{"paper_id":"f02374e1-c528-4419-a397-161bb4bd48d7","body_text":"469\nEndometriosis Therapy: Not Only Hormones and  \nSurgery - The Importance of a Holistic Approach\nCopyright @ Bardi M\nThis work is licensed under Creative Commons Attribution 4.0 License  AJBSR.MS.ID.002510\nAmerican Journal of\nBiomedical Science & Research\nwww.biomedgrid.com\n---------------------------------------------------------------------------------------------------------------------------------\nISSN: 2642-1747\nReview Article\nBardi M1*, Cornolti S2, Iliakis A1, Scorpiniti A3 and Vitali M4\n1Surgeon c/o Gynecological Division of the San Pietro Polyclinic - Ponte San Pietro (BG), Italy\n2Clinical psychologist and oncology area, specialized in the support of chronic diseases, Italy\n3Specialist in Gastroenterology and Digestive Endoscopy - Specialized in Acupuncture and Complementary Techniques, Italy\n4Rehabilitative Midwife and Osteopath - Owner of the Italian Pelvic Floor Center, Italy\n*Corresponding author: Massimo Bardi - Senior Consultant c/o Gynecologic Dept of Polyclinic San Pietro – Ponte San Pietro (BG), Italy.\nTo Cite This Article:  Bardi M, Cornolti S, Iliakis A, Scorpiniti A, Vitali M. Endometriosis Therapy: Not Only Hormones and Surgery - The \nImportance of a Holistic Approach. Am J Biomed Sci & Res. 2023 18(5) AJBSR.MS.ID.002510, DOI: 10.34297/AJBSR.2023.18.002510\nReceived: \n  April 17, 2023;  Published: \n  May 04, 2023\nIntroduction\nEndometriosis is one of the most common benign \ndisorders, affecting 6-10% of women of reproductive age [1]. \nThe disease is defined as the presence of endometrial glands \nand stroma outside the uterine cavity, and patients with \nendometriosis often suffer from dysmenorrhea, dyspareunia, \ndysuria, and chronic pelvic pain. About 50% of these patients \nare infertile. Since the disease is estrogen-dependent, \nmedical therapies primarily aim to down-regulate ovarian \nestrogen production [2]. Endometriosis is a chronic disease, \ncharacterized by pain of varying intensity, often diagnosed \nlate. Chronicity in itself indicates a pathological situation from \nwhich one will never fully recover, but this does not mean  \n \nthat physical symptoms, anxiety or psychological discomfort \ncannot be effectively treated by different forms of therapy. \nPelvic pain associated with endometriosis can be treated \nmedically and surgically. Surgery, however conservative \nit may be, removes the disease (although complete \neradication is sometimes impossible) but increases the risk \nof compromising the ovarian reserve and damaging affected \nor adjacent anatomical structures. The risk of postoperative \nrecurrences is high [3]. First-line medical treatments affect \nhormonal status by inducing a hypoestrogenic environment. \nCommonly used drugs are combined oral contraceptives \nand progestogens. Gonadotropin agonists and antagonists \nAbstract\nEndometriosis is a pathology that affects just under 10% of women of reproductive age and is characterized by symptoms, sometimes \nvery severe, which manifest themselves as dysmenorrhea, dyspareunia and chronic pelvic pain. Many women with this disease are \nalso infertile. To date, there is no therapy that cures the woman who is affected by it. Hormonal therapies and surgery tend to cure \nthe symptoms and slow down the course until menopause, a period in which, in the vast majority of cases, the disease resolves \nitself. The Authors intend to evaluate, through the review of the literature and the experience of “insiders” , a range of therapeutic \nforms that do not want to replace hormonal treatments or surgical techniques, which are still the subject of discussion, but which \naim to support of these to try to make the life of women with endometriosis the best possible. Thus, a new concept was born for \nthe Authors on how to deal with endometriosis: the concept of “holism” which leads us to evaluate this pathology in a complex of \ntherapeutic globality, without excluding a priori ways of treatment wrongly considered ineffective and therefore “not officers” . We \nwill address the concepts of adequate nutrition associated with the use of supplements and antioxidants, with the help offered by \nosteopathy, fitness, ozone therapy, acupuncture, up to the psychological support.\nKeywords: Endometriosis, Nutrition, Oxidative stress, Ozone therapy, Fitness, Osteopathy, Acupuncture, Psychology\n\n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n470\nare also used, but only for short periods because they are \nburdened with serious side effects such as bone loss. These \ntherapies are often limited by their high cost and frequent \nside effects [4]; furthermore, they all have a contraceptive \neffect which does not go well with the fact that the disease \naffects young women often with a high desire for pregnancy. \nThe real problem is that after discontinuation of therapy the \ndisease becomes active again and pain scores often return to \nbaseline values. About 50% of women with endometriosis \nexperience a recurrence of symptoms within 5 years, \nregardless of the therapeutic approach [5]. Non-hormonal \ntherapies are limited to non-steroidal anti-inflammatory \ndrugs (NSAIDs) whose effectiveness is very limited and can \nhave important side effects, especially if used for a long time \n[6].\nThe term “holism” comes from a Greek term for \n“integrity” . Holism in medicine represents a “global” state \nof health, the union of mind, body, environment and society. \nThe holistic approach considers the health and care of the \npatient as a whole, including their physical, psychological, \nsocial and spiritual well-being as they are not aligned with a \nspecific philosophy of care, starting from the awareness that \n“everything is more than sum of its parts” . A holistic approach \ntherefore establishes the need to intervene on the person \nthrough several parallel plans, but with a single purpose: a \nstate of real and all-encompassing well-being [7]. It should \nbe emphasized again that, to date, there is no therapy capable \nto care endometriosis. It is therefore important to continue \nto search for new safe and effective long-term treatments \n[8] and to evaluate all those supportive therapies that allow \nthe woman who is affected to experience the disease in the \nbest possible way. It is not the authors’ intention to claim \nthat the so-called “non-official” or “alternative” treatments \ncan effectively replace hormonal and/or surgical therapy. \nThe intention is to explore other therapeutic avenues \nthat can support the “official” therapy in the treatment of \nendometriosis.\nDiet\nAccording to the latest Australian national online survey, \nas many as 76% of women with endometriosis use non-\npharmacological practices and lifestyle choices such as \nrelaxation techniques, movement and nutrition. Nearly half \nof the women managed dietary support and diet effectiveness \nhad high self-reported improvement scores [9]. In recent \nyears, an increasing number of endometriosis patients have \nfocused on dietary factors that promote health and support \ntherapy [10].\nDiet is a highly controllable risk factor for many chronic \ndiseases, and its role as a contributor to endometriosis has \nbeen extensively explored. A literature review conducted \nby Parazzini, et. all . [11] suggested that women with \nendometriosis appear to consume fewer vegetables and \nomega-3 polyunsaturated fatty acids while consuming \nhigher amounts of red meat, coffee, and trans fats (not those \nfound naturally in foods but those added artificially to sweet \nand savory snacks). of industrial production). Red meats \nand butter intake are considered the primary sources for \nsaturated fat. In an Italian case-control study [11] the risk \nof endometriosis was significantly higher in women who \nreported a higher consumption of meat and ham but not \nbutter. These data contrasted with a Belgian clinical case-\ncontrol study [12] which indicated that the consumption \nof butter, but not meat, was marginally associated with \nthe risk of peritoneal endometriosis. However, it should be \nemphasized that a high intake of red meat is associated with \ndiscrete concentrations of estradiol and estrone sulphate \n[13] and, consequently, its consumption could directly \ncontribute to increasing the levels of circulating human \nsteroid hormone and therefore to the maintenance of the \ndisease. The intake of monounsaturated fats (olive oil, whole \nmilk products, nuts, lard, sesame oil, corn oil, popcorn, \nwhole grains and wheat cereals) does not appear to have any \nassociation with the risk of endometriosis [14]. Olive oil is \nan important source of micronutrients and a wide variety \nof valuable antioxidants not found in other oils. The high \ncontent of oleic acid makes olive oil not very susceptible to \noxidation. This oil also contains phenols which are believed \nto be powerful scavengers of superoxide and other reactive \nspecies [15]. \nDairy products are an important part of the diet because \nthey are rich in many amino acids and have a high calcium \ncontent. Studies have shown that dairy products, like \nproducts that contain high amounts of calcium, are negatively \ncorrelated with inflammatory and oxidative stress [16]. Altura \nand coll. [17] hypothesized that the high levels of magnesium \ncontained in dairy products would relax the smooth muscles \nof the salpinges with a consequent reduction of retrograde \nmenstruation, which according to many authors lies at the \nbasis of the pathogenesis of endometriosis. Therefore, some \nresearchers have speculated that intake of dairy products \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n471\nmight reduce the risk of endometriosis, but this hypothesis \nis based on limited studies and needs further testing. \nXiangying, et al.  [17] conducted a systematic meta-analysis \nto investigate the association between dairy products, and \ntheir amount in the daily diet, and the risk of endometriosis. \nThe meta-analysis involved 120,706 participants and showed \nthat the total intake of dairy products would reduce the risk \nof endometriosis with a dose-dependent relationship. The \nhealth benefits of green tea, red wine, garlic and fresh fruit \nand their effectiveness in preventing various diseases has \nbeen confirmed by several studies [18]. Catechins in green \ntea and polyphenols in red wine are products that are part of \nour daily food habits and have demonstrated many beneficial \neffects. Epigallocatechin-3-gallate (EGCG) is the main \ncatechin found in green tea and has been studied in recent \nyears for the treatment of various types of cancer, based on \nits antioxidant, antiangiogenic and antiproliferative effects. \nIts antimitotic properties have led to the idea that EGCG may \nbe useful for the treatment of endometriosis. Recent studies \nhave shown encouraging results in this area [19].\nAnother compound whose efficacy has been studied is \nresveratrol, a natural phytoalexin produced by some grape \nvarieties, peanuts and berries in response to fungal infections \nor UV radiation. The most significant concentrations of \nresveratrol are found in grape skins and therefore in red \nwines. Evidence indicates that this compound has anticancer, \nanti-inflammatory, and antioxidant properties as well as \npro-apoptotic and antiangiogenic effects [20]. Bruner-Tran \nand coll. evaluated the effect of resveratrol on experimental \nendometriosis in vivo and on the invasiveness of endometrial \nstromal cells in vitro [21]. Resveratrol reduced the number \nof endometrial implants per mouse by 60% (P < 0.001) \nand the total lesion volume per mouse by 80% (P < 0.001). \nThese observations may aid in the development of new \nendometriosis treatments. Similar results were achieved by \nthe experimentation of Ricci, et al. [22,23], performed on 56 \nfemale BALB/c mice, inducing endometriotic-like lesions \nand then treating them for 4 weeks with resveratrol and \nEGCG. The number of confirmed lesions observed per mouse \nwas significantly reduced. The volume of lesions developed \nalso decreased in statistically significant way. The reduction \nin both the number and size of the induced lesions is due \nto a decrease in epithelial cell proliferation and a significant \nincrease in the apoptotic index. An inhibitory effect of \nvascular proliferation has also been shown by reducing the \nlevels of VEGF in the peritoneal fluid.\nThe Supplements\nDietary supplementation has friends and enemies.\nThe basic concept lies in becoming aware that the \nindustrial revolution has led to an increase in the supply \nof food products, but large-scale production has been \ndetrimental to the quality of food. Pollution and radiation \nhave depleted the soils of 50% of nutrients. Therefore, \ncorrect food supplementation, which completes what is \nmissing from our diet today, however well-groomed, and \ncorrect, will allow our body to recover those nutrients which \nunfortunately it is currently no longer able to obtain in the \nright quantity from food. The President of the Mario Negri \nInstitute, dr. Silvio Garattini, on the contrary, maintains that \nnever as in recent decades has there been an abundance of \nfood in industrialized countries, often high in protein and \nhigh in calories, which is the basis of obesity, which is on the \nalarming increase. Therefore, the use of food supplements \nis limited to the prevention of malnutrition by default. \nTheir alleged health value in promoting physical well-\nbeing, delaying aging and reducing the risk of developing \ncertain well-being pathologies (cardiovascular or metabolic \ndiseases as well as some neoplasms) is to be demonstrated.\nWe will limit ourselves to indicating those supplements \nthat can help improve the well-being of women with \nendometriosis.\nOmega 3\nIt’s important to remind that endometriosis is a chronic \ninflammatory disease and it’s therefore correct to focus \non the purposes of inflammation, which is a physiological \nprocess, aimed at guaranteeing the integrity of the organism, \nand is triggered by harmful stimuli such as pathogenic \nmicroorganisms and tissue damage [24]. The purpose of \ninflammation is twofold: it intervenes to contain or eliminate \nthe factor determining the damage by preventing its spread \nand activate the repair processes of damaged tissues for \nthe restoration of tissue homeostasis [25]. Cortisone anti-\ninflammatory drugs and NSAIDs often have too aggressive \nan action with negative consequences such as dysregulation \nof the immune response, gastro-intestinal pathologies and \nalterations in renal function.\n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n472\nOmega-3 fatty acids are a category of essential \npolyunsaturated fatty acids which, as demonstrated by \nrecent studies, have an anti-inflammatory and antioxidant \naction, contributing to the formation of inflammatory \nmediators such as prostaglandins and leukotrienes. It is in \nfact important to modulate inflammation in order to respect \nits physiological role of maintaining homeostasis and tissue \nintegrity and, at the same time, preventing it from becoming \nchronic. In this context, proresolvins have a prominent place \nwhich are lipid mediators derived from polyunsaturated fatty \nacids that work as “agonists of inflammation resolution” , they \nstimulate the specific and natural processes of resolution, not \nalways perfectly functional, facilitating the return to tissue \nhomeostasis until healing [26,27]. Kumar demonstrated \nthat proresolvins are able to counteract the progression of \nendometriosis [28]. Lipoxin A4 is recognized as an estrogen \nreceptor agonist. The Author observed that a local treatment \nleads to the reduction of endometriotic lesions through the \nproduction of proinflammatory interleukins, the reduction \nof VEGF, the modulation of COX and MMP-9.\nMelatonin\nStarting from the observation that pinealectomy had \ninduced a worsening of endometriotic lesions in rats and \nthat the administration of melatonin had reversed this \neffect [29], we began to study more fully the correlation \nbetween this hormone and endometriosis. Schwertner \nin 2013 [30] with a randomized controlled, double-blind \nstudy, demonstrated that melatonin therapy (10 mg/day), \nin women with endometriosis, reduced overall pain scores \nby 39.8% and the use of analgesics by 80% after 8 weeks of \ntreatment. Subsequently we investigated [31] the expression \nof the melatonin receptor in the eutopic endometrium of \nhealthy women and in the eutopic and ectopic endometrium \nof women with surgically proven endometriosis. The \nstudy data demonstrated that the endometrium and \nendometriotic lesions possess an intact melatonin receptor \nsignaling pathway and that this inhibits estradiol-induced \ncell proliferation, supporting the hypothesis that the use \nof melatonin can be used as an adjuvant therapy. in the \nmanagement of endometriosis, even if the different receptor \nexpressions indicate differences in efficacy between \nperitoneal and ovarian pathology.\nVitamin D\nThe serum level of vitamin D in women with unilateral \novarian endometriomas has been studied [32] and in \nparticular the possible correlation between the size of the \nendometriomas and the serum levels of the vitamin has been \nevaluated. Hypovitaminosis D was diagnosed in 85.7% of \nthe women investigated with a significant linear correlation \nwith the diameter of the ovarian endometriomas: in the \n“hypovitaminosis D women” , the mean diameter of the \nendometrioma was 40.2 ± 22.6 mm, while in “women with \nnormal serum vitamin D levels” it was 26.7 ± 12.1 mm (p = 0.1). \nMiyashita, et al. [33] in 2016 isolated human endometriotic \nstromal cells (ESCs) isolated from ovarian endometriomas \nand cultured with 1,25(OH)2D3. They demonstrated that \nin vitro 1,25(OH)2D3 significantly reduced IL-1 or TNF-\ninduced inflammatory responses, such as IL-8 expression \nand prostaglandin activity. 1,25(OH)2D3 also reduced the \nnumber of viable endometriotic cells and their DNA synthesis \nbut did not affect apoptosis. Serum levels of the vitamin were \nalso significantly lower in women with severe endometriosis \nthan in controls and women with mild endometriosis. The \nAuthors concluded, indicating vitamin D as a modulator of \ninflammation and proliferation in endometriotic cells, that \na state of hypovitaminosis is associated with endometriosis, \nthus arguing that supplementation with Vit. D could be a \nnew therapeutic strategy for endometriosis management.\nNickel\nGastrointestinal symptoms such as abdominal pain, \nbloating, constipation, and diarrhea are common in \nendometriosis and also tend to worsen during menstruation \n[34]. In endometriosis, there is inflammatory activity with \nboth systemic and focused effects in the intestinal wall. \nA visceral sensitization occurs which leads to an intense \nsensation of pain and which contributes to the manifestation \nof “Irritable Bowel Disease” (IBS) [35]. Gastrointestinal \nsymptoms in endometriosis may also be due to an alteration \nof the enteric nervous system, which is responsible for the \ncontrol of muscular and secretory activity of the intestinal \ntract, reproductive tract and urinary tract [36]. In this \ncomplex neural system, any gastrointestinal inflammatory \nstimulus in the pelvic area can affect the functioning and \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n473\nresponses of other organs and in reverse. What Malin [37] \ndefines as “cross-reactivity” takes place. In the more specific \ncase of “deep infiltrating endometriosis” in the posterior \ncompartment, in which the endometrial cells infiltrate the \nintestine, the symptoms are accentuated both by the local \ninflammation mediated by the prostaglandins but above all \nby the mechanical obstruction and/or microhemorrhages \napplicants [38]. Recent studies have shown a higher \nprevalence of nickel (Ni) skin allergy in women with \nendometriosis, supporting a possible involvement of nickel \nin its etiopathogenesis [39,40]. On this basis it is possible to \nhypothesize that an IBS-like disorder, such as allergic contact \nmucositis, (Ni ACM), may be the cause or a contributing factor \nto gastrointestinal symptoms in women with endometriosis. \nThe high prevalence of Ni ACM in endometriosis and the \nrelief from symptoms after a low Ni diet should lead us to \nsuggest such a diet to this category of patients [41].\nAntioxidants\nOxidative stress is a concept introduced for the first \ntime in Denham Harman’s theory in 1956 [42]. The term \n“Oxidative Stress” indicates the set of alterations that occur \nin tissues, cells and biological macromolecules when they \nare exposed to an excess of oxidizing agents. A state of \noxidative stress results from the action of highly reactive \nunstable chemicals and ionizing radiation [43]. Free \noxygen radicals (ROS) are reactive oxygen species, mainly \nproduced by mitochondria, and are generated as metabolic \nbyproducts by biological systems [44]. Processes, such as \nprotein phosphorylation, activation of various transcription \nfactors, apoptosis, immunity, and differentiation all depend \non proper production and low-level presence of ROS within \ncells [45]. When ROS production increases, damaging effects \noccur on important cellular structures such as proteins, \nlipids, and nucleic acids. The cells implement a defensive \nantioxidant system [46] such as superoxide-dismutase, \ncatalase and glutathione peroxidase and increase the \nuse of vitamins E and C, in order to limit the production \nof ROS, inactivate and eliminate them, thus repairing \nthe cellular damage [47]. It is now widely accepted that \noxidative stress may be implicated in the pathophysiology of \nendometriosis by causing a general inflammatory response \nin the peritoneal cavity [48]. Macrophages, erythrocytes and \napoptotic endometrial tissue, which are transplanted into \nthe peritoneal cavity through retrograde menstruation, are \ninducers of oxidative stress. In fact, activated macrophages \nplay an important role in the degradation of erythrocytes \nthat release pro-oxidant and pro-inflammatory factors such \nas heme and iron, implicated in the formation of ROS [49,50].\nEndometriosis, therefore, is considered as a complicated \nchronic inflammatory process associated with an increase \nin oxidative stress markers [47]. Ngo, et al . [51] found \nthat a significant increase in endogenous oxidative stress \nbiomarkers induces proliferation of endometriotic cells \nwith disease progression. The authors found that patients \nwith endometriosis have lower levels of antioxidants, such \nas vitamin A, vitamin C and vitamin E, in the follicular fluid \nof mature oocytes before ovulation. These low levels reflect \nthe reproductive performance of the oocytes. Thus, an \nimbalance in the production of ROS in the follicular fluid of \nwomen with endometriosis could lead to a negative effect on \noocyte quality, implantation, and embryonic development \n[52], justifying the high incidence of infertility. They then \ndemonstrated that Vit C supplementation for 2 months (1 \ng/day) improved the quality of the oocytes and the embryo. \nA previous study [53] demonstrated that supplementation \nwith antioxidant vitamins (Vit E and Vit C) led to a significant \ndecrease in peritoneal fluid concentrations of inflammatory \nfactors and a reduction in chronic pelvic pain in women with \nendometriosis.\nOzone Therapy\nOzone (from the Greek όζω= to smell) is an unstable \ngas made up of 3 oxygen atoms. Therapy with a mixture of \noxygen and ozone has various pharmacological effects. It \nhas an anti-inflammatory action by reducing the synthesis \nof prostaglandins, a pain-relieving effect (improving tissue \ntrophism and promoting its repair) and a relaxing effect on \nthe muscles by increasing the amount of oxygen [54,55]. The \nsystemic administration of a mixture of oxygen and ozone \nis specifically indicated for chronic inflammatory diseases, \ncharacterized by a high oxidative stress secondary to an \nexcess of ROS [56]. As we have already seen, endometriosis \nis a disorder associated with inflammation and oxidative \nstress and it has been postulated that intraperitoneal ozone \ntreatment can protect antioxidant systems and down-\nregulate the concentration of inflammatory substances in \nthe context of peritoneal implants. In a study conducted on \nrats, ozone therapy was shown to significantly reduce the \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n474\nvolume of peritoneal endometrial implants, with minimal \nadverse effects on the ovarian tissue [57]. Aktun, et al . [58] \nstudied the potential therapeutic efficacy of ozone therapy \nin the treatment of induced peritoneal endometriosis in rats \nby comparing its activity with a GnRH agonist (leuporide \nacetate) and placebo. After ozone therapy, a significant \nincrease in the activity of antioxidant enzymes, Such As \nSuperoxide Dismutase (SOD) and a reduction in oxidative \nstress markers such as Malondialdehyde (MDA) were found \nin the peritoneal fluid. \nAccording to the authors, repeated administration of \nozone-oxygen therapy in non-toxic doses inhibits the growth \nof endometrial implants. Furthermore, no alterations in the \nserum levels of AMH were highlighted even if the number \nof primordial and preantral follicles had decreased after \nozone therapy. However, the number of atretic follicles \nwas similar in ozone therapy than in the control groups. \nFinally, we must also remember the important direct effect \nof ozone on antioxidant substances when it is administered \nby insufflation into a cavity, whether intraperitoneal or \nintrauterine. In conclusion, the anti-inflammatory action of \nozone therapy could play an important role in the treatment of \nendometriotic implants through its endogenous antioxidant \nmechanism and be of great relief for women suffering from \nendometriosis.\nImmunotherapy\nThere is a significantly higher incidence of immune-\nrelated disorders in patients with endometriosis, \nparticularly referring to autoimmune diseases, or their \ngenetic predisposition, and celiac disease. The coexistence \nof endometriosis with systemic lupus, Sj ögren’s syndrome, \nrheumatoid arthritis, autoimmune thyroiditis, multiple \nsclerosis, Addison’s disease and Chron’s disease has \nbeen shown to be much higher than in women without \nautoimmune diseases. Although there are no convincing \ndata on a possible causal mechanism linking these \npathologies with endometriosis, it is hypothesized that \nimpaired immune regulation is the substrate that associates \nendometriosis with autoimmune diseases [59]. Furthermore, \nconcomitant autoimmunity is associated with a more severe \ncourse of endometriosis [60]. Recently, some studies have \nhypothesized a potential link between endometriosis and \nceliac disease, as these conditions share some similarities \n[61,62] and patients with endometriosis have been found \nto suffer from celiac disease three times more often than \nhealthy women. In fact, the results of Santoro, et al. [63], who \nconfirm the potential association between celiac disease \nand endometriosis in Italian women, state that this trend \ndoes not reach statistical significance, however suggesting \nto implement screening for celiac disease in women with \nendometriosis. Certainly, however, the gluten free diet can \neliminate the pro-inflammatory stimulation [61] related to \nthe strong immune background present in endometriosis. \nRadoslaw and Coll postulate that immunotherapy may be \na promising and useful approach in the treatment of these \nconditions [64].\nThe Fitness\nActivity and exercise may have a number of beneficial \neffects on the symptoms associated with endometriosis. \nMerete Tennfjord and Coll. [65] evaluated eleven databases \nwith eligibility criteria for women with established \nendometriosis receiving a physical activity protocol with \nstandardized exercises. The Authors confirmed that, \nunfortunately, efficacy data cannot be reliably determined \nbased on the existing literature. However, the potentially \nbeneficial role of activity and physical exercise should be \ncommunicated to women with symptoms associated with \nendometriosis, considering that it is necessary to focus on \nthe type and dose of physical activity. The study by Ensari \n[66] also provides evidence that regular physical exercise is a \npotential pain moderator, provided that one exercises at least \n3 times a week. Unfortunately, specific recommendations for \nthe management of endometriosis pain are almost completely \nabsent and therefore it is necessary to organize future \nstudies that can serve to investigate the effects of physical \nactivity on endometriosis pain with a focus on various types \nof exercises, their intensity and duration and structure \nadequate guidelines. Since patients with endometriosis \ncan show complex symptoms, the cooperation of multiple \nspecialists, such as physiotherapists and osteopaths together \nwith gynecologists, could improve the quality of clinical \nresearch in this field and obtain favorable results on the \nsymptoms and evolution of the disease.\nOsteopathy\nWomen suffering from endometriosis live with a constant \npelvic contracture, which is partly due to the disease and \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n475\npartly linked to central inflammation phenomena that \nactivate the mechanism of chronic pain. The memory of pain \nis almost always present and this leads the patient to remain \nin a sort of lasting defensive structural attitude. Osteopathic \ninterventions can be used as complementary strategies to \nbetter manage the different conditions of endometriotic \ndisease. 60% of women diagnosed with endometriosis report \nchronic pelvic pain and it has been observed [67] that these \npatients are 13 times more likely to experience abdominal \npain than healthy subjects. Jaiswal et al.  [68] found a high \npresence of cytokines and growth factors in peritoneal \nfluid samples taken from women with endometriosis, \nwhich could contribute to the pathogenesis of pain and be \nconsidered real diagnostic markers. Indeed, in 20-28% of \npatients operated on for deep infiltrating endometriosis, a \nrecurrence of symptoms is reported even in the post-surgical \nphase, despite the absence of new foci [69]. This evidence \nhas led some researchers [70] to explore neuropathological \naspects inherent in neuroplastic modification patterns \ntypical of chronic pain (central-periphery bidirectional \ncommunication, resting state functional connectivity) \nand to investigate topics such as inflammation, including \nneurogenic inflammation, neuro angiogenesis, peripheral \nand central sensitization, allodynia and hyperalgesia [71].\nMagdalena and Coll. [70] found that in women with \nchronic pelvic pain there is an increased connection at \nrest between the areas belonging to somato-sensory pain \nprocessing and the regions responsible for cognitive and \nemotional processing. Through a cross-sectional study \nand insight into the relationships between myofascial \ndysfunction, sensitization and chronic pelvic pain, Phan \net, al.  [72] have added a piece to the manual therapeutic \napproach for endometriosis. Indeed, in affected women, an \nemerging semiotic finding is the reproducibility of symptoms \nby palpation of the soft tissues of the pelvis. These findings \nseem to suggest that in these women the parameters of \nmyofascial sensitization and dysfunction extend beyond the \npelvic region in relation to the modification of the central \nfunctional connection.\n It would therefore be legitimate to hypothesize that \nmuscle spasms localized in the soft tissues of the pelvic \nfloor, through precise mechanisms of viscero-somatic \nconvergence, may act as triggering factors and perpetuation \nof sensitization. Manual therapies therefore seem to prove to \nbe a possible approach that can be integrated with common \nendometriosis intervention strategies. In addition to the \nmolecular component, which we have just analyzed, the \ncellular component present in peritoneal fluids also seems \nto play an important role in the genesis of endometriosis, \nsuch as T lymphocytes, which secrete lymphokines, and \nmacrophages related to MIF (macrophage migration \ninhibitory factor). In recent years [73], there has been an \nincreased interest in approaches focused on the lymphatic \nsystem whose stomata have been identified in various areas \nof the peritoneum. These contain macrophage-rich lymphatic \naggregates that can engulf particles and pathogens present \nin the peritoneal cavity and are involved in the resolution of \nperitoneal inflammation and infection [74]. Even respiration \nseems to be one of the factors that can most influence \nsubdiaphragmatic lymphatic absorption which drains fluids \nfrom the peritoneal cavity towards the vascular system [75]. \nDuring exhalation, the diaphragmatic muscles relax and, by \nseparating, induce a valve opening such as to allow lymphatic \naccess to the stomata. Finally, coherently with the concepts \nof bodily integrity and totality, it is appropriate to report the \nconsiderations of B. Bordoni [76]. The author invites us not \nto forget the phenomena of functional synergy of the pelvic \ndiaphragm with the rest of the body diaphragms: buccal, \nupper thoracic, thoracic proper, pelvic. A correct balance \nof the aforementioned anatomical structures could in fact \nguarantee an important beneficial action on the circulation \nof body fluids (e.g. blood and lymph) and on the general \nhealth of the individual. The treatment of the five diaphragms \nis essential because preparing the body by releasing the \ndiaphragmatic muscle-tendon structures makes the work \non visceral efficacy more effective. Both manual therapies \nand the action on the lymphatic drainage of the peritoneal \ncavity, influenced by breathing, could make an additional \ncontribution to new osteopathic intervention rationales for \nthe treatment of endometriosis.\nAcupuncture\nTraditional Chinese Medicine (TCM) does not consider \nendometriosis as a disease in its own right, but recognizes, \ntreats and characterizes the signs and symptoms associated \nwith it. There is no univocal diagnosis of endometriosis \nbut a set of various pictures capable of determining the \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n476\nsymptomatology accused by the patient. According to the \nChinese view, the fundamental mechanism underlying this \npathology is blood stasis, which can be constitutional, derive \nfrom various types of disorders, from emotional factors, \nfrom an incorrect diet, from a bad lifestyle or more often \nby a combination of several factors. According to TCM, the \nwoman is Yin compared to the man and this not only for \nelements concerning the general physical conformation, but \nabove all because she uses a lot of blood, liquids and fluids \nin general and is in the continuous need to regenerate them. \nBlood, generated by the organs, is the basis of the menstrual \nmechanism, but the Qi that moves it and gives it dynamism \nis almost inseparable from it. In TCM Qi is considered as the \ndriving force of organ functions (“Kidney Qi” , “Liver Qi” , etc.), \nand at the same time, it is considered what nourishes and \nsustains all body tissues. Also, in TCM, Qi is often treated \nalmost like a bodily fluid.\nBlood and Qi, although distinct, are inextricably linked \nby relationships of mutual dependence: “Qi moves and keeps \nthe Blood in the vessels, it is the commander of the Blood” . \nBlood nourishes the organs which then produce and regulate \nQi, <<Blood is the mother of Qi>>. A regular flow of Blood is a \nnecessary condition for the regularity of Qi, but in the same \nway, a regular diffusion of Qi is an indispensable condition for \nthe diffusion of Blood. To further underline this relationship, \ntraditional medicine states that << Blood and Qi are two \nnames for the same nature >>. Menstrual flows, fertility, \npregnancy, lactation and all the physiological balance of the \nfemale organism are related to Qi, Blood, Jin and Tian gui. \nThese substances are intimately connected to each other: the \nQi governs the Blood and the Blood produces the Qi, the Jin \nnourishes the blood and the Blood in turn generates the Jin, \nthe Jin of the Kidney generates the Qi of Kidney, the state of \nthe Kidney is closely related to the Tian gui. “Tian Gui is the \nfeminine Essence” even if it is also present in the male. Tain \nGui is directly related to the kidney and is closely integrated \nand similar to the modern biomedical urinary and endocrine \nsystem. The Tian Gui is associated with the material basis \nof the male and female reproductive systems [77]. In the \nbalance of the female genital system, the organs connected to \nthe Yin and the Blood are naturally of particular importance \nand therefore the Liver, the Kidney, the Spleen (the three Yin \nof the foot). The greater involvement of one or the other will \nbe suggested by the complained symptomatology.\nThe Kidney governs the uterus through the ancestral \nQi, yanqi which is located there, and contains the Tiangui, \nwhich allows the menstrual cycle and fertility. This occurs \nthrough the lower Jiao and the Ren mai, Chong mai and \nkidney meridians. The Spleen, the trophic organ par \nexcellence, nourishes the ovary, also conserves the Blood \nand therefore presides over the physiology of the menstrual \ncycle; this occurs via the middle Jiao and the Stomach and \nSpleen meridians. The Liver <<preserves the Blood>>, that \nis, it stores it, just as the kidneys are the repository of the Jin, \nthe Liver is the repository of the Blood. The Blood storage \nfunction is not static, but is carried out dynamically through \na continuous release and collection action, regulating its \ndistribution throughout the body and it is a part of this \nBlood which, having descended into the Ren mai and Chon \nmai meridians, becomes menstrual: in reality for traditional \nChinese medicine, the Blood, having reached the uterus \nthrough these meridians, is made available for the formation \nof the fetus and only if this does not happen, having become \n“old” , is it expelled outside with menstruation after a month \n. All the work related to the movement of the Blood towards \nthese compartments and the new storage that preludes \nthe next cycle is regulated by the Liver: as a result, only a \nwell-harmonized Liver can guarantee menstrual periodicity \nand regularity. Finally, the course of the Liver meridian \nunderlines the important correlations it contracts with the \nphysiology of the female genital and reproductive system: \nthe meridian surrounds the genitals, crosses the pelvis and \nreaches the breast. The meridians, related internally with \nthe Organs, connect the whole organism in an organic whole \nand perform the function of transporting Qi and Blood and \nregulating Yin and Yang. Female physiology is practically \nlinked to the curious meridians Chong mai, Ren mai, Du mai \nand Dai mai (the curious meridians are virtual meridians \nthat appear when there are energy disturbances in the Main \nMeridians by acting as energy reserves) which, in addition \nto carrying the ‘Congenital, ancestral vital energy, in the \nwhole body and in the curious viscera (including the uterus), \nintegrate the functions of the main meridians [78]. \nTherefore, in endometriosis, according to Traditional \nChinese Medicine, Qi stasis dysmenorrhea occurs with blood \nstagnation, described as abdominal pain that precedes the \nmenstrual cycle by one to two days or is associated with it \nin the first days of the flow, often the patient feels a sense \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n477\nof tension in the lower abdominal quadrants, with difficulty \ninitiating and expelling the menstrual cycle itself. The pain \nsometimes also affects the hypochondria, the hips, the chest, \nthe sinuses (areas crossed by the meridians mentioned). \nMenstruation is scanty, dark sometimes with clots. What \nhas been described leads to the selection of specific points \non which the treatments are performed: from three to five \nmain therapeutic points are used to which secondary points \nare added; the needles are positioned perpendicular to the \nskin plane with the application of moxibustion or infrared \nlamp. All the needles are kept in place for 20-30 minutes \nand manipulated manually or with a variable frequency \nand low intensity electrostimulator in order to warm up \nthe meridians and disperse the cold, mobilize the blood and \nregulate menstruation. Treatments can be performed daily \nin the menstrual phase, and twice a week in other periods \nfor cycles of 15 sessions followed by a monthly session [79]. \nAcupuncture associated with conventional treatments of \nendometriosis contributes to the decrease of dysmenorrhea \nand to a greater regularity of the menstrual cycle.\nPsychological Support\nPain, which is the most important symptom of \nendometriosis, puts women in difficulty especially when it \nis intense or repetitive. Pain can affect at different levels: \nphysical, social, emotional, relational, existential and above \nall it can force you to deeply review some life projects, such \nas motherhood. Intense pain can be perceived as an enemy \nto be fought at any cost. But in this way, since the seat of pain \nis the body, one runs the risk of transforming one’s body \ninto an enemy rather than an essential resource for a full life \n[80]. To proactively manage this condition, the “recognition” \nphase is essential: the frequent delay in diagnosis - often \ndue to common symptoms (such as, for example, menstrual \npain), or overlapping with other pathologies, can generate \nconfusion, with a decrease of self-confidence, of one’s ability \nto listen and understand one another, to evaluate one’s \nstate of well-being and malaise [81]. An important first \nstep in working with women is to separate her profound \nidentity from the disease, to allow her to build a realistic \nself-narration, trying to give a new meaning to her life \nexperience, integrating the disease, thus ceasing to fight it \nas a bitter enemy, instead starting a process of acceptance \n[82]. This integration is also facilitated by the use of concrete \ntools that help manage everyday life: techniques such as \nmeditation, guided visualization, also supported by Virtual \nReality, help to relax body and mind to “stay” in time present, \nan important step to access well-being and serenity [80]. \nFurthermore, since they are methods that restore the \ncentral role of protagonist to the body, they also provide \nan opportunity to feel it as an ally and not as a “traitor” or \n“obstacle” . These concrete tools can be learned and managed \nindependently over time, to improve the quality of one’s \nlife. Thoughts characterized by hopes, realistic and positive \nopportunities, have a beneficial effect on the emotional state \nof the person, which in turn affects the neurological state \nand the immune system, as now amply demonstrated by \nPNEI (Psyco Neuro Endocrine Immunology). The activation \nof this virtuous circle (body-thoughts-emotions) has \nbeneficial effects on the psychophysical health of women, \nand consequently also on the network of relationships that \nsurround them [83]. Indeed, it is important to provide support \nto people who share the life of women with endometriosis \n[83]. The couple may have to review their approach to \nsexuality, or objectives and ways of thinking about forms of \nparenting outside of the biological one, in order to accept a \ndaily life marked by the manifestations of the disease. The \npartner, in particular, could find himself having to review his \nown way of being at the side of his partner, accepting the fact \nthat he cannot do anything concrete to change the situation, \nbut instead accompanying the process of acceptance, rather \nrecognizing the value of “being there” [84].\nNote: PNEI is a new model of personal care that deals \nwith the mutual interaction between behavior, mental \nactivity, the nervous system, the endocrine system and the \nimmune response of human beings.\nPert CB, Ruff MR, Richard J. Weber RJ and Herkenham \nM: Neuropeptides and their Receptors: A Pyschosomatic \nNetwork. THE JOURNAL OF IMMUNOLOGY. Vol. 135. No. 2. \nAugust 1985\nConclusions\nIn consideration of the fact that the medical and surgical \ntherapy of endometriosis have sometimes important limits of \nuse, it is often necessary to address the disease “as a whole” \nby considering other forms of treatment. Endometriosis \nis a complex pathology, which can affect a woman’s life on \nseveral levels, sometimes in a devastating way, and which \ntherefore needs to be taken care of globally in order to be \n\nAm J Biomed Sci & Res\nAmerican Journal of Biomedical Science & Research\nCopyright@ Bardi M\n478\nintegrated and accepted into a full and conscious life plan, \nallowing those who experience it, at different levels, to \nmanage it without necessarily being crushed by it.\nAcknowledgement\nNone.\nConflict of Interest\nNo conflict of interest.\nReferences\n1. Krina T Zondervan, D Phil, Christian M Becker, and Stacey A Missmer \n(2020) Endometriosis. N Engl J Med 382: 1244-1256.\n2. Valle RF, Sciarra JJ (2003) Endometriosis: treatment strategies. Ann N Y \nAcad Sci 997:229-239.\n3. Di Vasta AD, Stamoulis C, Sadler Gallagher J, Laufer MR, Raymond Anchan, \net al. 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