C. Australian Journal of Herbal and Naturopathic Medicine. 2019;31(2):64-76.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Endometrioma, Endometriosis-Associated Pain, Silymarin, IL-6, Sexual function\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-1632161/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-1632161/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eObjective: To study the effect of silymarin on interleukin-6 (IL-6) level, size of endometrioma lesion, pain, sexual function, and quality of life (QoL) in women diagnosed with endometriosis.\\u003c/p\\u003e\\u003cp\\u003eMaterials and methods: This randomized, double-blind placebo-controlled clinical trial was performed on 70 women with endometriosis which was divided into two groups of intervention and control. The intervention was 140 mg silymarin (or matching placebo) administered twice daily for 12 weeks. The volume of endometrioma lesions, IL-6, pain, sexual function, and QoL were analyzed before and after the intervention.\\u003c/p\\u003e\\u003cp\\u003eResults: The means of endometrioma volume (P =0.04), interleukin-6 (P = 0.002), and pain (P\\u0026lt;0.001) were reduced significantly in the silymarin group after intervention. However, the QoL, FSFI did not improve substantially in the two groups (P \\u0026gt; 0.05).\\u003c/p\\u003e\\u003cp\\u003eConclusion: Silymarin significantly reduced interleukin-6 levels, sizes of endometrioma lesions, and pain-related symptoms.\\u003c/p\\u003e\\u003cp\\u003eThe trial has been registered in the Iranian Registry of Clinical Trials (IRCT20150905023897N5) on 4\\u003csup\\u003eth\\u003c/sup\\u003e February 2020 (04/02/2020) (https://en.irct.ir/trial/42215) and the date of initial participant enrollment was 2\\u003csup\\u003end\\u003c/sup\\u003e March 2020 (02/03/2020).\\u003c/p\\u003e\",\"manuscriptTitle\":\"Effect of silymarin on Interleukin-6 level and size of endometrioma lesions in women with ovarian endometriosis: a randomized, double-blind placebo-controlled trial\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2022-05-19 17:18:25\",\"doi\":\"10.21203/rs.3.rs-1632161/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Major revision\",\"date\":\"2022-07-15T17:16:28+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2022-06-30T21:42:38+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"d8ceaa3a-b2ff-47de-b8d0-eff24029d20f\",\"date\":\"2022-06-21T14:04:12+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"81e20e0d-e0f8-4c26-889d-b6237d19553f\",\"date\":\"2022-06-20T19:46:11+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2022-06-20T19:31:10+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2022-06-20T13:49:27+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2022-05-17T06:14:39+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2022-05-17T06:12:47+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Scientific Reports\",\"date\":\"2022-05-07T07:02:59+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"d4708445-dc6d-4dec-8f81-41637cd65e75\",\"owner\":[],\"postedDate\":\"May 19th, 2022\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2022-10-10T06:14:29+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2022-05-19 17:18:25\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-1632161\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-1632161\",\"identity\":\"rs-1632161\",\"version\":[\"v1\"]},\"buildId\":\"_2-kVJe1T_tPrBINL-cwx\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC0","license_restricted":false}