{"paper_id":"77efb8ff-4d8e-4f3c-bf29-2215d425be57","body_text":"Dietary therapy: a new strategy for management of chronic pelvic pain\nFrancesco Sesti1*, Talia Capozzolo1, Adalgisa Pietropolli1, Marco Collalti1, Maria Rosa Bollea2\nand Emilio Piccione1\n1Endometriosis Center, Section of Gynecology and Obstetrics, Department of Surgical Sciences, Tor Vergata University\nHospital, Rome, Italy\n2Section of Clinical Nutrition, Department of Internal Medicine, Tor Vergata, University Hospital, Rome, Italy\nAbstract\nChronic pelvic pain (CPP) can be identified as a chronic nociceptive, inflammatory and neuropathic pain characterised by spontaneous\npain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult\nto treat. Currently, the main approaches to treatment include counselling supported by reassuring ultrasound scanning or psychotherapy,\nattempting to provide reassurance using laparoscopy to exclude serious pelvic pathology, hormonal therapy and neuroablative treatment\nto interrupt nerve pathways. Dietary supplementation has been suggested as a means to treat chronic medical illnesses that are poorly\nresponsive to prescription drugs or in which therapeutic options are limited, costly or carry a high side-effect profile. A comprehensive\nsearch of the PubMed database was performed using the search terms ‘chronic pelvic pain’, ‘oxidative stress’, ‘antioxidants’ and ‘dietary\ntherapy’. The systematic review focuses on both randomised and non-randomised controlled trials from 2005 onwards, in which CPP\nwas the end point. Given the complexity and not well-understood aetiology of CPP, its treatment is often unsatisfactory and limited to\npartial symptom relief. Dietary therapy with antioxidants improves function of the immune system and in fighting free radical damage.\nAgents with antioxidant activity are able to improve CPP without undesired effects and any important metabolic changes associated\nwith hormonal suppression therapy. In conclusion, dietary therapy with antioxidants could be considered as a new effective strategy in\nthe long term for CPP, and may be better accepted by patients. Further randomised trials with larger series and long-term follow-up to\nconfirm these observations are needed.\nKey words: Pelvic pain: Oxidative stress: Antioxidants: Dietary therapy\nIntroduction\nThe present review comprehensively explores the litera-\nture for evidence of chronic pelvic pain (CPP) in women,\nsuch as nociceptive, inflammatory and neuropathic pain.\nBased on these findings, the focus of the present review\nwas to provide some insight into the potential role and\nclinical use of dietary supplementation in the management\nof CPP. The present systematic review focuses on both ran-\ndomised and non-randomised controlled trials from 2005\nonwards, in which CPP was the end point. To identify rel-\nevant studies we performed a comprehensive search of the\nPubMed database, using the search terms ‘chronic pelvic\npain’, ‘oxidative stress’, ‘antioxidants’ and ‘dietary therapy’.\nEpidemiology and impact on quality of life\nWomen with CPP present a diagnostic and therapeutic\nchallenge. Pelvic pain is a major health problem and affects\nbetween 4 and 39 % of women and accounts for 10–40 %\nof all out-patient gynaecological visits\n(1). A quarter of\nwomen with CPP miss nearly 15 h of work per month,\nwhich accounts for a $14 billion loss in productivity per\nyear(2). The estimated combined cost of CPP owing to\nloss of productivity, diagnosis, and medical and surgical\ntreatment is $39 billion annually\n(2).\nCPP is a non-menstrual pelvic pain of 6 or more months’\nduration that is severe enough to cause functional disability\nor require medical or surgical treatment\n(3). Pelvic pain is a\nsyndromic complex; universally it is the unpleasantness of\nthe experience that characterises pain, and this makes pain\nan emotionalexperience, not simplya sensoryexperience(4).\nSo, the constant presence of pain may be responsible for\naffective changes in dynamics: family, social and sexual.\nIn a study by Sepulcri & do Amaral (5), the prevalence\nof anxiety was 73 and 37 % in pelvic pain and control\nsubjects, respectively, as evaluated by the Spielberger\nState-Trait Anxiety Inventory and the Hamilton Rating\nScale for Anxiety. The prevalence of depression was 40\n* Corresponding author: Dr Francesco Sesti, fax þ39 06 20 902 921, email Francesco.Sesti@uniroma2.it\nAbbreviations: COX, cyclo-oxygenase; CPP, chronic pelvic pain; NGF, nerve growth factor.\nNutrition Research Reviews (2011), 24, 31–38 doi:10.1017/S0954422410000272\nq The Authors 2010\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press\n\nand 30 % in the pelvic pain and control groups, respect-\nively, as evaluated by the Beck Depression Inventory and\nthe Hamilton Rating Scale for Depression. Patients with\nhigher anxiety and depression scores also presented\nlower quality-of-life scores\n(5).\nAetiology\nSpecific causes of CPP may include many disorders of the\nreproductive tract such as pelvic endometriosis, interstitial\ncystitis, adhesions (40 % of cases), pelvic congestion\nsyndrome (20 % of cases), pelvic inflammatory disease,\nor diseases of the gastrointestinal system, urological\norgans, musculoskeletal system and psychoneurological\nsystem\n(6,7). Moreover, it has been postulated that an associ-\nation may exist between CPP and sexual/physical abuse(8).\nHowever, as confirmed by Sharma et al. in a recent study,\nCPP is usually associated with pelvic pathology and\nrequires laparoscopy before it can be attributed to a psy-\nchosomatic cause\n(7).\nUp to half of CPP cases have been found to be associ-\nated with either genitourinary symptoms or symptoms of\nirritable bowel syndrome\n(9). Women with CPP often\ndevelop visceral and somatic hyperalgesia as a result of\nvisceral hypersensitivity arising from the gastrointestinal\nand urinary tracts and the reproductive organs\n(10). Further-\nmore, interstitial cystitis and irritable bowel syndrome may\nbe associated with endometriosis, dysmenorrhoea, vulvo-\ndynia and adhesions through the recruitment of additional\nneural pathways, thereby substantially complicating the\ndiagnosis\n(11).\nDiagnosis\nA thorough history, clinical examination and imaging\nstudies provide considerable information but are insuffi-\ncient to arrive at a diagnosis in all cases. There are many\nreports in the literature that CPP is best investigated lapar-\noscopically before any treatment is planned\n(7,12).I ti s\nimportant to remember that a negative laparoscopy is not\nsynonymous with no diagnosis or no disease. More discri-\nminative use of laparoscopy, carefully based on the\npatient’s history, physical examination, laboratory, and\nimaging findings, might decrease the rate of negative lapar-\noscopies from 39 to 4 %\n(13).\nPathophysiology\nFig. 1 shows the proposed mechanism of action for endo-\nmetriosis-related CPP.\nNociceptive pelvic pain\nNociceptive pain occurs in response to a noxious stimulus\nthat initiates the nociceptive pathway. The clinical charac-\nteristics of visceral pelvic pain include that it is not always\nlinked to injury and thus may be functional; it frequently\nresults in somatic referral of pain, possibly because of\ncentral convergence of visceral and somatic afferents; it\ntends to be diffuse or poorly localised, probably because\nof the low concentration of nociceptive afferents within\nviscera\n(14).\nMany nociceptors in viscera are silent nociceptors that\ndo not normally respond to intense mechanical or thermal\nstimuli, but when there is inflammation of the surrounding\ntissue they become sensitised and respond to several stim-\nuli\n(15). Moreover, the severity of visceral pain does not\nalways reflect the severity of the pain-generating condition,\nin acute and also chronic visceral pelvic pain\n(15).\nThe nerves that function as nociceptors are primarily C\nand Ad fibres(13).\nThere is clear evidence that mechanisms of nociceptive\npain are implied in CPP and that peripheral and central\nsensitisation leads to abnormal perception of both painful\nand non-painful stimuli contributing to visceral hyperalge-\nsia and allodynia\n(13). Temporal and spatial summation of\npain stimuli is also thought to be important in the develop-\nment of hyperalgesia at the site of an irritated organ that\ndevelops as a result of enhanced excitability of respective\nneuronal soma within the dorsal root ganglia\n(16).\nThe major evidence for nociceptive pelvic pain as a trigger\nmechanism for CPP is represented by endometriosis and\ncomes from clinical trials of laparoscopic surgical ablation\nor excision of endometriotic lesions\n(17). In this context it is\nimportant to recognise that there was incomplete relief of\npain after surgical treatment of endometriosis and that many\nwomen continued to have some degree of pelvic pain\n(13).\nInflammatory pelvic pain\nInflammatory pain is due to the response to tissue injury\nand the resulting inflammatory process; it may be a\nnormal pain, but in some cases it becomes chronic or per-\nsistent and represents a pathological pain mechanism (13).\nThe most frequent pelvic cause of the CPP-related inflam-\nmatory process is endometriosis\n(18).\nInflammatory\nmast cell-derived cytokines\nand algogenic mediators\nPeritoneal\nchronic inflammation\nDeep intraperitoneal\nadhesion formation\nand fibrotic thickening\nPelvic nerve injury\nand central neural processes\nof peripheral\nnerve impulse patterns\nShed menstrual blood\nin endometriotic\nimplants\nDeep infiltration\nwith tissue damage\nCPP\nFig. 1. Proposed mechanism of action for endometriosis-related chronic\npelvic pain (CPP).\nF. Sesti et al.32\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press\n\nSome research has confirmed that endometriotic\nimplants develop a sensory and sympathetic nerve\nsupply both in rats and in humans\n(19,20). The nerve inva-\nsion by means of perineural and endoneural invasion, as\nwell as the presence of degranulating mast cells near\nnerve structures, could be responsible for the inflammatory\npain and hyperalgesia\n(21). After tissue damage, a variety of\nimmune mediators are released, which exert algesic actions\nby acting directly on nociceptors, or indirectly via the\nrelease of other mediators, most notably prostanoids\n(22).\nThere is increasing knowledge of the intracellular cas-\ncades that are activated in nociceptors by mediators such\nas TNF- a, IL-1 b, IL-6, NO, nerve growth factor (NGF)\nand cyclo-oxygenase (COX)-2, which ultimately either acti-\nvate or sensitise these neurons\n(22).\nMast cells, residing in the nerve, are the first cells to be\nactivated and contribute to the recruitment of neutrophils\nand macrophages. In the setting of inflammation, mast\ncells degranulate and release their inflammatory mediators\nand may activate or sensitise primary nociceptive neur-\nons\n(22). These initial events promote the recruitment of\nT-cells, which reinforce and maintain inflammatory\nreactions.\nDeregulation of neural transmission appears be pro-\nduced by neurotransmitters, neuromodulators, neuropep-\ntide hormones or paracrine regulators including the\nneuroendocrine system cells stained with specific immuno-\nhistochemical markers such as neuron-specific enolase,\nsynaptophysin, chromogranin A and cytokeratin\n(23).\nIn modulation of acute inflammation, monocyte chemo-\ntactic protein 1/chemokine (C-C motif) ligand 2 (MCP-1/\nCCL2) appears to be at least one of the factors responsible\nfor this increase of activated macrophages, stimulating\nmacrophages to secrete growth factors and cytokines,\nincreasing levels of many inflammatory cytokines\n(24).\nAfter peripheral nerve injury, the site of damage is\ntypified by the activation of resident immune cells, and\nrecruitment and proliferation of non-neuronal elements,\nwhich release factors (for example, TNF- a, IL-1, IL-6,\nC-chemokine ligand 2, histamine, PGE\n2 and NGF) that\ninitiate and maintain sensory abnormalities after injury.\nThese factors may either induce activity in axons or are trans-\nported retrogradely to cell bodies in the dorsal root ganglia,\nwhere they may alter gene expression of the neurons\n(22).\nTNF-a is a cytokine that has an essential role in inflamma-\ntory process and in CPP. As well documented, TNF-a stimu-\nlates the expression of PG synthase-2, which in turn\nincreases the production of PGE\n2 and PGF2a,a ni n d i r e c t\nmechanismbywhichTNF- amaycauseinflammatorypain (25).\nBetween them, IL-1, IL-6 and IL-8 have many biological\nfunctions such as inducingthe synthesis of inflammatory pros-\ntaglandins and promoting fibroblast proliferation, collagen\ndeposition and fibrinogen formation, which can contribute\nto the pathophysiology of chronic painful symptoms\n(26).\nRecent evidence has revealed that NGF, a cytokine\nproduced by Schwann cells, keratinocytes, fibroblasts, T\nlymphocytes and macrophages, regulated by oestrogen\nand progesterone, involved in the extension and mainten-\nance of sympathetic and primary sensory nerves, is greater\nexpressed in pelvic symptomatic endometriotic lesions\n(27).\nNGF promotes sprouting of nociceptors, increases the\nnumber of sensory neurons, and is known to contribute\nto persistent inflammatory and also neuropathic pain.\nNGF induces the expression of substance P and calcitonin\ngene-related peptide, which are neuropeptides involved in\nthe modulation of central pain transmission\n(27).\nIn the peritoneal fluid of women with CPP elevated\nlevels of prostaglandins have been found, especially\nPGE\n2 and PGF2a. These prostaglandins are mediators of\ninflammation, as well as direct generators of pain, activat-\ning nerve endings to pain, and trigger the release of\nother algesic mediators, such as serotonin and histamine\nfrom other cells and afferent nerves\n(28).\nThe increase of PGE 2 is due to the up-regulation of\nCOX-2. This is the rate-limiting enzyme that catalyses the\ninitial step in the formation of prostaglandins from arachi-\ndonic acid. COX-2 expression is induced by a number of\ninflammatory, mitogenic and physical stimuli and is stimu-\nlated by oestradiol\n(29). So, a positive feedback loop\nappears to be present in women with endometriosis-\nrelated painful symptoms that supports the continuous\nformation of oestradiol and PGE\n2.\nNeuropathic pelvic pain\nNeuropathic pain is usually accompanied by nerve injury\nor prolonged neuronal pressure but, additionally, the acti-\nvation of cells involved in the immune response may con-\ntribute indirectly to the development of CPP and frequently\nleads to a chronic pain state by neural plasticity and\ncentral sensitisation\n(30). Also, visceral cross-sensitisation is\nbelieved to be due to increased, persistent nociceptive\ninput from inflamed reproductive system organs that sensi-\ntise neurons, that receive input not only from the inflamed\nreproductive organs, but also from unaffected visceral\norgans by a phenomenon called convergent input\n(31).\nMoreover, the nociceptive memory manifests itself most\nprominently as post-injury sensitisation; that is, after tissue\ndamage, pain that results from subsequent stimulation is\nexaggerated and prolonged and can be initiated by low-\nintensity stimuli.\nAtwal et al. studied nerve fibre concentration, microneur-\noma formation and perivascular nerve proliferation within\nthe lower segment of the uterus and found that changes\nobserved in innervation of the endometrium were much\nmore prominent in uteri from women with endometriosis\nand with CPP than from women without either\n(32).\nChronic pelvic pain and oxidative stress\nReactive oxygen species are a double-edged sword; they\nserve as key signal molecules in physiological processes,\nDietary therapy and chronic pelvic pain 33\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press\n\nbut also they have a role in pathological processes invol-\nving the reproductive tract(33).\nGiven the limited data and complex environment of the\nperitoneal cavity, it is unclear when and why oxidative\nstress may occur in relation to CPP. In addition, circulating\nlevels of oxidative stress due to other causes such as per-\nsistent organic compounds and exposure to environmental\ntoxicants, for example, 2,3,7,8-tetrachlorodibenzo-p-dioxin\nand heavy metals, may further induce symptomatic pelvic\ndiseases.\nIt has been suggested that in women with endometrio-\nsis-related CPP there is an increased peritoneal level of\nlipid peroxidation markers and their by-products in a\nmacrophage-rich inflammatory milieu. This finding is\nassociated with an altered expression of pro-oxidants and\na drop in antioxidant levels, with alterations in free radical\ndetoxification pathways, consequentially\n(34).\nAs a potential inducer of NF- kB, which activates genes\ninvolved in cell adhesion, secretion of inflammatory cyto-\nkines, and recruitment of macrophages, oxidative stress\nmay help to trigger the chain of events that leads to the\ndevelopment of symptomatic pelvic diseases\n(35).\nOxidative stress induces a cytotoxic effect by peroxi-\ndation of membrane phospholipids, increased cell mem-\nbrane permeability, loss of membrane integrity, enzyme\nactivation, structural damage to DNA and cell death\n(36).\nThe presence of activated macrophages and LDL together\nmay lead to oxidation. Increased number and activity of\npolymorphonuclear leucocytes and oxidative stress-\ninduced macrophages lead to an increased production of\nreactive oxygen species with higher levels of lipid peroxide\naccompanied by the release of more cytokines and other\nimmune mediators, such as NO\n(37).\nVarious cytokines released by abnormal immune\nresponses might stimulate macrophages and/or endo-\nmetrial cells to persistently produce a large amount of\nNO\n(38).\nPeritoneal macrophages express higher levels of the\ninducible NO synthase isoform, persistently marked\nthroughout the menstrual cycle, in contrast to cyclic vari-\nations in healthy subjects, and produce more NO in\nresponse to immune stimulation in vitro\n(39). NO is a free\nradical initially implicated in low-grade inflammation,\nwhile elevated peritoneal NO levels are consistent with\nthe increased number and activity of macrophages\n(40).\nElevated levels of the marker of lipid peroxidation lyso-\nphophatidyl choline, a potent chemotactic factor for mono-\ncytes/T-lymphocytes, were seen in the peritoneal fluid of\nwomen with endometriosis\n(28). Non-terminal oxidation\nmay have a role in the pathophysiology of endometriosis.\nMinimally oxidised LDL is present in the peritoneal fluid\nof women with endometriosis in place of the terminally\noxidised LDL\n(41,42). The ratio of lysophosphatidyl choline,\na breakdown product of oxidised-LDL, to phosphatidyl\ncholine suggests minimally oxidised LDL rather than oxi-\ndised LDL.\nRetrograde menstruation is likely to carry highly pro-oxi-\ndant factors into the peritoneal cavity. In addition, it is\nlikely that damaged blood cells releasing metal ions as\nwell as haeme and Fe, cell debris transplanted into the per-\nitoneal cavity by menstrual reflux, and apoptotic endo-\nmetrial cells would provide an ideal target for the\nrecruitment of peritoneal fluid monocytes\n(43).\nOn the other hand, expression of antioxidant enzymes\n(superoxide dismutase, glutathione peroxidase, catalase)\nand non-enzymic antioxidants (taurine, vitamin C, vitamin\nE) appears to be reduced in the peritoneal fluid of patients\nwith developing CPP compared with fertile symptom-free\ncontrol women\n(28). These enzymes play an important role\nin converting reactive oxygen species to water to prevent\noverproduction of reactive oxygen species, and in the\nbreakdown of free radicals. Thereby, antioxidants might\nprevent the pathological effects of oxidative stress that\nare exerted by various mechanisms.\nTherapeutic approach\nConventional treatments\nGiven the complexity and not well-understood aetiology of\nCPP, its treatment is often unsatisfactory and limited to par-\ntial symptom relief.\nCurrently, the main approaches to treatment include\ncounselling supported by reassuring ultrasound scanning\nor psychotherapy, attempting to provide reassurance\nusing laparoscopy to exclude serious pelvic pathology,\nhormonal therapy, and neuroablative treatment to interrupt\nnerve pathways\n(44).\nThe treatment of CPP can focus on treating with medical\nor surgical interventions the underlying disease that might\nbe a cause or a contributor to CPP, or on treating the pain\nitself, or on both\n(45).\nDifferent pharmacological profiles and mechanisms to\ninterrupt or decrease the transmission of pain information\nmight be beneficial to decrease pain.\nClinical experience suggests that non-narcotic analge-\nsics, including acetaminophen, acetylsalicylic acid and\nnon-steroidal anti-inflammatory drugs are the first-line\ntherapy for pain relief treating neural and biochemical\npathways of CPP\n(44). The potential of side effects with\nanalgesic drugs, especially with chronic use, are significant,\nand careful observation is important.\nOnly after all other reasonable attempts at pain control\nhave failed and when persistent pain is the major impedi-\nment to improved function, tricyclic antidepressants, sero-\ntonin-noradrenaline reuptake inhibitors, and, as a last\nresort, opioids for CPP should be considered\n(45). Opioids\nare the major category of analgesics with central activity\nused for chronic pain, whereas their use is controversial.\nHowever, in a Cochrane analysis of treatments for CPP,\nonly progestogen therapy such as medroxyprogesterone\nacetate (50 mg once daily) and lysis of severe deep\nF. Sesti et al.34\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press\n\nadhesions were found to be associated with an improved\noutcome(46).\nFinally, a recent pilot study proposed the combination of\npalmitoylethanolamide and polydatin as a support for medi-\ncal therapies to treat CPP associated with endometriosis to\nobtain pain relief and a reduction in the analgesic drugs\nusually employed for the control of pain\n(47). It has been\nreported that palmitoylethanolamide and its derivates play\na role in controlling inflammation associated with mast cell\nactivation, whereas polydatin is a resveratrol with well-\nknown antioxidant and anti-chemotactic activities, as well\nas a regulator of aspecific leucocyte activation\n(48,49).\nDietary therapy\nOn account that potential benefit of medical therapy must\nbe balanced against potential risk, dietary supplementation\nhas been suggested to treat chronic medical illnesses that\nare poorly responsive to prescription drugs or in which\ntherapeutic options are limited, costly or carry a high\nside effect profile\n(50).\nOver the past decade, many studies have provided evi-\ndence that higher intakes of fruit and vegetables, rich in\nantioxidants, among other micronutrients, improve the\nfunction of the immune system and fight free radical\ndamage\n(51).\nIn the USA, dietary supplements are currently governed\nby the Food and Drug Administration under the Dietary\nSupplement Health and Education Act. The act defines a\nsupplement as ‘a product (other than tobacco) intended\nto supplement the diet that bears or contains one or more\nof the following: a vitamin, mineral, herb or other botanical,\namino acid, a dietary substance used by man to supplement\nthe diet by increasing the total dietary intake or a concen-\ntrate, metabolite, constituent, extract or combination of\nany of the ingredients described above’\n(52). Unfortunately,\nthere is a deficit of well-designed, randomised, controlled\ntrials to evaluate the efficacy and safety of complementary\ndietary therapy to manage CPP.\nThere is clear evidence for the effectiveness of n-3 fatty\nacids, vitamin E, vitamin B\n1, vitamin B 3 and Mg in pain\nrelief and the need for less additional medication in\ncyclic pelvic pain by a decreased release of prostaglandins,\nprimarily PGE\n2 and PGF2a, which cause inflammation, pain\nand spastic uterine contractions(53,54).\nInhibitors of COX enzyme function, such as vitamins and\nn-3 fatty acids, can block prostaglandins and thromboxane\nA2 biosynthesis released from plasma membrane phospho-\nlipids by phospholipase A 2 and subsequent downstream\nevents(55). Moreover, oestrogen and progesterone withdra-\nwal leads to the stimulation of PGF 2a production via\nreactive oxygen species-induced NF-kB activation(35).\nSo, manipulation of dietary PUFA composition demon-\nstrably affects the pro-inflammatory activities of many cell\ntypes involved in the immune response and inflammatory\nreactions\n(56).\nPUFA supplementation has important effects on the\nsynthesis and biological activity of prostaglandins and\ncytokines such as IL-1, IL-2, IL-6, TNF and interferon, and\nmight be useful in the management of chronic painful\nsymptoms by reducing the inflammatory response and\nmodulating cytokine network\n(57).\nIn the dynamic structures of the cell membrane, the\nintrinsic structural synergy via ester bonds of fatty acids\nsuch as DHA and EPA, phospholipids and antioxidants in\nthe ‘triple cell membrane synergy’ steadies and increases\nmembrane fluidity, improving its biochemical perform-\nance(58).\nHealthy, non-inflammatory eicosanoid balance is\nmaintained throughout the body by way of a homeostatic\nbalance between n-3 and n-6 fatty acids in cell membranes.\nTable 1 shows n-6:n-3 fatty acid ratios in food.\nIn the presence of high n-6:n-3 PUFA ratios of dietary\nintake, biosynthesis of their metabolites steadies a promi-\nnent production of 2-series prostaglandins (PGE\n2, PGF2a),\nthromboxane A2 and 4-series leucotrienes, which also are\ninvolved in the pathogenesis of pelvic pain, in contrast to\nhigh n-3:n-6 PUFA ratios(56).\nIn addition, PGE 2 is thought to be a potent inducer of\naromatase activity in endometriotic stromal cells. Of note,\nperitoneal macrophages from women with CPP release sig-\nnificantly more prostaglandins.\nLikewise, Mg inhibits the biosynthesis of PGF 2a, as well\nas having a role in myometrial relaxation and vasodilata-\ntion, and vitamin B6 is involved in the production of PGE2.\nMoreover, a diet based on vitamin B, vegetables, fibres\nand antioxidants decreases oestrogenic state-related body\nfat excess implicated in the oestrogen-dependent growth\nof endometriotic tissue(56).\nIn actual fact, dietary supplementation induces enzymes\nof oestradiol metabolism such as the up-regulation of\n17-b-hydroxysteroid dehydrogenase (types 1 and 7) and\nsulfatase; the subsequent defective formation and\nTable 1. Food n-3:n-6 fatty acid ratios\nFood n-3 (g) n-6 (g)\nFatty fish (per 100 g)\nSalmon, fresh or tinned mackerel,\nfresh or smoked herring\n2·2 –\nPressed vegetable oils (per 10 g)\nMaize oil – 5\nSesame oil – 4·5\nSoya oil 0·8 5\nSunflower-seed oil – 6\nLinseed oil or 40 g linseeds 5·8 1·4\nWheat germ oil 0·5 5\nOlive oil – 1\nDried fruit\nShelled walnuts (per 20 g;\nfive medium-sized walnuts)\n1·32 5\nGroundnuts, pistachios or\nalmonds (per 10 g)\n–1\nLegumes\nTinned chick peas (per 100 g) – 2\nDietary therapy and chronic pelvic pain 35\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press\n\nmetabolism of steroid hormones are responsible for the\npromotion and development of endometriosis(59).\nIt may be supposed that nutritional intake has significant\ninfluence whenever there is an imbalance between the pro-\nduction of reactive oxygen species and aberrant expression\nof antioxidant systems, improving painful symptoms, with-\nout undesired effects and any important metabolic changes\nassociated with hormonal therapy\n(54–59) .\nIn this context, a-tocopherol is considered to be the\nmost important vitamin which prevents the peroxidation\nof PUFA\n(60). The mechanism of vitamin E involves\nendogenous arachidonic acid release and its conversion\nto prostaglandins by affecting phospholipase A\n2 and\nCOX. Activation of phospholipase A 2 is considered to be\nregulated by protein kinase C and the increase in the con-\ncentration of intracellular Ca. Vitamin E was found to inhi-\nbit protein kinase C in the bovine brain\n(60). It should be\nused cautiously in women who are on anticoagulants\nbecause vitamin E can have antiplatelet properties and\ndaily intake should be limited to 400 IU or less\n(60,61).\nVitamin E is available as a synthetic (d-I- a-tocopherol,\nalso referred to as a-tocopherol or SRR-tocopherol) formu-\nlation. The natural formulation is more bioavailable\nand, thus, greater in potency by a ratio of 1·36 to 2:1\n(62).\nMoreover, 400 IU of natural vitamin E is not equivalent\nto 400 IU of synthetic vitamin E.\nAt present, only one randomised controlled trial has\nbeen designed to evaluate the effectiveness for the out-\ncomes of chronic painful symptoms and quality of life of\ndietary therapy compared with hormonal suppression\ntreatment or placebo after conservative surgery for sympto-\nmatic endometriosis stage III–IV (Revised American\nFertility Society (r-AFS) classification)\n(63). A total of 222\nconsecutive women who underwent conservative pelvic\nsurgery were initially randomised to receive a placebo,\ntreatment only as a control, or a post-operative adjunctive\nhormonal therapy with gonadotrophin-releasing hormone\nanalogue (GnRH-a) or with continuous low-dose mono-\nphasic oral contraceptive or dietary therapy for 6 months.\nDietary therapy was a protocol consisting of nutritional\nintake in addition to vitamins (vitamins B\n6, A, C, E),\nmineral salts (Ca, Mg, Se, Zn, Fe), VSL3 lactic ferments\n(a compound containingBifidobacterium breve, B. longum,\nB. infantis, Lactobacillus acidophilus, L. casei, L. bulgaricus\nand Steptococcus thermophilus ), and fish oil, giving an\nenergy intake between 1600 and 2000 kcal (6690 and\n8370 kJ). The post-operative hormonal suppression\ntherapy and nutritional supplementation groups had less\nCPP than the control group at 12 months’ follow-up\n(P,0·001). As to the outcome of control pain in the\npatients treated with dietary supplementation, compared\nwith post-operative hormonal therapy, both therapies\nwere similarly effective in reducing painful symptoms.\nSo, agents with antioxidant activity are able to improve\nendometriosis-related symptoms, without undesired\nprolonged hypo-oestrogenism state effects and any import-\nant metabolic change of hormonal suppression therapy.\nMoreover, a recent study suggests that specific types of\ndietary fat such as trans-unsaturated fat are associated\nwith the incidence of laparoscopically confirmed endome-\ntriosis, and that these relationships may indicate modifiable\nrisk\n(64). This evidence additionally provides another dis-\nease association that supports efforts to remove trans-fat\nfrom hydrogenated oils from the food supply.\nSesti et al. provide evidence that post-operative hormo-\nnal and dietary therapies were the most effective treatment,\nnot only in terms of painful symptoms control, but also in\nterms of general health perception and vitality, when\ncompared with post-operative placebo administration\n(63).\nConversely, the same authors showed that a 6-month\ncourse of dietary therapy or hormonal suppression treat-\nment after laparoscopic cystectomy had no significant\neffect on the recurrence rate of ovarian endometriosis\nwhen compared with surgery plus placebo\n(65). Further\nrandomised trials with larger series and long-term follow-\nup to confirm these observations are needed.\nConclusions\nCPP is a prevalent problem in women with healthcare costs\nassociated. Women who suffer from CPP are a hetero-\ngeneous group, and the possible diagnosis, treatment and\ncontributing factors are varied and complex.\nAfter looking for the most common causes and ruling\nout serious disease, the approach of treating either the\nunderlying condition or the pain itself or both is effective.\nIt allows the use of pain-directed therapies that, albeit not\ncurative, permit the patient to progress toward a more sat-\nisfactory quality of life that is not dominated by pain.\nIn every case, a multidisciplinary and integrative approach\nmay offer expanded therapeutic solutions that are ben-\neficial for some outcome measures.\nAt present, the experience of medical or surgical inter-\nventions for treating CPP is expansive; however, random-\nised controlled trials performed to evaluate other medical\ninterventions are few and unsatisfactory. In this context,\ndietary supplements with antioxidants could be considered\nas a new effective strategy in the long term for CPP; these,\nnot being limited in their use by time, can be used in long-\nterm therapy and may be better accepted by patients.\nSo, it is to be hoped that urgently required research in\nthe future will identify complementary therapies and evalu-\nate their efficacy in treating CPP.\nAcknowledgements\nThis research received no specific grant from any funding\nagency in the public, commercial or not-for-profit sectors.\nThe contribution of each author to the paper was as fol-\nlows: F. S. was involved in study design and in drafting of\nthe manuscript; T. C. was involved in the review of the\nF. Sesti et al.36\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press\n\nliterature and writing of the manuscript; A. P. was involved\nin English language and style revision; M. 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Sesti et al.38\nNutrition Research Reviews\nhttps://doi.org/10.1017/S0954422410000272 Published online by Cambridge University Press","source_license":"CC0","license_restricted":false}