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<p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>Available online 26 July 2024</p><p>2468-7847/© 2024 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.</p><p>Review</p><p>The effects of oral nutritional supplements on endometriosis-related pain: A</p><p>narrative review of clinical studies</p><p>Tamiris Julio a,b,*, Bruna Alves Fenerich a, Gabriela Halpern b, Pedro Carrera-Bastos c,d,e,</p><p>Eduardo Schor b, Alexander Kopelman b</p><p>a Division of Nutrition, Institute of Health Sciences, Paulista University, Ribeirão Preto, São Paulo, Brazil</p><p>b Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil</p><p>c Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden</p><p>d Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain</p><p>e Centro de Estudios Avanzados en Nutrición (CEAN), Cádiz, Spain</p><p>A R T I C L E I N F O</p><p>Keywords:</p><p>Endometriosis</p><p>Endometrioma</p><p>Nutritional supplements</p><p>Dietary supplements</p><p>Bioactive compounds</p><p>A B S T R A C T</p><p>Endometriosis is a condition that can cause significant pain and discomfort for women, and the clinical and</p><p>surgical treatments available have variable efficacy and can have adverse effects. These drawbacks often lead to</p><p>poor adherence and therapeutic failure. Consequently, there has been increasing interest in the use of nutritional</p><p>supplements as an adjuvant therapy for endometriosis. To facilitate clinical decision-making in managing women</p><p>with endometriosis, a narrative review of clinical studies was conducted to investigate the effects of oral</p><p>nutritional supplements on endometriosis-related pain. A literature search of the English-language PubMed/</p><p>MEDLINE database was performed using appropriate keywords to identify clinical studies involving oral nutri-</p><p>tional supplements and reporting on endometriosis-related pain. This narrative review included 20 studies</p><p>published between 2013 and 2023, comprising 12 randomized controlled trials, six non-comparative trials, and</p><p>two observational studies. The studies investigated the effects of various nutritional supplements on</p><p>endometriosis-related pain, including vitamins, fatty acids, probiotics, medicinal plants, and bioactive com-</p><p>pounds. A significant decrease in endometriosis-related pain was found in three out of five studies on vitamins,</p><p>four out of six studies on fatty acids, one study on probiotics, two studies on medicinal plants, and five out of six</p><p>studies on bioactive compounds. These nutritional supplements exhibited diverse biological activities, such as</p><p>anti-inflammatory, antioxidant, antiproliferative, and antiangiogenic effects, all of which are relevant for</p><p>managing endometriosis. These findings suggest that oral nutritional supplements could be included as part of a</p><p>multidisciplinary treatment for endometriosis to decrease pain and enhance overall medical treatment.</p><p>1. Introduction</p><p>Endometriosis is a debilitating chronic, inflammatory, and estrogen-</p><p>dependent disease characterized by the presence of endometrial-like</p><p>tissue outside the uterine cavity, infiltrating nearby anatomical struc-</p><p>tures [1,2]. It affects about 10 % of women in their reproductive age [3],</p><p>corresponding to approximately 176 million globally [4]. While the</p><p>peak incidence occurs between 25 and 35 years of age, endometriosis</p><p>can also manifest in girls prior to menarche [5] and in postmenopausal</p><p>women [6].</p><p>The precise pathogenesis of endometriosis remains incompletely</p><p>understood. However, the implantation theory proposed by John</p><p>Albertson Sampson [7] suggests that misplaced endometrial cells</p><p>outside the uterus actively and responsively contribute to the develop-</p><p>ment of endometriosis. This ectopic growth appears to be associated</p><p>with hormonal dysregulation, particularly progesterone resistance and</p><p>estrogen dominance [8]. Other pathogenic mechanisms involved in</p><p>endometriosis include aromatase expression in the eutopic endome-</p><p>trium, increased angiogenesis, decreased apoptosis, proliferation and</p><p>migration of endometrial cells, oxidative stress, and an inflammatory</p><p>environment extending beyond the pelvic structures [9–11].</p><p>Recently, Taylor and colleagues described endometriosis as a</p><p>* Corresponding author at: Tamiris Julio. Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 821, São</p><p>Paulo, São Paulo, Brazil.</p><p>E-mail address: aj_tamiris@alumni.usp.br (T. Julio).</p><p>Contents lists available at ScienceDirect</p><p>Journal of Gynecology Obstetrics and Human Reproduction</p><p>journal homepage: www.elsevier.com/locate/jogoh</p><p>https://doi.org/10.1016/j.jogoh.2024.102830</p><p>Received 18 April 2024; Received in revised form 12 July 2024; Accepted 25 July 2024</p><p>mailto:aj_tamiris@alumni.usp.br</p><p>www.sciencedirect.com/science/journal/24687847</p><p>https://www.elsevier.com/locate/jogoh</p><p>https://doi.org/10.1016/j.jogoh.2024.102830</p><p>https://doi.org/10.1016/j.jogoh.2024.102830</p><p>https://doi.org/10.1016/j.jogoh.2024.102830</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.jogoh.2024.102830&domain=pdf</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>2</p><p>systemic inflammatory condition “with multiple manifestations, outside</p><p>the parameters of a classic gynecological disease” [2]. This disorder is</p><p>often associated with infertility and can cause pelvic pain, dysmenor-</p><p>rhea, dyspareunia, dysuria, dyschezia, fatigue and depression, thus</p><p>significantly impacting the social and mental well-being of affected</p><p>women [1,12].</p><p>The etiology of endometriosis involves a complex interplay of</p><p>various factors, including genetic predisposition [13,14], anatomical</p><p>features [15,16], immunological disorders [17,18], environmental ex-</p><p>posures [19,20] and lifestyle-related factors [21] such as a lower body</p><p>mass index [22,23] and diet [24–26]. Recent studies have highlighted</p><p>the significant role of inflammation and oxidative stress in endometri-</p><p>osis impacting the proliferation, angiogenesis, and apoptosis of endo-</p><p>metrial cells both within and outside the uterus [27–31].</p><p>Despite several scientific efforts to unravel the mechanisms under-</p><p>lying endometriosis, these are still unclear, and there are currently no</p><p>pharmacological therapies able to effectively treat this condition.</p><p>Indeed, the current treatment of endometriosis is mainly focused on</p><p>suppressing the growth of endometriotic lesions, managing pain, and</p><p>addressing some of the systemic effects of the disease [32]. According to</p><p>the European Society of Human Reproduction and Embryology (ESHRE)</p><p>Guideline on Endometriosis [33], the pharmacological treatment of</p><p>endometriosis-associated pain consists in combining analgesics, partic-</p><p>ularly non-steroidal anti-inflammatory drugs (NSAIDs), with hormone</p><p>treatments including combined hormonal contraceptives, progestogens,</p><p>GnRH agonists, GnRH antagonists, and aromatase inhibitors. However,</p><p>these available drugs exhibit variable efficacy and often come with</p><p>adverse effects, leading to discontinuation or therapeutic failure [34].</p><p>In cases where pain persists despite clinical treatment or when</p><p>complications like intestinal stenosis or hydronephrosis arise, minimally</p><p>invasive surgery is recommended as a treatment option for endometri-</p><p>osis [33,35,36]. Nevertheless, surgery is primarily cytoreductive and not</p><p>curative [37]. 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effects of oral nutritional supplements on endometriosis-related pain: A narrative review of clinical studies</p><p>1 Introduction</p><p>2 Methods</p><p>3 Results and discussion</p><p>3.1 Vitamin supplements</p><p>3.1.1 Vitamin C and Vitamin E</p><p>3.1.2 Vitamin D</p><p>3.2 Fatty acid supplements</p><p>3.2.1 Palmitoylethanolamide</p><p>3.2.2 Omega-3 polyunsaturated fatty acids</p><p>3.3 Probiotics</p><p>3.4 Medicinal plants</p><p>3.4.1 Pycnogenol (Pinus pinaster)</p><p>3.4.2 Garlic (Allium sativum)</p><p>3.5 Bioactive compounds</p><p>3.5.1 3,3′-diindolylmethane</p><p>3.5.2 Resveratrol</p><p>3.5.3 Melatonin</p><p>3.5.4 Combination of bioactive compounds</p><p>4 Conclusions</p><p>CRediT authorship contribution statement</p><p>Declaration of competing interest</p><p>References</p><p>that have analyzed the effects of nutraceuticals and medicinal</p><p>plants on endometriosis, but to date, there is, to the best of our knowl-</p><p>edge, no review article compiling and analyzing this body of research,</p><p>including important data, such as dosage, treatment duration, and</p><p>adverse effects.</p><p>Thus, in the current narrative review, we aimed to comprehensively</p><p>assess all categories of clinical studies to elucidate the effects of oral</p><p>nutritional supplements on endometriosis-related pain (ERP). Our</p><p>objective is to provide valuable insights for clinical decision-making in</p><p>the management of endometriosis, paving the way for potential non-</p><p>pharmacological interventions to improve patient outcomes.</p><p>2. Methods</p><p>We conducted a literature search using the PubMed/MEDLINE</p><p>database to identify relevant articles. The search was performed using</p><p>variations of the terms ‘endometriosis’ or ‘endometrioma’ in different</p><p>combinations of relevant vocabulary words together with free-text terms</p><p>searched in the title or abstract. The specific search terms employed</p><p>included ‘nutrients’, ‘dietary supplements’, ‘vitamins’, ‘minerals’, ‘an-</p><p>tioxidants’, ‘probiotics’, ‘prebiotics’, ‘flavonoids’, ‘bioactive com-</p><p>pounds’, ‘nutraceuticals’, ‘phytochemicals’, and ‘fatty acids’.</p><p>We confined our search criteria to research articles published in</p><p>English between January 2013 and June 2023. Publications of clinical</p><p>studies investigating the effect of oral nutritional supplementation on</p><p>ERP in women with surgically or magnetic resonance imaging/ultra-</p><p>sound- confirmed endometriosis were included, while conference ab-</p><p>stracts, narrative review articles, organizational guidelines, animal or</p><p>laboratory studies and studies involving women with unconfirmed</p><p>endometriosis were excluded.</p><p>The results are presented as a narrative review of the available evi-</p><p>dence examining the effect of oral nutritional supplementation as an</p><p>adjuvant treatment for ERP.</p><p>3. Results and discussion</p><p>The initial literature review conducted in the PubMed/MEDLINE</p><p>database yielded a total of 81 records. After removing eight duplicates,</p><p>73 reports were assessed by screening titles and abstracts. From this</p><p>screening, 37 full-text articles were reviewed, while 17 articles were</p><p>excluded since they did not meet the inclusion criteria. In all, we iden-</p><p>tified 20 studies that met the inclusion criteria. Details about the se-</p><p>lection process are depicted in the flow chart (Fig. 1).</p><p>To facilitate data organization, an evidence table was created for</p><p>each category of nutritional supplements. The relevant studies have</p><p>been summarized and their findings are reported in the following five</p><p>sections: 1. Vitamin supplements (Table 1); 2. Fatty acid supplements</p><p>(Table 2); 3. Probiotics (Table 3); 4. Medicinal plants (Table 4); 5.</p><p>Bioactive compounds (Table 5).</p><p>Additionally, Fig. 2 provides a summary of the potential roles of each</p><p>oral nutritional supplement in endometriosis, accompanied by the</p><p>associated molecular mechanisms.</p><p>3.1. Vitamin supplements</p><p>3.1.1. Vitamin C and Vitamin E</p><p>Oxidative stress is suspected of playing an important role in the</p><p>pathophysiology of endometriosis and may cause a general inflamma-</p><p>tory response in the peritoneal cavity [43,44]. Vitamins C and E act as</p><p>antioxidants by scavenging reactive oxygen species, neutralizing lipid</p><p>hydroperoxyl radicals, and protecting proteins from alkylation, which</p><p>provides protection against oxidative stress-induced cellular damage</p><p>and has relevance for inflammatory disorders [45,46].</p><p>Two studies [47,48] investigating the effects of vitamins C and E as</p><p>antioxidant supplements in ERP were identified (Table 1). In a ran-</p><p>domized placebo-controlled trial, Santanan et al. [47] found a signifi-</p><p>cant reduction in chronic pelvic pain after two months of combined</p><p>vitamin C and E supplementation compared to placebo (Table 1). In</p><p>another randomized controlled trial (RCT) conducted by Amini et al.</p><p>(Amini et al., 2021), ERP was assessed using a visual analog scale (VAS)</p><p>before and after the intervention. The study reported significant re-</p><p>ductions in chronic pain, dysmenorrhea and dyspareunia in the inter-</p><p>vention group compared to the placebo group following 8 weeks of</p><p>supplementation (Table 1). However, both studies did not provide data</p><p>regarding the tolerance of these supplements or the potential reduction</p><p>in the usage of NSAIDs during or after the intervention with the com-</p><p>bination of vitamins C and E.</p><p>Although the direct effect of vitamins C and E on endometriosis re-</p><p>mains unclear, the aforementioned studies offer promising results for its</p><p>use in alleviating ERP. The interventions showed a reduction in in-</p><p>flammatory and oxidative stress markers, providing insight into their</p><p>potential mechanisms of action. Santanan et al. reported a significant</p><p>decrease in peritoneal inflammatory markers, namely the cytokine</p><p>interleukin (IL)− 6 (P ≤ 0.06) and the chemokines RANTES (P ≤ 0.002),</p><p>and monocyte chemotactic protein-1 (MCP-1) (P ≤ 0.01) after vitamin</p><p>C/E supplementation [47]. Similarly, Amini et al. [48] showed that</p><p>these nutrients significantly reduced oxidative stress markers such as</p><p>malondialdehyde (MDA) (P = 0.002) and reactive oxygen species (ROS)</p><p>(P < 0.001), without affecting total antioxidant capacity (TAC).</p><p>Given the additive antioxidant capacity of vitamins C and E [46] and</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>3</p><p>their established safety profile [49], oral supplementation with these</p><p>nutrients holds promise as an intervention for relieving ERP.</p><p>3.1.2. Vitamin D</p><p>Beyond its role in calcium homeostasis and bone health, vitamin D</p><p>exerts immunomodulatory effects [50]. This is due to the fact that</p><p>several immune cells express the vitamin D receptor (VDR) and some</p><p>can evenmetabolize vitamin D into more active molecules. Indeed, there</p><p>is evidence that vitamin D can increase anti-inflammatory cytokines,</p><p>while decreasing the expression of pro-inflammatory ones [51–53],</p><p>highlighting its potential for managing chronic inflammatory diseases.</p><p>Three studies [54–56] examining the effects of vitamin D on</p><p>endometriosis-related pain reported conflicting outcomes (Table 1). In a</p><p>double-blind RCT, Almassinokiani et al. [54] found no significant dif-</p><p>ferences in pelvic pain and dysmenorrhea between the intervention</p><p>group receiving oral vitamin D (cholecalciferol) and the placebo group</p><p>after laparoscopy. Another study by Nodler et al. (2020) [55] reported</p><p>that although vitamin D levels significantly increased only in the</p><p>vitamin D supplementation group, there were no significant differences</p><p>in pain scores compared to the placebo group. However, Mehdiza-</p><p>dehkashi et al. [56] demonstrated a significant decrease in the</p><p>dysmenorrhea score, but not in dyspareunia and dyschezia scores</p><p>following oral vitamin D supplementation compared to placebo in a</p><p>double-blind RCT. None of the studies provided data on adverse events</p><p>associated with vitamin D supplementation or NSAIDs usage during and</p><p>after the intervention.</p><p>Vitamin D deficiency, as assessed by serum or plasma 25-hydroxyvi-</p><p>tamin D [25(OH)D] levels, has been associated with an increased risk of</p><p>developing endometriosis [57]. For instance, women with serum 25</p><p>(OH)D levels below 20 ng/mL have a 2.7-fold increased risk of endo-</p><p>metriosis when compared to those with levels above 20 ng/mL (P =</p><p>0.01) [58], suggesting a potential role of vitamin D in the pathogenesis</p><p>and/or symptoms of endometriosis.</p><p>The presence of the VDR and vitamin D metabolizing enzymes in</p><p>ovarian (granulosa cells and cumulus cells), endometrial and myo-</p><p>metrial tissues [59] suggests that vitamin D affects the local immune</p><p>environment and may reduce peritoneal inflammation. Accordingly,</p><p>Mehdizadehkashi et al. [56] showed a significant reduction in</p><p>high-sensitivity C-reactive protein (CRP) (P ≤ 0.001) and a significant</p><p>increase in TAC (P = 0.001) after vitamin D supplementation in women</p><p>with endometriosis compared to placebo. Likewise, Delbandi et al. [50]</p><p>showed that vitamin</p><p>D3 exhibited important effects on endometriotic</p><p>stromal cells from women with endometriosis, including down-</p><p>regulation of pro-inflammatory cytokines and decreased cell invasion</p><p>and proliferation. In summary, vitamin D supplementation, due to its</p><p>anti-inflammatory, antioxidant, antiproliferative and anti-invasive ef-</p><p>fects, holds promise as a valuable intervention in endometriosis, with</p><p>the available evidence suggesting that serum/plasma concentration of</p><p>25(OH)D should be maintained above 20 ng/dl, and possibly even</p><p>higher – in the range of 40 to 60 ng/mL [60].</p><p>3.2. Fatty acid supplements</p><p>3.2.1. Palmitoylethanolamide</p><p>Palmitoylethanolamide (PEA) is an endogenous bioactive lipid</p><p>belonging to the group of ALIamides (amid antagonists of local autacoid</p><p>injury). PEA exhibits anti-inflammatory and analgesic activities by</p><p>down-regulating mast-cell degranulation [61]. Mast cells may be</p><p>involved in ERP and hyperalgesia, as they can act on nerve structures.</p><p>There is a close histological relationship between mast cells and nerves,</p><p>and an increased presence of activated and degranulating mast cells has</p><p>been observed in deep endometriosis [62].</p><p>Four non-comparative studies [63–66] analyzed the relationship</p><p>between PEA supplementation and ERP (Table 2). Two studies utilized a</p><p>combination of PEA and trans-polydatin [63,65], one study supple-</p><p>mented a mixture of PEA and alpha-lipoic acid [64], and another study</p><p>used a combination of PEA, alpha-lipoic acid and myrrh [66]. All studies</p><p>showed the effectiveness of supplementation in reducing chronic pelvic</p><p>pain, dysmenorrhea, and dyspareunia (P < 0.05), while two studies [63,</p><p>65] showed a significant reduction in dyschezia (P < 0.05), and one</p><p>study [65] reported an improvement in dysuria (P < 0.05). Of note, two</p><p>studies [64,65] showed a significant reduction in the use of NSAIDs and</p><p>analgesics at the end of the intervention (P< 0.05). Nevertheless, except</p><p>for the study by Stochino Loi et al. [65], which reported no adverse</p><p>events during the intervention with PEA and trans-polydatin, these</p><p>studies did not mention the occurrence or absence of side effects</p><p>resulting from the supplementation.</p><p>Altogether, the aforementioned non-comparative studies showed</p><p>that PEA has beneficial effects in ERP, but its small sample sizes, lack of</p><p>control groups and the heterogeneous nature of the interventions</p><p>Fig. 1. Flowchart illustrating the selection process of studies.</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>4</p><p>Table 1</p><p>Summary of data extracted from the included articles about the effects of vitamin supplements on ERP.</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ± SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment tools Clinical</p><p>outcomes</p><p>Intervention</p><p>group</p><p>Control group</p><p>Vitamin C and Vitamin E</p><p>Santanam et al.</p><p>2013 [47],</p><p>Atlanta</p><p>Randomized</p><p>clinical trial</p><p>(46:13) 19–41 years Women with</p><p>varying</p><p>severity</p><p>endometriosis</p><p>were included</p><p>Vitamin E 1200</p><p>UI (3 capsules</p><p>of 400 mg</p><p>each) and</p><p>Vitamin C 1000</p><p>mg (2 tablets of</p><p>500 mg each)</p><p>combination</p><p>daily for 8</p><p>weeks</p><p>Placebo pills daily for 8</p><p>weeks</p><p>Pain score was</p><p>assessed at</p><p>baseline, bi-</p><p>weekly and after</p><p>treatment using</p><p>an arbitrary</p><p>scale: none, mild,</p><p>moderate and</p><p>severe</p><p>Chronic pelvic</p><p>pain</p><p>Decrease in pain:</p><p>Intervention</p><p>group (43 %) |</p><p>Placebo group (0</p><p>%)</p><p>Dysmenorrhea</p><p>Decrease in pain:</p><p>Intervention</p><p>group (37 %) |</p><p>Placebo group</p><p>(36 %)</p><p>Dyspareunia</p><p>Decrease in pain:</p><p>Intervention</p><p>group (24 %) |</p><p>Placebo group (0</p><p>%)</p><p>(P = 0.0055)</p><p>Amini et al. 2021</p><p>[48], Iran</p><p>Randomized</p><p>clinical trial</p><p>(30:30) Intervention:</p><p>35.7 1 ± 5.71</p><p>Control:</p><p>38.03 ± 6.47</p><p>1–3 stages of</p><p>laparoscopic-</p><p>proven</p><p>endometriosis</p><p>Vitamin C 1000</p><p>mg (2 tablets of</p><p>500 mg each)</p><p>and Vitamin E</p><p>800 UI (2</p><p>tablets of 400</p><p>UI each) and</p><p>combination</p><p>daily for 8</p><p>weeks</p><p>Placebo pills (mannitol</p><p>and magnesium</p><p>stearate</p><p>polyvinylpyrrolidone)</p><p>daily for 8 weeks</p><p>Pain was</p><p>assessed using</p><p>VAS pre-post</p><p>treatment</p><p>Chronic pelvic</p><p>pain</p><p>Intervention</p><p>group VAS score</p><p>pre-post: 26.66</p><p>± 27.84 - 12.43</p><p>± 13.28 |</p><p>Placebo group:</p><p>16.96 ± 16.28 -</p><p>18.63 ± 18.35</p><p>(P < 0.001)</p><p>Dysmenorrhea</p><p>Intervention</p><p>group VAS score</p><p>pre-post: 50.53</p><p>± 32.12 - 17.56</p><p>± 16.65) |</p><p>Placebo group:</p><p>51.00 ± 34.21 -</p><p>31.56 ± 26.39</p><p>(P < 0.001)</p><p>Dyspareunia</p><p>Intervention</p><p>group VAS score</p><p>pre-post: 26.66</p><p>± 28.27 - 15.43</p><p>± 18.47) |</p><p>Placebo group:</p><p>20.73 ± 21.77 -</p><p>18.10 ± 19.93</p><p>(P < 0.001)</p><p>Vitamin D</p><p>Almassinokiani</p><p>et al. 2016 [54],</p><p>2016, Iran</p><p>Randomized</p><p>clinical trial</p><p>(19:20) Vitamin D</p><p>group: 30.84</p><p>± 5.79</p><p>Placebo</p><p>group: 28.95</p><p>± 4.71</p><p>Not reported Vitamin D</p><p>group:</p><p>50 000 IU</p><p>vitamin D3</p><p>weekly for 12</p><p>weeks</p><p>Placebo one capsule</p><p>weekly for 12 weeks</p><p>Dysmenorrhea</p><p>and/or pelvic</p><p>pain were</p><p>assessed using</p><p>VAS at baseline</p><p>and 4 weeks after</p><p>the end of</p><p>intervention</p><p>Pelvic pain</p><p>Intervention</p><p>group VAS score</p><p>pre (SD): 1.53</p><p>(1.54) | Placebo</p><p>group: 1.89</p><p>(2.40), (P =</p><p>0.538)</p><p>Intervention</p><p>group VAS score</p><p>post (SD): 0.84</p><p>(1.74) | Placebo</p><p>group: 0.68</p><p>(1.70), (P =</p><p>0.24)</p><p>Dysmenorrhea</p><p>Intervention</p><p>group VAS score</p><p>pre (SD): 3.84</p><p>(continued on next page)</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>5</p><p>preclude the ability to draw definitive conclusions. Further research</p><p>incorporating larger sample sizes and controlled study designs is</p><p>necessary to clarify the potential of PEA as a treatment for ERP.</p><p>3.2.2. Omega-3 polyunsaturated fatty acids</p><p>Omega (ω)− 3 supplementation shows promise in managing</p><p>endometriosis-associated pain due to its anti-inflammatory, anti-</p><p>proliferative, antiangiogenic, and anti-apoptotic properties [67]. In</p><p>addition to relieving symptoms, omega-3 has been associated with</p><p>preventing the pathogenesis of endometriosis [68].</p><p>Two randomized studies [55,69] investigated the potential of ω− 3</p><p>polyunsaturated fatty acids (PUFAs) in alleviating ERP. Abokhrais et al.</p><p>Table 1 (continued )</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ± SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment tools Clinical</p><p>outcomes</p><p>Intervention</p><p>group</p><p>Control group</p><p>[2] | Placebo</p><p>group: 4.42</p><p>(2.65), (P =</p><p>0.365)</p><p>Intervention</p><p>group VAS score</p><p>post (SD): 2.10</p><p>(2.33) | Placebo</p><p>group: 2.73</p><p>(2.84), (P =</p><p>0.45)</p><p>Nodler et al. 2020</p><p>[55], USA</p><p>Randomized</p><p>clinical trial</p><p>Total: 69</p><p>Vitamin D</p><p>group: 27</p><p>Fish oil</p><p>group: 20</p><p>Placebo</p><p>group: 22</p><p>Vitamin D</p><p>group: 20.0 ±</p><p>2.7</p><p>Fish oil</p><p>group: 18.9 ±</p><p>3.1</p><p>Placebo</p><p>group: 20.1 ±</p><p>3.5</p><p>Not reported Vitamin D</p><p>group: 2000 IU</p><p>vitamin D3</p><p>daily for 6</p><p>months.</p><p>Fish oil group:</p><p>1000 mg fish</p><p>oil (488 mg</p><p>EPA and 178</p><p>mg DHA) daily</p><p>for 6 months</p><p>Placebo one capsule</p><p>daily for 6 months</p><p>Pain was</p><p>assessed using</p><p>VAS for only</p><p>pelvic pain at</p><p>baseline and</p><p>after 6 months</p><p>Pelvic pain</p><p>Vitamin D group</p><p>VAS score</p><p>(mean):</p><p>Baseline: 7.0</p><p>(6.2, 7.8) | 6</p><p>months: 5.5 (4.2,</p><p>6.8), P = 0.02</p><p>Fish oil group</p><p>VAS score</p><p>(mean):</p><p>Baseline: 5.9</p><p>(4.8, 7.0) | 6</p><p>months: 5.2 (3.7,</p><p>6.8), P = 0.39</p><p>Placebo group</p><p>VAS score</p><p>(mean):</p><p>Baseline: 6.0</p><p>(5.1, 6.9) | 6</p><p>months: 4.4 (3.0,</p><p>5.8), P = 0.07</p><p>Mehdizadehkashi</p><p>et al. 2021 [56],</p><p>Iran</p><p>Randomized</p><p>clinical trial</p><p>(30:30) Vitamin D</p><p>group: 34.8 ±</p><p>7.1</p><p>Placebo</p><p>group: 35.6 ±</p><p>7.0</p><p>Not reported vitamin D</p><p>50,000IU</p><p>supplements</p><p>each 2 weeks</p><p>Placebo capsules each 2</p><p>weeks</p><p>Pain was</p><p>assessed using</p><p>VAS at baseline</p><p>and after 12</p><p>weeks</p><p>Dysmenorrhea</p><p>Intervention</p><p>group VAS score</p><p>pre-post: 8.0 ±</p><p>1.8 – 4.8 ± 1.7</p><p>Placebo group</p><p>VAS score pre-</p><p>post: 6.8 ± 2.6 –</p><p>4.9 ± 2.8 (P =</p><p>0.03)</p><p>Dyspareunia</p><p>Intervention</p><p>group VAS score</p><p>pre-post: 6.1 ±</p><p>2.6 - 3.8 ± 2.3</p><p>Placebo group</p><p>VAS score pre-</p><p>post: 7.3 ± 2.5 –</p><p>5.2 ± 2.6 (P =</p><p>0.38)</p><p>Dyschezia</p><p>Intervention</p><p>group VAS score</p><p>pre-post: 7.1 ±</p><p>2.7 – 4.2 ± 2.0</p><p>Placebo group</p><p>VAS score pre-</p><p>post: 6.6 ± 1.5 –</p><p>4.8 ± 1.9 (P =</p><p>0.11)</p><p>Legend: VAS = visual analogue scale.</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>6</p><p>Table 2</p><p>Summary of data extracted from the included articles about the effects of fatty acids supplements on ERP.</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ±</p><p>SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment tools Clinical outcomes</p><p>Intervention group Control group</p><p>Palmitoylethanolamide (PEA)</p><p>Giugliano</p><p>et al. 2013</p><p>[63], Italy</p><p>Prospective</p><p>study</p><p>Group A: 19</p><p>Group B: 28</p><p>Group A:</p><p>36.7 ±</p><p>5.2</p><p>Group B:</p><p>34.6 ±</p><p>6.5</p><p>Group A:</p><p>endometriotic</p><p>location in recto-</p><p>vaginal septum</p><p>Group B:</p><p>endometriotic</p><p>location on ovary</p><p>400 mg micronized PEA</p><p>plus 40 mg transpolydatin</p><p>daily for 90 days</p><p>None Pain was assessed</p><p>using VAS at</p><p>baseline and after</p><p>90 days</p><p>Chronic pelvic pain</p><p>Group A: VAS score</p><p>pre-post: 5.8 - 2.3 |</p><p>Group B VAS score</p><p>pre-post: 4.6 - 1.6</p><p>(P < 0.0001)</p><p>Dysmenorrhea</p><p>Group A: VAS score</p><p>pre-post: 6.5 - 3.8 |</p><p>Group B VAS score</p><p>pre-post: 6.9 - 3.8</p><p>(P < 0.0001)</p><p>Dyspareunia</p><p>Group A: VAS score</p><p>pre-post: 4.1 - 1.5 |</p><p>Group B VAS score</p><p>pre-post: 3.7 - 1.4</p><p>(P < 0.0001)</p><p>Dyschezia</p><p>Group A: VAS score</p><p>pre-post: 4.1 - 2.9 |</p><p>Group B VAS score</p><p>pre-post: 1.6 - 0.9</p><p>(P < 0.001)</p><p>Caruso et al.</p><p>2015 [64],</p><p>Italy</p><p>Non-</p><p>comparative</p><p>study</p><p>56 Total</p><p>26.6 ± 6</p><p>Not reported 300 mg</p><p>PEA and 300 mg alpha-</p><p>lipoic acid - 1</p><p>administration 2</p><p>times a day for 9 months</p><p>None Pain was</p><p>measured using</p><p>VAS at baseline</p><p>and during the</p><p>treatment. The</p><p>enrolment</p><p>process</p><p>envisaged a cut-</p><p>off >5.</p><p>The frequency of</p><p>NSAIDs drugs</p><p>assumption were</p><p>evaluated.</p><p>Chronic pelvic pain</p><p>VAS score pre > 5:</p><p>56 patients (100 %)</p><p>| VAS score pos> 5:</p><p>7 patients (17.1 %),</p><p>P < 0.001</p><p>Dysmenorrhea</p><p>VAS score pre > 5:</p><p>51 patients (91.56</p><p>%) | VAS score pos</p><p>> 5: 3 patients (7.3</p><p>%), P < 0.001</p><p>Dyspareunia</p><p>VAS score pre > 5:</p><p>32 patients (57.1</p><p>%) | VAS score pos</p><p>> 5: 5 patients</p><p>(12.2 %), P < 0.001</p><p>Reduction in the</p><p>use of NSAIDs</p><p>10 %, 70 % and 78</p><p>% respectively at</p><p>the 3rd, 6th and 9th</p><p>month (P < 0.001)</p><p>Stochino Loi</p><p>et al. 2019</p><p>[65],</p><p>Greece</p><p>Single-arm,</p><p>non-</p><p>randomized,</p><p>open-label</p><p>pilot study</p><p>30 ≥18 and</p><p>≤48</p><p>years</p><p>Not reported 600 mg um-PEA twice daily</p><p>for 10 days followed by m</p><p>(PEA/PLD) (400mg+40</p><p>mg) twice daily for 80 days</p><p>– the drugs were taken</p><p>orally 12 horas apart</p><p>None Pain was</p><p>measured using</p><p>VAS at baseline</p><p>and during the</p><p>treatment.</p><p>Analgesic use was</p><p>monitored</p><p>Chronic pelvic pain</p><p>VAS score pre-post:</p><p>7.2 ± 1.2 – 2.6 ±</p><p>0.4 (P < 0.05)</p><p>Dysmenorrhea</p><p>VAS score pre-post:</p><p>7.7 ± 1.1 – 5.5 ±</p><p>0.5 (P < 0.05)</p><p>Dyspareunia</p><p>VAS score pre-post:</p><p>4.9 ± 1.3 – 1.9 ±</p><p>0.4 (P < 0.05)</p><p>Dyschezia</p><p>VAS score pre-post:</p><p>3.6 ± 0.9 – 1.8 ±</p><p>0.3 (P < 0.05)</p><p>Dysuria</p><p>VAS score pre-post:</p><p>2.5 ± 0.7 – 1.6 ±</p><p>0.5 (P = n.s)</p><p>Consumption of</p><p>analgesics</p><p>Baseline: 2 tablets |</p><p>(continued on next page)</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>7</p><p>[69] conducted a pilot study, employing a two-arm, parallel</p><p>double-blinded RCT to assess participant recruitment and retention rates</p><p>and evaluate the efficacy of ω− 3 PUFAs for ERP. Over an 8-week</p><p>intervention period, a trend towards improvement in pelvic pain</p><p>scores was observed in both intervention arms, suggesting a strong</p><p>placebo effect (Table 2). Similarly, in a double-blind, randomized,</p><p>placebo-controlled trial, Nodler et al. [55] found no significant differ-</p><p>ence (Table 1) in the VAS score for ERP between the group receiving fish</p><p>Table 2 (continued )</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ±</p><p>SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment tools Clinical outcomes</p><p>Intervention group Control group</p><p>End of treatment:</p><p>0.5 tablet (P <</p><p>0.05)</p><p>de Leo et al.</p><p>2019 [66],</p><p>Italy</p><p>Multi-center</p><p>study</p><p>60 30.6 ±</p><p>5.02</p><p>Ovarian</p><p>endometrioma</p><p>Mean diameter</p><p>endometriosis cyst</p><p>(mm) - 25.09</p><p>±6.65</p><p>400 mg alpha-lipoic acid,</p><p>300 mg pal-</p><p>mitoiletanolamide and 100</p><p>mg myrrh (Pelvinox), two</p><p>tablets per day for 6 months</p><p>None Pain was</p><p>measured using</p><p>VAS at baseline</p><p>and during the</p><p>treatment</p><p>Chronic pelvic pain</p><p>VAS score pre-post:</p><p>5 ± 2.11 - 3.28</p><p>±1.37 (P < 0.05)</p><p>Dysmenorrhea</p><p>VAS score pre-</p><p>post:7.68±1.55 -</p><p>4.52±1.77 (P <</p><p>0.05)</p><p>Dyspareunia</p><p>VAS score pre-post:</p><p>5.72±2.2 - 4.38</p><p>±1.62 (P < 0.05)</p><p>Omega-3</p><p>Abokhrais</p><p>et al. 2020</p><p>[69],</p><p>United</p><p>Kingdom</p><p>Randomized</p><p>pilot trial</p><p>Total: 33</p><p>PUFA group:</p><p>14</p><p>Placebo</p><p>group: 13</p><p>PUFA</p><p>group:</p><p>35.43 ±</p><p>8.57</p><p>Placebo</p><p>group:</p><p>36.08 ±</p><p>9.59</p><p>PUFA group: 10</p><p>superficial</p><p>peritoneal, 1</p><p>ovarian, 2 deep</p><p>endometriosis;</p><p>Placebo group: 9</p><p>superficial</p><p>peritoneal, 1</p><p>ovarian, 1 deep</p><p>endometriosis</p><p>1000 mg Omega-3twice a</p><p>day for 8 weeks</p><p>Placebo (olive</p><p>oil soft gelatin</p><p>capsules) one</p><p>capsule twice</p><p>a day for 8</p><p>weeks</p><p>Pain was</p><p>measured by VAS</p><p>at baseline and</p><p>during the</p><p>treatment</p><p>Pelvic pain</p><p>Intervention group</p><p>VAS score pre-post</p><p>(mean): 4.92 ± 2 -</p><p>4.96 ± 1.73</p><p>Placebo group VAS</p><p>score pre-post</p><p>(mean): 5.21 ± 2.5</p><p>- 4.54 ± 2.44</p><p>P = 0.383</p><p>Legend: VAS = visual analogue scale.</p><p>Table 3</p><p>Summary of data extracted from the included articles about the effects of probiotics on ERP.</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ± SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment tools Clinical outcomes</p><p>Intervention group Control</p><p>group</p><p>LactoFem®</p><p>Khodaverdi</p><p>et al. 2019</p><p>[72], Iran</p><p>Pilot</p><p>randomized</p><p>triple-blind</p><p>placebo-con-</p><p>trolled trial</p><p>(19:18) Intervention:</p><p>33.81 1 ±</p><p>6.85</p><p>Control: 33.69</p><p>± 5.63</p><p>Laparoscopic</p><p>confirmed</p><p>endometriosis.</p><p>Intervention: 4</p><p>patients with stage</p><p>III and 12 with stage</p><p>IV</p><p>Control: 16 patients</p><p>with stage IV</p><p>LactoFem® one capsule</p><p>per day for 8 weeks</p><p>LactoFem® capsule</p><p>contains 109 colony of</p><p>four different</p><p>lactobacillus strains</p><p>(L. acidophilus,</p><p>Lactobacillus plantarum,</p><p>Lactobacillus fermentum</p><p>and Lactobacillus gasseri)</p><p>Placebo</p><p>one</p><p>capsule</p><p>per day</p><p>for 8</p><p>weeks</p><p>Pain was</p><p>assessed using</p><p>VAS at baseline</p><p>and after 8 and</p><p>12 weeks pos-</p><p>intervention</p><p>Chronic pelvic pain</p><p>Change between</p><p>0 and 8 weeks</p><p>(intervention vs</p><p>control): 3.35 ±</p><p>2.18 vs 3.03 ± 0.37</p><p>(P = 0,119)</p><p>Dysmenorrhea</p><p>Change between</p><p>0 and 8 weeks</p><p>(intervention vs</p><p>control): 3.46 ±</p><p>2.97 vs 2.18 ± 1.06</p><p>(P = 0,0018)</p><p>Dyspareunia</p><p>Change between</p><p>0 and 8 weeks</p><p>(intervention vs</p><p>control): 3.55 ±</p><p>2.27 vs 2.02 ± 0.38</p><p>(P = 0,117)</p><p>Overall pain score</p><p>Change between</p><p>0 and 8 weeks</p><p>(intervention vs</p><p>control): 7.33 ±</p><p>7.00 vs 4.11 ± 1.68</p><p>(P = 0,017)</p><p>Legend: VAS = visual analogue scale.</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>8</p><p>oil (which is a source of ω− 3 PUFAs) and the placebo group. Abokhrais</p><p>et al. [69] reported no adverse events in the intervention group, whereas</p><p>the study conducted by Nodler et al. [55] did not mention any data on</p><p>side effects. The use of NSAIDs during and after the intervention was not</p><p>reported in either study [55,69].</p><p>In summary, the limited number of trials investigating omega-3</p><p>supplementation does not provide sufficient support for its use in</p><p>women with endometriosis, emphasizing the need for larger and better-</p><p>designed RCTs to further explore this issue.</p><p>3.3. Probiotics</p><p>The Lactobacillus genus encompass a diverse group of potentially</p><p>beneficial and non-pathogenic bacteria, recognized for their probiotic</p><p>properties. The role of probiotics in modulating the gut microbiota and</p><p>improving the intestinal mucosal barrier involves several mechanisms,</p><p>including competitive exclusion of pathogens, immunomodulatory ef-</p><p>fects, and regulation of neurotransmitter synthesis. These mechanisms</p><p>contribute to the prevention and treatment not only of gastrointestinal</p><p>disorders but also of extra-intestinal chronic diseases [70,71].</p><p>In a pilot randomized triple-blind placebo-controlled trial, women</p><p>who underwent surgical treatment and had not received hormonal</p><p>intervention in the last three months experienced a significant decreased</p><p>in pain scores for both dysmenorrhea and overall pain after 8 weeks of</p><p>supplementation with a group of lactobacilli [72]. No adverse effects</p><p>related to the lactobacilli intervention were observed in this study. Un-</p><p>fortunately, the authors did not assess the use of NSAIDs during and after</p><p>the intervention.</p><p>This positive effect of a probiotic containing 109 colony forming</p><p>units (CFU) of multiple Lactobacillus strains, including Lactobacillus ac-</p><p>idophilus, Lactiplantibacillus plantarum (formerly</p><p>named Lactobacillus</p><p>plantarum), Limosilactobacillus fermentum (formerly named Lactobacillus</p><p>fermentum), and Lactobacillus gasseri, on ERP may be attributed to the</p><p>immunogenic properties of lactobacilli, particularly Lactobacillus gasseri.</p><p>In endometriosis, there is a significant decrease in the activity of</p><p>natural killer (NK) cells, especially in the peritoneal fluid and peripheral</p><p>blood [18,73,74]. Experimental studies have shown that Lactobacillus</p><p>gasserimay stimulate the production of IL-12 [75,76], which is known to</p><p>activate the cytotoxicity of NK cells [77,78]. Therefore, the inclusion of</p><p>probiotics in the management of endometriosis may improve the ability</p><p>of NK cells to clear the ectopic endometrium. Despite the positive re-</p><p>sults, further studies evaluating the use of probiotics in endometriosis</p><p>need to be conducted before evidence-based recommendations can be</p><p>made.</p><p>3.4. Medicinal plants</p><p>3.4.1. Pycnogenol (Pinus pinaster)</p><p>The exact mechanisms by which Pycnogenol, a proprietary extract</p><p>derived from the bark of the French maritime pine tree (Pinus pinaster),</p><p>affects endometriosis and decreases ERP are still unclear. Kohama et al.</p><p>[79] reported that Pycnogenol decreased serum levels of CA-125, a</p><p>serological biomarker used for the non-invasive diagnosis of</p><p>moderate-severe endometriosis [80]. Moreover, Pycnogenol may pro-</p><p>mote the suppression of nuclear factor kappa B (NF-κB)-dependent in-</p><p>flammatory gene expression, as shown in an ex vivo study conducted</p><p>with healthy volunteers [81]. Accordingly, various studies have re-</p><p>ported that Pycnogenol has anti-inflammatory and free radical</p><p>Table 4</p><p>Summary of data extracted from the included articles about the effects of medicinal plants on ERP.</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ± SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment tools Clinical outcomes</p><p>Intervention group Control group</p><p>Pycnogenol</p><p>Maia Jr</p><p>et al.</p><p>2013</p><p>[84],</p><p>Brazil</p><p>Randomized</p><p>clinical trial</p><p>45 22–37 Stage I or II: 26</p><p>patients,</p><p>Stage III ou IV:</p><p>16 patients</p><p>according</p><p>ASRM</p><p>Group 2 (n = 14):</p><p>oral contraceptive</p><p>(gestodene 75 µg/</p><p>EE 30 µg) + 100 mg</p><p>of Pycnogenol (50</p><p>mg every 12 h) for 3</p><p>months</p><p>Group 4 (n = 11):</p><p>oral contraceptive</p><p>(drospirenone 3</p><p>mg/EE 30 µg) +</p><p>100 mg of</p><p>Pycnogenol (50 mg</p><p>every 12 h) for 3</p><p>months</p><p>Group 1 (n = 7):</p><p>oral</p><p>contraceptive</p><p>(gestodene 75 µg/</p><p>EE 30 µg) alone</p><p>for 3 months</p><p>Group 3 (n = 13):</p><p>oral</p><p>contraceptive</p><p>(drospirenone 3</p><p>mg/EE 30 µg)</p><p>alone for 3</p><p>months</p><p>Pelvic pain, including</p><p>dysmenorrheal, was</p><p>assessed using VAS</p><p>graded from 0 to 10,</p><p>on which 0 was</p><p>indicative of no pain</p><p>and 10 the most</p><p>excruciating pain</p><p>Dysmenorrhea</p><p>Group 1 VAS</p><p>score pre-post</p><p>(mean): 8 ± 1- 4</p><p>± 1.4</p><p>Group 2 VAS</p><p>score pre-post</p><p>(mean): 7 ± 0.8-</p><p>0.5 ± 0.6</p><p>P < 0.001</p><p>Group 3 VAS</p><p>score pre-post</p><p>(mean): 7.5 ±</p><p>0.6- 4.3 ± 1.1</p><p>Group 4 VAS</p><p>score pre-post</p><p>(mean): 7.6 ±</p><p>0.5- 0.7 ± 1</p><p>P < 0.001</p><p>Garlic (Allium sativum)</p><p>Amirsalari</p><p>et al.</p><p>2021</p><p>[94],</p><p>Iran</p><p>Randomized</p><p>placebo-</p><p>controlled</p><p>triple-blind</p><p>clinical trial</p><p>(60:60) Intervention:</p><p>29.4 1 ± 8.54</p><p>Control:</p><p>29.71 ± 5.67</p><p>Not reported 400 mg garlic</p><p>tablets (1100 µg of</p><p>allicin) for 4, 8 and</p><p>12 weeks</p><p>Placebo pills for</p><p>4, 8 and 12 weeks</p><p>Pain was assessed</p><p>using VAS scale before</p><p>the intervention and</p><p>1-, 2- and 3-month</p><p>follow-ups</p><p>Overall severity</p><p>pain</p><p>Intervention</p><p>group VAS score</p><p>pre-post (12</p><p>weeks): 6.51 ±</p><p>0.86 to 1.83 ±</p><p>1.25 (P = 0.001)</p><p>Control group</p><p>VAS score pre-</p><p>post (12 weeks):</p><p>6.41 ± 1.12 to</p><p>6.65 ± 1.37 (P =</p><p>0.002)</p><p>Legend: VAS = visual analogue scale; EE = ethinylestradiol.</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>9</p><p>Table 5</p><p>Summary of data extracted from the included articles about the effects of bioactive compounds on ERP.</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ± SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment</p><p>tools</p><p>Clinical outcomes</p><p>Intervention group Control group</p><p>3,3′-diindolylmethane (DIM)</p><p>Morales-</p><p>Prieto</p><p>et al. 2018</p><p>[101],</p><p>Germany</p><p>Clinical</p><p>observation</p><p>based on case</p><p>series</p><p>(4:4) Group</p><p>DNG+DIM:</p><p>30.75 ± 3.2</p><p>Group DNG:</p><p>35.5 ± 6.86</p><p>Not reported DNG+DIM group: 2 mg</p><p>dienogest once per day and</p><p>100 mg DIM three times per</p><p>day for 3 months</p><p>DNG group:</p><p>2 mg dienogest</p><p>once per day for</p><p>3 months</p><p>Pain was</p><p>assessed using</p><p>VAS after 1, 2</p><p>and 3 months</p><p>Pelvic pain</p><p>DNG+DIM group</p><p>VAS score pre-</p><p>post: 69.2 ± 12.9</p><p>to 5.5 ± 5.5 (P <</p><p>0.01)</p><p>DNG group VAS</p><p>score pre-post:</p><p>62.8 ± 8 to 20.8</p><p>± 14.8 (P < 0.05)</p><p>Resveratrol</p><p>Mendes Da</p><p>Silva et al.</p><p>2017</p><p>[108],</p><p>Brazil</p><p>Randomized</p><p>clinical trial</p><p>(22:22) Intervention:</p><p>35.4 ± 7.1</p><p>Control: 32.4</p><p>± 7</p><p>Not reported Resveratrol+ COC group:</p><p>levonorgestrel 0.15 mg/EE</p><p>0.03 mg + resveratrol 40</p><p>mg daily for 42 days</p><p>COC group:</p><p>levonorgestrel</p><p>0.15 mg/EE 0.03</p><p>mg + placebo</p><p>daily for 42 days</p><p>Pain was</p><p>assessed using</p><p>VAS before and</p><p>after treatment.</p><p>The use os</p><p>analgesics were</p><p>also assessed</p><p>Pain</p><p>Resveratrol +</p><p>COC group VAS</p><p>score pre-post:</p><p>5.7 to 3.2</p><p>COC group VAS</p><p>score pre-post:</p><p>5.4 to 3.9</p><p>P = 0.7</p><p>Number of</p><p>women using</p><p>analgesics</p><p>similar amount of</p><p>pain medication</p><p>in both arms</p><p>Melatonin</p><p>Schwertner</p><p>et al. 2013</p><p>[115],</p><p>Brazil</p><p>Randomized</p><p>clinical trial</p><p>(20:20) Melatonin</p><p>group: 36.76</p><p>± 6.4</p><p>Placebo</p><p>group: 37.63</p><p>± 5.5</p><p>Endometriosis</p><p>stage:</p><p>Melatonin</p><p>group</p><p>Stage I: n = 2;</p><p>Stage II: n = 4;</p><p>Stage III: n = 7;</p><p>Stage IV: n = 7</p><p>Placebo group</p><p>Stage I: n = 3;</p><p>Stage II: n = 3;</p><p>Stage III: n = 9;</p><p>Stage IV: n = 5</p><p>10 mg melatonin tablets for</p><p>8 weeks (all patients began</p><p>the treatment at the onset</p><p>of the menstrual cycle)</p><p>Placebo tablets</p><p>for 8 weeks</p><p>Pain was</p><p>measured using</p><p>VAS during the</p><p>treatment</p><p>period</p><p>Worst pain during</p><p>the last 24 h</p><p>(daily)</p><p>Melatonin group</p><p>VAS score: 2.78 |</p><p>Placebo group:</p><p>4.58 (P < 0.001)</p><p>Dysmenorrhea</p><p>Melatonin group</p><p>VAS score: 4.24 |</p><p>Placebo group:</p><p>6.84 (P < 0.001)</p><p>Dyspareunia</p><p>Melatonin group</p><p>VAS score: 4.68 |</p><p>Placebo group:</p><p>6.08 (P < 0.001)</p><p>Dyschezia</p><p>Melatonin group</p><p>VAS score: 4.12 |</p><p>Placebo group:</p><p>6.30 (P < 0.0001)</p><p>Dysuria</p><p>Melatonin group</p><p>VAS score: 5.35 |</p><p>Placebo group:</p><p>6.33 (P < 0.001)</p><p>Söderman</p><p>et al. 2023</p><p>[116],</p><p>Sweden</p><p>Randomized</p><p>clinical trial</p><p>(20:20) Melatonin</p><p>group: 35.90</p><p>(6.61)</p><p>Placebo</p><p>group: 34.20</p><p>(7.68)</p><p>Not reported 20 mg melatonin tablets</p><p>daily for two consecutive</p><p>menstrual cycles or 60</p><p>consecutive days for</p><p>amenorrhoeic participants</p><p>Placebo tablets</p><p>daily for two</p><p>consecutive</p><p>menstrual cycles</p><p>or 60</p><p>consecutive days</p><p>for</p><p>amenorrhoeic</p><p>participants</p><p>Pain was</p><p>measured using</p><p>numeric rating</p><p>scale (NRS)</p><p>during the</p><p>treatment</p><p>period.</p><p>EAPP</p><p>Melatonin group</p><p>NRS: 2.9 |</p><p>Placebo group:</p><p>3.3 (P = 0.446)</p><p>Dyspareunia</p><p>Melatonin group</p><p>NRS: 0.7 |</p><p>Placebo group:</p><p>1.1 (P = 0.499)</p><p>Dyschezia</p><p>Melatonin group</p><p>NRS: 1.0 |</p><p>Placebo group:</p><p>1.7 (P = 0.263)</p><p>Dysuria</p><p>Melatonin group</p><p>(continued on next page)</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>10</p><p>scavenging activities, while also exerting analgesic and apoptotic effects</p><p>[82,83].</p><p>One office-based study investigated the administration of Pycnoge-</p><p>nol in patients with endometriosis who were undergoing postoperative</p><p>hormonal therapy containing either gestodene or drospirenone [84].</p><p>After three months of intervention, pain scores significantly decreased in</p><p>the groups receiving oral contraceptives alone (groups 1 and 3) or</p><p>combined with Pycnogenol (groups 2 and 4). Importantly, the reduction</p><p>in pain was more pronounced in the groups receiving oral contraceptives</p><p>+ Pycnogenol (groups 2 and 4) compared to groups 1 and 3 (Table 4).</p><p>Pycnogenol supplementation did not present any additional adverse</p><p>effects compared to those already recorded with the use of oral con-</p><p>traceptives alone. However, the use of NSAIDs during and after the</p><p>intervention was not assessed in this study.</p><p>Combining a progestin with Pycnogenol shows promise in terms of</p><p>improving the efficacy of hormonal treatment and managing ERP, but</p><p>further studies are needed to elucidate the underlying mechanisms of</p><p>these effects and to determine the appropriate dosage and duration of</p><p>intervention.</p><p>Table 5 (continued</p><p>)</p><p>Reference/</p><p>Country</p><p>Study type Sample size</p><p>(intervation/</p><p>control)</p><p>Age</p><p>(Mean ± SD)</p><p>Type of</p><p>endometriosis</p><p>Type and duration of supplementation Assessment</p><p>tools</p><p>Clinical outcomes</p><p>Intervention group Control group</p><p>NRS: 1.1 |</p><p>Placebo group:</p><p>1.1 (P = 0.930)</p><p>Antioxidant Blends</p><p>Signorile at</p><p>al. 2017</p><p>[135],</p><p>Italy</p><p>Cohort (30:30:30) Group 1: 34.0</p><p>Group 2: 34.8</p><p>Group 3: 35.2</p><p>All patients</p><p>were defined as</p><p>stage IV</p><p>Group 1: 1002 mg linoleic</p><p>acid, 432 mg alpha</p><p>linolenic acid, 172.8 mg</p><p>linoleic acid, 200 mg</p><p>quercetin, 20 mg</p><p>nicotinamide, 400mcg 5-</p><p>methyltetrahydrofolate</p><p>calcium salt, 20 mg titrated</p><p>turmeric, 19.5 mg titrated</p><p>parthenium every 12 h for 3</p><p>months</p><p>Group 2: linseed oil and 5-</p><p>methyltetrahydrofolate</p><p>calcium salt every 12 h, for</p><p>3 months</p><p>Group 3: placebo</p><p>2 doses a day,</p><p>every 12 h, for 3</p><p>months</p><p>Pain was</p><p>measured by</p><p>VAS before and</p><p>after treatment</p><p>Percentage of</p><p>patients with high</p><p>VAS score before</p><p>/after treatment:</p><p>Chronic pelvic</p><p>pain</p><p>Group 1: 62 %/18</p><p>% | Group 2: 60</p><p>%/45 % | Group</p><p>3: 62 %/60 %</p><p>Dysmenorrhea</p><p>Group 1: 62 %/18</p><p>% | Group 2: 65</p><p>%/41 % | Group</p><p>3: 66 %/62 %</p><p>Dyspareunia</p><p>Group 1: 30 %/15</p><p>% | Group 2: 32</p><p>%/37 % | Group</p><p>3: 30 %/30 %</p><p>Lete et al.</p><p>2018</p><p>[136],</p><p>Spain</p><p>Multicenter,</p><p>open-label,</p><p>non-</p><p>comparative</p><p>clinical trial</p><p>398 34.6 ± 7.2 Not reported N-acetyl cysteine 600 mg,</p><p>alpha lipoic acid 200 mg,</p><p>bromelain 25 mg and zinc</p><p>10 mg - 1 dose 2 times a day</p><p>for 6 months</p><p>None EAPP was</p><p>assessed using</p><p>VAS after 3and</p><p>6 months.</p><p>NSAIDs</p><p>requirements</p><p>were also</p><p>assessed</p><p>Pelvic pain</p><p>Baseline VAS</p><p>score: 6.68 ±</p><p>1.97 (86.4 %</p><p>needed NSAIDs) |</p><p>After 3 months:</p><p>4.55 ± 1.97 (57.4</p><p>% needed</p><p>NSAIDs) | After 6</p><p>months: 3.52 ±</p><p>1.91 (37.4 %</p><p>needed NSAIDs)</p><p>P < 0.0001</p><p>Fadin et al.</p><p>2020</p><p>[137],</p><p>Italy</p><p>Open-label,</p><p>single-center,</p><p>versus</p><p>historical</p><p>control study</p><p>Total: 33 ≥18 and ≤50</p><p>years</p><p>Not reported 200 mg of quercetin + 210</p><p>mg of turmeric (of which</p><p>200 mg of curcuminoids) +</p><p>150 mg of N-acetylcysteine</p><p>(1 tablet of ALLIENDo® a</p><p>day) for 2 months</p><p>None Pain was</p><p>measured by a</p><p>0–10 numeric</p><p>rating scale</p><p>(NRS) before</p><p>and after</p><p>treatment.</p><p>The frequency</p><p>of NSAIDs</p><p>drugs</p><p>assumption</p><p>were evaluated.</p><p>Pelvic pain</p><p>NRS score pre-</p><p>post treatment:</p><p>5.7 to 2.1 (P <</p><p>0.01)</p><p>Dysmenorrhea</p><p>NRS score pre-</p><p>post treatment:</p><p>6.1 to 2.8 (P <</p><p>0.01)</p><p>Dyspareunia</p><p>NRS score pre-</p><p>post treatment:</p><p>5.3 to 2.5 (P <</p><p>0.01)</p><p>Number of</p><p>women using</p><p>NSAIDs</p><p>Baseline: 27 out</p><p>of 33 | End of</p><p>treatment: 14 out</p><p>of 33 (P < 0.01)</p><p>Legend: DIM = 3,3′-diindolylmethane, DNG = dienogest; VAS = visual analogue scale; EE = ethinylestradiol; EAPP = Endometriosis-associated pelvic pain; NSAIDs =</p><p>Nonsteroidal anti-inflammatory agents; NRS = numeric rating scale.</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>11</p><p>3.4.2. Garlic (Allium sativum)</p><p>The exact mechanisms by which this medicinal plant affects ERP are</p><p>not entirely clear, but according to an experimental study, garlic extract</p><p>can suppress the proliferation and expression of the adhesion molecules</p><p>intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion</p><p>molecule-1 (VCAM-1) in tumour necrosis factor-alpha (TNF-α)-activated</p><p>human endometrial stromal cells isolated from patients with endome-</p><p>triosis by inhibiting the activation of NF-κB and activator protein-1 (AP-</p><p>1), two pivotal transcription factors involved in the regulation of</p><p>inflammation [85]. Furthermore, studies conducted on other conditions,</p><p>unrelated to endometriosis, have attributed antiangiogenic [86–88],</p><p>antioxidant [89–91] and anti-inflammatory [92,93] activities to garlic</p><p>extracts and their isolated constituents.</p><p>Clinical studies on the use of garlic in the management of ERP are</p><p>still scarce (Table 4). However, a randomized placebo-controlled triple-</p><p>blind clinical trial demonstrated the effectiveness of garlic in reducing</p><p>pain scores compared to placebo in women affected by endometriosis</p><p>[94]. Unfortunately, neither the side effects of supplementation nor the</p><p>use of NSAIDs were reported by the authors.</p><p>The results of the several studies that tested the effects of garlic</p><p>supplementation on various conditions, combined with the positive</p><p>outcome from the RCT conducted by Amirsalari et al. [94] suggests that</p><p>garlic supplementation may hold promise as a management option for</p><p>endometriosis. However, further clinical trials are needed to investigate</p><p>the biological activities, optimal doses, and duration of intervention in</p><p>women with endometriosis.</p><p>3.5. Bioactive compounds</p><p>3.5.1. 3,3′-diindolylmethane</p><p>DIM is a unique biologically active dimer derived from indole-3-</p><p>carbinol (I3C), which is present in the Brassica species of cruciferous</p><p>vegetables (e.g., kale, broccoli, cauliflower and cabbage) [95,96]. DIM</p><p>possesses anti-inflammatory [97], antiangiogenic [98] and anti-</p><p>proliferative [99] properties. Additionally, it exhibits an anti-estrogenic</p><p>effect [100]. Indeed, in estrogen-sensitive cells, it is able to decrease</p><p>estrogen receptor alpha (ERα) signalling and specifically counteract the</p><p>effects of estrogen [100].</p><p>In a clinical observation based on a case series of eight women with</p><p>endometriosis [101], the intervention with dianogest (DNG) combined</p><p>with 3,3′-diindolylmethane (DIM) reduced pelvic pain (Table 5) and</p><p>improved bleeding pattern (number and duration of episodes) compared</p><p>to the group that received DNG alone (P < 0.05). The authors reported</p><p>no adverse effects in the DNG-DIM group, while the tolerance to treat-</p><p>ment was less favorable in the group that received the DNG alone. The</p><p>use of NSAIDs during and after the intervention was not described in this</p><p>study. Due to the limitations of this study, particularly the small sample</p><p>size, further studies with a larger number of participants are needed to</p><p>better understand the effects of DIM.</p><p>Given the above, it can be concluded that DIM’s biological actions</p><p>could potentially benefit endometriosis patients by controlling pain and</p><p>reducing the proliferation of endometriotic cells. However, its use in the</p><p>management of this disease has been poorly studied, thus hindering any</p><p>definitive conclusions.</p><p>3.5.2. Resveratrol</p><p>Resveratrol is a non-flavonoid polyphenol broadly found in various</p><p>plant sources such as grapes, blueberries, plums, apples and peanuts</p><p>[102]. Its anti-inflammatory [103,104], antioxidant [105], anti-</p><p>proliferative [106], antiangiogenic [38,104] and pro-apoptotic [107]</p><p>activities make it a potential candidate for the management of endo-</p><p>metriosis. Furthermore, resveratrol’s ability to inhibit aromatase</p><p>expression and alter estrogen biosynthesis adds to its potential in the</p><p>management of endometriosis.</p><p>A parallel, double-blind, randomized, placebo-controlled trial</p><p>investigated the effect of a mixture of combined oral contraceptive</p><p>(COC) with resveratrol on pelvic pain in endometriosis [108]. Pain was</p><p>assessed using the VAS at seven, 21 and 42 days after intervention. The</p><p>resveratrol + COC group showed a decrease in pain scores at the end of</p><p>the seven-day intervention. However, no significant difference in pain</p><p>scores was observed between the resveratrol+ COC group and the group</p><p>using COC alone at the end of the 42-day intervention (Table 5). Both</p><p>groups reported mild side effects and similar analgesic usage. Serum</p><p>levels of CA-125 and prolactin were measured by enzyme-linked</p><p>immunosorbent assay. While CA-125 levels decreased after treatment</p><p>in both the COC group (P = 0.01) and the resveratrol + COC group (P =</p><p>0.02), prolactin levels did not vary by intervention.</p><p>Conversely, a non-comparative study showed that resveratrol</p><p>potentiated the effect of oral contraceptives in relieving ERP by inhib-</p><p>iting the expression of both aromatase and cyclooxygenase-2 (COX-2) in</p><p>ectopic endometrium [109]. However, further well-designed clinical</p><p>trials are required to provide robust evidence supporting the effects of</p><p>Fig. 2. Pathogenic mechanisms of endometriosis and the main biological activities of nutritional supplements reviewed.</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>12</p><p>resveratrol in the</p><p>management of endometriosis.</p><p>3.5.3. Melatonin</p><p>Melatonin is a pleiotropic molecule with antioxidant, anti-</p><p>inflammatory, analgesic, antiproliferative, antiangiogenic and pro-</p><p>apoptotic properties [110]. Preclinical research has shown that mela-</p><p>tonin inhibits estradiol-induced proliferation of endometrial epithelial</p><p>cells [111] and regulates estrogen-receptor expression in breast cancer</p><p>cells [[112]]. Melatonin also plays a role in the expression and modu-</p><p>lation of aromatase activity in endothelial cells [113]. In addition,</p><p>melatonin has been shown to regulate myometrial contractions in rats</p><p>[114]. These documented biological actions of melatonin make it a</p><p>supplement of great interest in the management of pain associated with</p><p>endometriosis.</p><p>A randomized, double-blind, 2-group parallel, clinical trial investi-</p><p>gated the effect of melatonin compared to a placebo on ERP after 8</p><p>weeks of intervention [115]. The melatonin group exhibited signifi-</p><p>cantly lower pain scores, as measured by the VAS, for daily pain, dys-</p><p>pareunia, dysmenorrhea, dyschezia and dysuria compared to the</p><p>placebo group (Table 5). In addition, the melatonin-supplemented group</p><p>reported improved sleep quality and an 80 % reduction in the risk of</p><p>using analgesics. However, the study did not provide data on adverse</p><p>events. Conversely, a double-blind RCT conducted by Söderman et al.</p><p>[116] found no significant differences in ERP between the oral mela-</p><p>tonin group and the placebo group. No adverse effects were observed in</p><p>this study.</p><p>Nevertheless, the contradictory results from the limited number of</p><p>RCTs on melatonin and ERP highlight the need for further research.</p><p>3.5.4. Combination of bioactive compounds</p><p>The combination of different bioactive compounds offers a potential</p><p>approach for managing endometriosis-related symptoms due to the</p><p>synergistic actions of different molecules with anti-inflammatory and</p><p>antioxidant effects, as discussed further below.</p><p>Curcumin, a polyphenol isolated from turmeric, is a potential anti-</p><p>inflammatory compound [117]. Several studies have highlighted the</p><p>anti-inflammatory [118], antiangiogenic [118] and pro-apoptotic [119]</p><p>actions of curcumin in endometriosis. Moreover, curcumin exhibits an</p><p>anti-proliferative effect on endometrial cells by reducing estrogen pro-</p><p>duction [120]. Although there is some evidence on the antioxidant effect</p><p>of curcumin in other conditions, there is a need for future studies to</p><p>investigate the action of curcumin on oxidative stress in endometriosis.</p><p>RCTs are also needed to determine the optimal dosage, treatment</p><p>duration, and potential side effects of curcumin supplementation for the</p><p>management of endometriosis.</p><p>Quercetin, an important flavonoid derived from capers, exhibits a</p><p>wide range of biological activities including anti-inflammatory, anti-</p><p>oxidant and antiangiogenic effects and has been studied in different</p><p>conditions such as obesity, inflammation, various types of cancer, dia-</p><p>betes, and cardiovascular diseases [121–124]. In the context of endo-</p><p>metriosis, in vivo and in vitro studies have shown that quercetin inhibits</p><p>the proliferation of endometrial cells and induces their apoptosis [125].</p><p>Additionally, an animal study suggests that quercetin may have</p><p>anti-estrogenic and progestogenic effects [126]. While the existing</p><p>research highlights the potential benefits of quercetin in endometriosis,</p><p>clinical trials are necessary to evaluate its therapeutic effects specifically</p><p>in women with this condition.</p><p>Alpha-lipoic acid (α-LA) is a naturally occurring small molecule</p><p>found in various organisms and can be obtained in minor amounts from</p><p>certain foods such as broccoli, tomatoes, and spinach [127]. Preclinical</p><p>research has demonstrated the potential of α-LA in managing endome-</p><p>triosis. In an experimental animal study, α-LA has been shown to</p><p>decrease the volume of endometrial implants due to its antioxidant and</p><p>anti-inflammatory activities [128]. Moreover, findings from an in vitro</p><p>study suggested that α-LA has the potential to inhibit the progression of</p><p>endometriosis by reducing the adhesion and invasion of endometrial</p><p>cells [129]. While these preliminary findings are promising, further</p><p>research is needed to validate the efficacy of α-LA in human subjects</p><p>with endometriosis.</p><p>N-acetylcysteine (NAC) is the acetylated form of the naturally</p><p>occurring amino acid cysteine and possesses antioxidative and anti-</p><p>inflammatory activities [130]. Porpora et al. [131] showed that NAC</p><p>treatment can lead to a reduction in ovarian endometrioma size. This</p><p>effect may be attributed to the downregulation of COX-2 expression,</p><p>resulting in reduced levels of prostaglandin E2 (PGE2). In turn,</p><p>decreased PGE2 levels can limit the availability of estrogens within the</p><p>ectopic endometrium by inhibiting aromatase activity [132]. These</p><p>findings suggest that NAC holds promise as a potential therapeutic op-</p><p>tion for endometriosis. However, further research, particularly</p><p>well-designed clinical trials, is needed to fully understand the efficacy,</p><p>optimal dosage, and potential side effects of NAC in the management of</p><p>endometriosis-related symptoms.</p><p>Bromelain, a sulfhydryl proteolytic enzyme found in pineapple, ex-</p><p>hibits potential anti-inflammatory, immunomodulatory, and anti-</p><p>thrombotic properties [133]. Agostinis and colleagues [134] demon-</p><p>strated the efficacy of bromelain when combined with NAC and α-LA in</p><p>both in vivo and in vitro models of endometriosis due to its significant</p><p>anti-inflammatory properties. Further studies are warranted to explore</p><p>the comparative effects of bromelain as a standalone therapy versus</p><p>standard treatments. Additionally, assessing the use of bromelain in</p><p>combination with traditional therapies could provide valuable insights</p><p>into its potential to enhance the standard medical management of ERP.</p><p>Three non-comparative studies [135–137] have examined the effect</p><p>of combining different bioactive compounds on ERP. In one study,</p><p>Signorile et al. [135] administered a combination of quercetin, curcu-</p><p>min, parthenium (a plant extract), nicotinamide (vitamin B3), 5-</p><p>methyltetrahydrofolate and both omega-3 and omega-6 PUFAs. Lete</p><p>et al. [136] used a mixture of NAC, α-LA, bromelain and zinc, while</p><p>Fadin et al. [137] investigated a combination of quercetin, curcumin and</p><p>NAC. All of these studies showed that supplementing women with</p><p>endometriosis with the aforementioned combinations of bioactive</p><p>compounds was effective in reducing chronic pelvic pain. Additionally,</p><p>two of the studies [135,137] showed improvements in dysmenorrhea</p><p>and dyspareunia following supplementation (Table 5). Notably, Lete et</p><p>al. and Fadin et al. [136,137] reported a significant reduction in the</p><p>number of women using NSAIDs after supplementation with the previ-</p><p>ously mentioned bioactive compounds (P < 0.01).</p><p>Regarding side effects, Signorile et al. [135] did not assess their</p><p>presence during the intervention, while Fadin et al. [137] reported no</p><p>adverse events. In contrast, Lete et al. [136] reported that 13 patients</p><p>withdrew from treatment due to nausea and vomiting.</p><p>One of the three studies investigated the inflammatory parameters of</p><p>the patients during the study. Signorile et al. [135] observed a significant</p><p>decrease in serum levels of PGE2 after the intervention, suggesting that</p><p>the combination of bioactive compounds used in this study exerted an</p><p>anti-inflammatory action.</p><p>4. Conclusions</p><p>Several oral nutritional supplements exhibit anti-inflammatory,</p><p>antioxidant, antiproliferative, and antiangiogenic activities, and the</p><p>beneficial effects recorded to date encourage their use as therapeutic</p><p>strategies, either alone or in combination with other interventions, for</p><p>managing endometriosis-related symptoms, including pain.</p><p>This narrative review highlights that 15 out of 20 clinical studies</p><p>reported a significant decrease in ERP and describes the biological ac-</p><p>tivities of each oral nutritional supplement investigated in these studies.</p><p>Most of these supplements, including vitamin C/E combination, vitamin</p><p>D, palmitoylethanolamide,</p><p>probiotics, Pycnogenol, garlic, 3,3′-diindo-</p><p>lylmethane, melatonin, and mixtures of bioactive compounds such as</p><p>curcumin, quercetin, alpha-lipoic acid, N-acetylcisteine, and bromelain,</p><p>have the potential to modulate the pathophysiological processes</p><p>T. Julio et al.</p><p>Journal of Gynecology Obstetrics and Human Reproduction 53 (2024) 102830</p><p>13</p><p>involved in endometriosis.</p><p>Considering the current level of evidence, despite the heterogeneity</p><p>of the included studies, we conclude that antioxidants vitamins,</p><p>particularly the combined supplementation of Vitamin C and Vitamin E,</p><p>should be considered for pain management in endometriosis. These</p><p>nutrients have shown consistent findings across multiple studies,</p><p>including well-designed randomized controlled trials.</p><p>The affordability, potential for enhancing the effects of standard</p><p>treatments, minimal side effects, decrease in the use of NSAIDs, pain</p><p>reduction, and potential for controlling disease progression are some of</p><p>the main strengths of these oral nutritional supplements, which support</p><p>their inclusion in the management of endometriosis. However, given the</p><p>limitations of the studies analyzed in this review, further well-designed</p><p>clinical trials are necessary to provide more robust evidence regarding</p><p>the role of oral nutritional supplements in the management of this</p><p>condition.</p><p>CRediT authorship contribution statement</p><p>Tamiris Julio: Conceptualization, Methodology, Formal analysis,</p><p>Investigation, Resources, Writing – review & editing. Bruna Alves</p><p>Fenerich: Conceptualization, Methodology, Formal analysis, Investi-</p><p>gation, Resources, Writing – review & editing. Gabriela Halpern:</p><p>Conceptualization, Methodology, Writing – review & editing. Pedro</p><p>Carrera-Bastos: Conceptualization, Methodology, Formal analysis,</p><p>Investigation, Resources, Writing – review & editing. Eduardo Schor:</p><p>Conceptualization, Methodology, Writing – review & editing. 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