{"paper_id":"54b42161-b499-4dff-945e-54e8f12d88f2","body_text":"7 \nKosin Medical Journal 2013;28:7 -12.\nhttp://dx.doi.org/10.7180/kmj.2013.28.1.7 KMJ\nReview Article\nNutritional Treatment: New Strategy for Management of Chronic\nPelvic Pain\nJong Soon Choi 1, Heung Yeol Kim 2 \n1Department of Family Medicine, College of Medicine, Kosin University, Busan, Korea\n2Department of Obstetrics and Gynecology, College of Medicine, Kosin University, Busan, Korea\nChronic pelvic pain is a common condition in women of reproductive a ge and can be described as chronic nociceptive,\ninflammatory and neuropathic pain characterized by spontaneou s pain or a response to various stimuli. Oxidative stress\nis a component of the inflammatory reaction as sociated with pain processes. Iron and NF- κB are well-known inducers o f\noxidative stress, and reactive ox ygen species (ROS) are associated with chronic pelvic pain and play an important role in\nthe regulation of genes expressing immuno regulators, cytokines, and other molecules.  Chronic pelvic pain treatment is often\nunsatisfactory and limited to symptom control. However, diet ary treatment with antioxidants  can improve the function o f\nthe immune system and overcome free radical damage. Therefor e, dietary supplementation is suggested as a means to trea t\nsome chronic medical conditions that respond poorly to medication. In summar y, dietary treatment with antioxidants could\nbe considered for new strategy for treatment of chronic pelv ic pain and may be better tolerated by patients than curren t\ntreatments.\nKey Words: Antioxidant, Chronic pelvic pain, Inflammation, Oxidative stress\nCorresponding Author: Heung Yeol Kim, Department of Obstetrics and Gynecology, College of Medicine, \nKosin University, 34 Amnamdong, Seo-gu, Busan, 602-702, Korea\nTEL: +82-51-990-6226  FAX: +82-51-990-3300  E-mail: hykyale@yahoo.com\nReceived:\nRevised:\nAccepted:\nJuly 18, 2012\nJuly 22, 2012\nAugust 17, 2012\nChronic pelvic pain (CPP) is a common condition \nin women of reproductive age; rates of consultation \nfor CPP in general practice are similar to those for \nasthma and migraine.\n1 CPP can be identified as a \nconstellation of chronic inflammatory processes from \nvarious stimuli, such as oxidative stress, toxins, and \nchemicals. To treat CPP, a multidisciplinary approach \nto care and management produces the best results.\n2 \n  Hydroxyl radicals are the most reactive free radical \nspecies known. They have the ability to react with \na wide range of cellular constituents such as amino \nacid residues and purine and pyrimidine DNA bases \nto initiate a free radical chain reaction. Oxidative \nstress has been proposed as a potential factor that may \nbe involved in endometriosis,\n3 a  c h r o n i c  p e l v i c  \ninflammatory process. Two inflammatory mediators \nthought to be involved in CPP are iron and NF-kB.\n  The purpose of this article was to show that dietary \ntreatment with antioxidants improves the function of \nthe immune system and fights free radical damage. \nAgents with antioxidant activity may relieve CPP \nwithout side effects. Therefore, using nutrition \ntreatments such as dietary antioxidants (magnesium, \nvitam in D) m ay prove beneficial for CPP control.\n\u0012\u000f\u0001%FGJOJUJPO\n  CPP is a common disease in women of reproductive \nage; it causes disability and distress and also results \ni n  s i g n i f i c a n t  c o s t s  t o  h e a l t h  s e r v i c e s .\n4 T h e  m o s t  \ncommonly used definition of CPP considers only the \n\nKosin Medical Journal 2013;28:7-12.\n8\nlocation and duration of the pain: recurrent or \nconstant pain in the lower abdominal region that has \nlasted for at least six m onths. \n  C P P  c a n  b e  i d e n t i f i e d  a s  a  c h r o n i c  n o c i c e p t i v e ,  \ninflammatory and neuropathic pain characterized by \nspontaneous appearance and a response to painful, \ninnocuous stimuli.\n5 \n  CPP is a diagnostic and management challenge that \nrequires a multisystem approach. This condition may \nhave a single cause or multiple causes, and some \nwomen never receive a definitive diagnosis. CPP is \nalso associated with psychological conditions how-\never, the establishment of psychosocial factors as \ncause or effect of the pain is difficult.\n\u0013\u000f\u0001$VSSFOU\u0001USFBUNFOU\u0001BQQSPBDI\u0001PG\u0001$11\n  According to one study, the current treatment \napproach is counseling supported by ultrasound \nmonitoring, psychotherapy, laparoscopy to exclude \nserious pelvic pathology, hormonal therapy, and \nneuroablative treatment to interrupt nerve pathways.\n5 \nAnother report indicated that management includes \ncounseling or psychotherapy, attempting to provide \nreassurance using laparoscopy to exclude serious \npathology, progestogen therapy (such as m edroxy-\nprogesterone acetate), and surgery to interrupt nerve \npathways.\n4\n  Laparoscopic surgery and treatment with medroxy-\nprogesterone acetate, danazol or nafarelin were more \ne f f e c t i v e  t h a n  c o n t r o l  t r e a t m e n t s .  M e d i c a l  t h e r a p y  \nafter surgical treatment significantly reduced pain, but \nsix months after therapy was stopped there was no \ndifference between women who were treated and those \nw ho were not treated postoperatively.\n6\n  Because CPP treatment is often unsatisfactory and \nlimited to partial symptom relief, we suggest dietary \nsupplementation as a means to treat chronic medical \nillnesses that respond poorly to prescription medica-\ntions. Dietary therapy with antioxidants improves the \nfunction of the immune system and fights free radical \ndamage. Another advantage is that antioxidants can \nimprove CPP without side effects.\n\u0014\u000f\u0001&GGFDU\u0001PG\u0001PYJEBUJWF\u0001TUSFTT\n  Hydroxyl radicals are the most reactive free radical \nspecies known and have the ability to react with a \nwide range of cellular constituents, such as amino acid \nr e s i d u e s  a n d  p u r i n e  a n d  p y r i m i d i n e  D N A  b a s e s  t o \ninitiate a free radical chain reaction known as lipid \nperoxidation. Oxidative stress has been proposed as \na potential factor involved in endometriosis.\n3\n  ROS are intermediate species produced by normal \noxygen metabolism. To protect themselves from ROS, \ncells have developed a wide range of antioxidant \nsystems to inactivate ROS, limit ROS production, and \nrepair cell damage.\n  Univalent reduction of oxygen results in production \no f  t h e  s u p e r o x i d e  a n i o n .  T h e  d i s m u t a t i o n  o f  t w o  \nsuperoxide anions, catalyzed by superoxide dismutase, \nleads to the formation of hydrogen peroxide. Hydro-\ngen peroxide is detoxified by glutathione peroxidase \nor inactivated to H20 and O2. Optimal protection is \nachieved only when an appropriated balance among \nsuperoxide dismutase, glutathione peroxidase, and \ncatalase is maintained. The hydroxyl radical is highly \ntoxic to cells asit can react with all cellular com-\nponents.\n  T he  bo dy’s antioxidative system includes enzymatic \nantioxidants such as catalase, SOD, glutathion peroxi-\ndase, thioredoxin reductase, G. reductase, G.S- \ntransferase, and G6PD. Nonenzymatic antioxidants \nare known as endogenous antioxidants (glutathion- \n\nNutritional Treatment: New Strategy for Management of Chronic P elvic Pain\n9 \nSH, cysteine-SH, bilirubin, uric acid, lipoic acid, \ncoenzyme Q10) while exogenous antioxidants include \nvitamins C and E, beta-carotene, lycopene, selenium, \ncopper, zinc, and magnesium.\n  Oxidative stress may occur when the balance \nbetween ROS production and antioxidant defense is \ndisrupted. The increasing number of diseases associa-\nted with oxidative stress suggests that the oxidative \nbalance may be precarious.\n7 Overexpression of ROS \ninduces cellular damage and impairs cellular function \nby altering protein activity and gene expression. ROS \nare important in regulating redox-sensitive transcrip-\ntion factors implicated in endometriosis.\n8 Oxidative \nstress occurs in endometriosis via expression of \nxanthine oxidase, an enzyme that produces ROS.\n9\n  Two inflammatory mediators have been identified: \niron and NF-kB. Iron can generate free radical species \nthat are able to react with a wide range of cellular \nconstituents, thus inducing cellular damage. Overpro-\nduction of ROS impairs cellular function by altering \ng e n e  e x p r e s s i o n  v i a  r e g u l a t i o n  o f  r e d o x - s e n s i t i v e  \ntranscription factors such as NF-kB. Iron overload \nprovokes iron-mediated damage, oxidative injury, and \ninflammation.\n10 I r o n  i s  k n o w n  t o  i n d u c e  o x i d a t i v e  \nstress, leading to macromolecular oxidative damage, \ntissue injury and chronic inflammation. Iron was \nrecently suggested to be involved in endom etriosis \ndevelopment. Oxidative stress and proinflammatory \ncytokines are potent activators of the NF-kB \npathway.\n11 NF-kB activation leads to expression of \np r o i n f l a m m a t o r y  g e n e s  l i k e  c y t o k i n e s ,  w h i c h  m a y  \nprovide positive feedback to the pathway. Inflamma-\ntory cytokines (interleukin-1,6, TNF-alpha) are in-\ncreased and activated in endometriosis patients.\n12 \nNF-kB is activated by diverse proinflammatory \nstimuli such as tumor necrosis factor (TNF)-alpha, \nLPS, and oxidative stress, and may lead to multiple \ngenes implicated in inflammation, immunity, \napoptosis, cell proliferation, tissue invasion and \nangiogenesis.\n\u0015\u000f\u00017JUBNJO\u0001%\u0001BOE\u0001QFMWJD\u0001QBJO\n  Vitamin D is a lipid-soluble micronutrient produced \nin the skin when provitamin D (7-dehydrocholesterol) \nin cell membranes is exposed to ultraviolet B rays \nand converted into cholecalciferol (D3). Circulating \nD3 is then bound by vitamin D binding protein and \ntransported in serum to be stored in adipose tissue \nor delivered to the liver, where it is converted to \n25-hydroxyvitamin D2 [25 (OH)D]. This metabolite \nis referred to as the total 25 (OH)D and is measured \nin most clinical studies. The 25-hydroxyvitamin D2 \nis then activated by conversion to calcitriol in the \nkidney. Synthesis of 25 (OH)D and 1,25 (OH)2D3 is \ncoupled with calcium homeostasis. Serum levels of \nvitamin D are regulated by parathyroid hormone, \nphosphorus, and calcium  levels.\n  Vitamin D is a micronutrient vital in calcium \nhomeostasis levels and musculoskeletal function. \nVitamin D insufficiency shows clinical signs of rickets \nand osteomalacia. The pelvic floor is a unique part \no f  t h e  b o d y ,  a n d  i t s  f u n c t i o n  i s  d e p e n d e n t  o n  \ninterrelationships between muscle, nerve, connective \ntissue, and bone. Pelvic floor disorders result when \nthese relationships are disrupted. \n  Pelvic floor muscle weakness is clinically observed \nin women with pelvic floor disorder symptoms and \nmay be impacted by insufficient serum vitamin D \nlevels. Sufficient vitamin D serum levels may facilitate \nan increase in pelvic floor muscle efficiency and a \ndecrease in detrusor contractibility. Vitamin D \nregulates inflammatory cytokine levels,\n13 and calci-\n\nKosin Medical Journal 2013;28:7-12.\n10\ntriol also stimulates antioxidant gene expression in \na dose-response manner, making it a potential target \nas a pharm acologic pro-oxidant.\n14\n  Vitamin E levels are also significantly lower in the \nperitoneal fluid of women with endometriosis because \nantioxidants in peritoneal fluid are consumed during \noxidation reactions. Vitamin E plays an important role \nin protecting biological membranes by preventing \nperoxidation. It may also help prevent activation of \nredox-sensitive pathways, which have been implica-\nted in abnormal cell proliferation and inflammatory \nresponses.\n15\n  Free radical scavengers, such as vitamin C and E, \nneutralize free radicals in chronic inflammatory \ndisease.\n\u0016\u000f\u0001.BHOFTJVN\u0001BOE\u0001QFMWJD\u0001QBJO\n  Magnesium was recognized as an essential nutrient \nin mice in 1932,\n16 a n d  w a s  a l s o  a c c e p t e d  a s  a n  \nimportant nutrient in humans.17 Magnesium deficiency \nis not uncommon among the general population. Its \nintake has decreased over the years, especially in the \nWestern world.\n18 Low magnesium status has been \nassociated with numerous pathological conditions \ncharacterized as having a chronic inflammatory stress \ncomponent. Recently, magnesium deficiency was \nsuggested as a risk factor in some chronic diseases, \nsuch as osteoporosis, cardiovascular disease, and \ndiabetes. Magnesium deficiency is now considered to \ncontribute to chronic diseases, and the role of \nmagnesium as a therapeutic agent is being tested in \nnumerous large clinical trials. For example, recent \nresearch showed that lower serum magnesium (Mg) \nlevels are associated with chronic kidney disease.\n19\n  Hypomagnesemia was reported to promote endo-\nthelial cell dysfunction, leading to inflammation and \noxidative stress.\n20 Magnesium sulfate administration \ninhibits placental inflammation during LPS-mediated \nmaternal infection and attenuates excessive inflam-\nmation at the maternal-fetal interface. Several pla-\ncental inflammatory genes which are regulated by LPS \nwere silenced by magnesium sulfate treatment.\n21 In \nrats, magnesium deficiency over only a few days \ninduced a clinical inflammatory syndrome charac-\nterized by macrophage activation, release of infla-\nmmatory cytokines and acute phase proteins, and \nexcessive production of free radicals. When magne-\nsium concentration was increased, the inflammatory \nresponse decreased. Thus, reduction in the extra-\ncellular magnesium resulted in cell activation.\n22\n  Therefore, since magnesium reduces inflammatory \nsyndromes and inhibits oxidative stress. magnesium \nsupplementation can be beneficial in treatment of \nchronic diseases such as chronic pelvic pain.\n\u0017\u000f\u00017JUBNJO\u0001&\u0001BOE\u0001QFMWJD\u0001QBJO\n  Vitamin E levels are significantly lower in the \nw o m e n  w i t h  e n d o m e t r i o s i s  b e c a u s e  a n t i - o x i d a n t s  \nconsumed during oxidataion reactions.\n23,24 P a t i e n t s  \nwith endometriosis not only presented increased lipid \nperoxidation but also maintained lower vitamin E \nlevels than the control group.\n25 Vitamins C and E \nsupplementation was associated with a decrease in the \nconcentration of oxidative stress markers in women \nwith endometriosis.\n26 \n  Vitamin E have important action in protecting \nbiological membranes by preventing peroxidation. It \nmay also play a role in preventing activation of \nredox-sensitive pathways, which implicated in \nabnormal cell proliferation and inflammatory \nresponse.\n\nNutritional Treatment: New Strategy for Management of Chronic P elvic Pain\n11 \nCONCLUSION\n  CPP can be identified as a group of chronic in-\nflammatory processes resulting from various stimuli, \nsuch as oxidative stress, toxins, or chemicals. Current \ntreatment approaches include counseling supported by \nultrasound monitoring, psychotherapy, and laparo-\nscopy to exclude serious pelvic conditions. Recently, \ndietary therapy studies have suggested that antioxi-\ndants improve the function of the immune system and \nfight free radical damage. Vitamin D in particular \nregulates inflammatory cytokine levels calcitriol also \nstimulates antioxidant gene expression because pelvic \nf l o o r  d i s o r d e r  s y m p t o m s  m a y  b e  i m p a c t e d  b y  i n -\nsufficient serum vitamin D.\n  Hypomagnesemia was reported to induce endo-\nthelial cell dysfunction and lead to inflammation and \noxidative stress. Therefore, magnesium supplementa-\ntion can be beneficial in chronic diseases, such as CPP. \nIn conclusion, dietary therapy with antioxidants could \nb e  c o n s i d e r e d  a s  a  n e w  e f f e c t i v e  s t r a t e g y  i n  t h e  \nlong-term management of chronic pelvic pain.\nREFERENCE\n 1. Cheong Y, William Stones R. Chronic pelvic pain: aetiology \nand therapy. Best Pract Res Clin Obstet Gynaecol 2006;20: \n695-711.\n 2. Gelbaya TA, El-Halwagy HE. Focus on primary care: chronic \npelvic pain in women. Obstet Gynecol Surv 2001;56:757-64.\n 3. Gupta S, Agarwal A, Sekhon L, Krajcir N, Cocuzza M, Falcone \nT. Serum and peritoneal abnormalities in endometriosis: \npotential use as diagnostic markers. Minerva Ginecol 2006;58: \n527-51.\n 4. Stones RW, Mountfield J. Interventions for treating chronic \npelvic pain in women. Cochrane Database Syst Rev 2000;4: \nCD000387.\n 5. Sesti F, Capozzolo T, Pietropolli A, Collalti M, Bollea MR, \nPiccione E. Dietary therapy: a new wtrategy for management \nof chronic pelvic pain. Nutr Res Rev 2010;25:1-8.\n 6. Howard FM. An evidence-based medicine approach to the \ntreatment of endometriosis-associated chronic pelvic pain: \nplacebo-controlled studies. J Am Assoc Gynecol Laparosc \n2000;7:477-88.\n 7. Hippeli S, Elstner EF. Transitional metal ion-catalyzed oxygen \nactivation during pathogenic processes. FEBS Lett 1999;443: \n1-7.\n 8. Guo SW, Nuclear factor-kappa b (NF-κB): an unsuspected major \nculprit in the pathogenesis of endometriosis that is still at large? \nGynecol Obstet Invest 2007;63:71-97.\n 9. Ota H, Igarashi S, Tnaka T. Xanthine oxidase in eutopic and \nectopic endometrium in endometriosis and adenomyosis. Fertil \nSteril 2001;75:785-90.\n10. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after \nintracerebral haemorrhage. Lancet Neurol 2006:5:53-63.\n11. Lousse JC, Van Langendonckt A, González-Ramos R, Defrère \nS, Renkin E, Donnez J. Increased activation of nuclear \nfactor-kappa B (NF-kappaB) in isolated peritoneal macrophages \nof patients with endometriosis. Fertil Steril 2008;90:217-20.\n12. Montagna P, Capellino S, Villaggio B, Remorgida V, Ragni \nN, Cutolo M, et al. Peritoneal fluid macrophages in endome-\ntriosis: correalation between the expression of estrogen receptors \nand inflammation. Fertil Steril 2008;90:156-64.\n13. Liu NQ, Kaplan AT, Lagishetty V, Ouyang YB, Ouyang Y, \nSimmons CF, et al. Vitamin D and the regylation of placental \ninflammation. J Immunol 2011;186:5968-74.\n14. Halhali A, Figueras AG, Díaz L, Avila E, Barrera D, Hernández \nG, et al. Effects of calcitriol on calbindins gene expression \nand lipid peroxidation in human placenta. J Steroid Biochem \nMol Biol 2010;121:448-51.\n15. Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative \nstress and peritoneal endometriosis. Fertil Steril 2002;77:861-70.\n16. Kruse HD, Orent ER, McCollum EV. Studies on magnesium \ndeficiency in animals: I. Symptomatology resulting from Mg \ndeprivation. J Biol Chem 1932;96:519-39.\n17. Haury VG, Cantarow A. Variations of serum magnesium in \n52 normal and 440 pathologic patients. J Lab Clin Med 1942; \n27:616-22.\n18. Saris NE, Mervaala E, Karppanen H, Khawaja JA, Lewenstam \nA. Magnesium. An update on physiological, clinical and \nanalytical aspects. Clin Chim Acta 2000;294:1-26.\n19. Kanbay M, Goldsmith D, Uyar ME, Turgut F, Covic A. \nMagnesium in chronic kidney disease: challenges and \nopportunities. Blood Purif 2010;29:280-92.\n\nKosin Medical Journal 2013;28:7-12.\n12\n  Peer Reviewers' Commentary\n  Chronic pelvic pain is a common condition in women of reprodu ctive age and can be described as chronic nociceptive, \ninflammatory and neuropathic pain characterized by spontaneous pain or a response to various stimuli. Oxidative \nstress is a component of the inflammatory reaction associated w ith pain processes. Iron an d NF-κB are well-known \ninducers of oxidative stress, and reactive oxygen species (ROS)  are associated with chronic pelvic pain and play \nan important role in the regulation of genes expressing immunor egulators, cytokines, and other molecules. Chronic \npelvic pain treatment is often unsatisfactory and limited to sy mptom control. However, dietary treatment with antioxidants \ncan improve the function of the immune system and overcome free  radical damage. Therefore, dietary supplementation \nis suggested as a means to treat  some chronic medical condition s that respond poorly to medication. In this review, \ndietary treatment with antioxida nts could be considered for new  strategy for treatment of chronic pelvic pain and \nmay be better tolerated by patients than current treatments.\n(Comment: Editorial Committee)\n20. Chaumais MC, Lecerf F, Fattal S, Savale L, Günther S, Huertas \nA, et al. A study of magnesium deficiency in human and \nexperimental pulmonary hypertension. Magnes Res 2012;25: \n21-7.\n21. Dowling O, Chatterjee PK, Gupta M, Tam Tam HB, Xue X, \nLewis D, et al. Magnesium sulfate reduces bacterial LPS- \ninduced inflammation at the maternal-fetal interface. Placenta \n2012;33(5):392-8.\n22. Rayssiguier Y, Mazur A. Magnesium and inflammation: lessons \nfrom animal models. Clin Calcium 2005;15:245-8.\n23. Murphy AA, Santanam N, Parthasarathy S. Endometriosis: a \ndisease of oxidative stress?. Semin Reprod Endocrinol 1998;16: \n263-73.\n24. Murphy AA, Santanam N, Morales AJ, Parthasarathy S. Lyso-\nphosphatidyl choline, a chemotactic factor for monocytes/ \nT-lymphocytes is elevated in endometriosis. J Clin Endocrinol \nMetab 1998;83(6):2110-3.\n25. Campos Petean C, Ferriani RA, dos Reis RM, de Moura MD, \nJordão AA Jr, Navarro PA. Lipid peroxidation and vitamin E \nin serum and follicular fluid of infertile women with peritoneal \nendometriosis submitted to controlled ovarian hyperstimulation: \na pilot study. Fertil Steril 2008;90:2080-5.\n26. Mier-Cabrera J, Genera-García M, De la Jara-Díaz J, Perichart- \nPerera O, Vadillo-Ortega F, Hernández-Guerrero C. Effect of \nvitamins C and E supplementation on peripheral oxidative stress \nmarkers and pregnancy rate in women with endometriosis.Int \nJ Gynaecol Obstet 2008;100:252-6.","source_license":"CC0","license_restricted":false}