Chronic pelvic pain: mastcells, medical and psychological ... · Chronic pelvic pain: mastcells, medical and psychological comorbidity Alessandra Graziottin MD Center of Gynecology

Chronic pelvic pain:mastcells,

medical and psychological comorbiditycomorbidity

Alessandra Graziottin MDCenter of Gynecology and Medical Sexology H. San Raffaele Resnati, Milan, Italy

www.alessandragraziottin.itwww.alessandragraziottin.it

DISCLOSURE• Speakers ’ bureau:

Bayer, Biotest, Epitech, Janssen-Cilag, Pantarhei, Sanofi, Valeas

• Advisory Boards :• Advisory Boards :Bayer, Janssen -Cilag , Novonordisk , Theramex , Valeas

• Consultant :Bayer , Epitech , Theramex

Question 1.

Chronic Pelvic Pain

What is the new evidence What is the new evidence on the common

biological correlates of chronic pelvic pain

and inflammation?

NEUROGENIC (“ NOCICEPTIVE”)

NEUROGENIC (“ NOCICEPTIVE”)

SOMATIC

VISCERAL

SUPERFICIAL

DEEP

Classification of Pain

NEUROPATHICNEUROPATHIC

PAINVISCERAL

PERIPHERAL

CENTRALBonica, 1993; Melzack & Wall, 2000;

Turk et Al, 2001; Behrman et Al, 2006; Bernardes et al, 2007 A.Graziottin, 2011

Pain perception in womencontributing factors

Biological factorsPAIN: severity of tissue damageneurological, mucocutaneous, vascularmuscular, endocrineimmunitaryimmunitary

Contextual factors•quality of family support•socioeconomic level•working conditions•social acceptance or not

•meaning of pain

Psychologicalfactors•fear of pain and its meaning•coping strategies•psychosexual history•body image

A.Graziottin, 2010

Bonica, 1993; Melzack & Wall, 2000; Turk et Al, 2001; Behrman et Al, 2006; Graziottin, 2000, 2006; Latthe et al, 2006, Graziottin, 2010

NonNon--cyclical chronic pelvic pain: risk factorscyclical chronic pelvic pain: risk factors-- a meta analysis a meta analysis --

PallaviPallavi LattheLatthe etet Al, Al, FactorsFactors predisposingpredisposing women women toto chronicchronic pelvicpelvic painpain: : systematicsystematic reviewreviewBMJ 332; 74BMJ 332; 74--755, 2006755, 2006

NonNon--cyclical chronic pelvic pain: risk factorscyclical chronic pelvic pain: risk factors-- a meta analysis a meta analysis --

Pallavi Latthe et Al, Factors predisposing women to chronic pelvic pain: systematic review Pallavi Latthe et Al, Factors predisposing women to chronic pelvic pain: systematic review BMJ 332; 74BMJ 332; 74--755, 2006755, 2006

Anxiety and depression

Type of pain Anxiety Depression

Dysmenorrhea OR=2.77 OR=2.59Non Non sensuality:OR=8.12

Dyspareunia OR=3.23 OR=7.77

CPP OR=2.28 OR=2.69PTSD=OR 5.47

Psychosomatic=8.01Pallavi Latthe et Al, Factors predisposing women to chronic pelvic pain: Pallavi Latthe et Al, Factors predisposing women to chronic pelvic pain: systematic review BMJ 332; 74systematic review BMJ 332; 74--755, 2006755, 2006

A.Graziottin, 2006

The protagonists of the Chronic Pelvic Pain

scenarioChronicChronic

inflammationinflammation

PeripheralPeripheral NervousNervousSystem System PAINPAIN

CentralCentral NervousNervousSystemSystem

EndometriosisEndometriosis

WhoWho isis the the directordirectorofof the the painpain orchestra ?orchestra ?

The The mastmast--cellcellisis the the powerfulpowerful protagonistprotagonistbehindbehind the the clinicalclinical scenarioscenarioofof inflammationinflammation and and painpain

Picture: Picture: CourtesyCourtesy ofof R. Della ValleR. Della Valle

More More thanthan 45.000 45.000 paperspapers (!) (!) creditcreditthe the mastcellmastcell toto bebe the the directordirector

ofof the the chronicchronic inflammationinflammation orchestraorchestra

THE UPTHE UP--REGULATED MASTCELLREGULATED MASTCELLMenstrualMenstrual bloodblood

in the in the tissuetissue

NeurogenicNeurogenic stimulusstimulus& & neurotrophicneurotrophic changeschanges

x 52x 52--58% 58% enlargementenlargementofof peripheralperipheral neuronsneurons

x 10 x 10 ProliferationProliferation ofof painpain fibersfibersBornsteinBornstein, 2001, 2004, 2008; , 2001, 2004, 2008; BohmeBohme--starkestarke, 1998, 2001 , 1998, 2001

Mechanical traumaMechanical traumaIntercourseIntercourse!!!!!!

Chemical &Chemical &physical noxaephysical noxae

EstrogensEstrogens AgonistAgonist

A.GraziottinA.Graziottin, 2005, 2005

VasoactiveVasoactivefactorsfactors

HystamineHystamine

BradychinineBradychinine

SerotonineSerotonine

NERVE GROWTH NERVE GROWTH FACTOR (x 50!)FACTOR (x 50!)

Dupont et Al, 2001Dupont et Al, 2001

InfectionsInfections

AgonistAgoniststimulistimuli

FromFrom inflammationinflammation toto chronicchronic painpain

Acute Acute inflammationinflammation healinghealing RestitutioRestitutio ad ad

integrumintegrum

PersistencePersistence or or recurrencerecurrence ofoffactorsfactors causingcausing tissuetissue damagedamage

and and inflammationinflammation

NociceptiveNociceptivepainpain

RegulatedRegulatedMastcellMastcell

UpUp--regulatedregulatedMastcellMastcell ModulationModulationand and inflammationinflammation

ChronicChronic tissuetissue inflammationinflammationUpUp--regulatedregulated mastcellsmastcells

ChronicChronicpainpain

NeuropathicNeuropathicpainpain

A.GraziottinA.Graziottin, 2010, 2010DepressionDepression

MastcellMastcell ModulationModulationofof

mastcellsmastcellsisis keykey

The The interactioninteractionbetweenbetween mastcellsmastcellsand and nervenerve fibersfibersisis the the biologicalbiological

prerequisiteprerequisite ofof the the

CortesyCortesy ofof di di R.dellaR.della Valle, 2007Valle, 2007

prerequisiteprerequisite ofof the the shiftshift fromfrom acute acute toto

chronicchronicneuropathicneuropathic painpain

NAKANISHI and FURUNO. NAKANISHI and FURUNO. Cellular & Molecular Immunology Cellular & Molecular Immunology 20082008

TimeTime--coursescourses ofof FluoFluo--33 fluorescencefluorescence

intensityintensity changeschanges inin RBLsRBLs andand inin SCGSCG

neuritesneurites.. AnAn arrowarrow indicatesindicates thethe timetime

pointpoint ofof bradykininbradykinin additionaddition..

NerveNerve--inducedinduced mastmast cellcell activationactivation..

DifferentialDifferential interferenceinterference contrastcontrast imageimage andand

sequentialsequential CaCa22++ imagesimages afterafter thethe additionaddition ofof

bradykininbradykinin (time(time == 00)) inin thethe SCGSCG--RBLRBL coco--

cultureculture..

NAKANISHI and FURUNO. NAKANISHI and FURUNO. Cellular & Molecular Immunology Cellular & Molecular Immunology 20082008

TimeTime--coursescourses ofof FluoFluo--33 fluorescencefluorescence intensityintensity

changeschanges inin RBLsRBLs andand inin SCGSCG neuritesneurites.. AnAn arrowarrow

indicatesindicates thethe timetime pointpoint ofof antigenantigen additionaddition..

MastMast cellcell--inducedinduced neuriteneurite activationactivation.. RepresentativeRepresentative DICDIC imageimage

andand sequentialsequential CaCa22++ imagesimages afterafter thethe additionaddition ofof antigenantigen (time(time ==

00)) inin thethe SCGSCG--RBLRBL coculturecoculture.. ArrowheadsArrowheads indicateindicate thethe neuriteneurite

whichwhich isis stronglystrongly activatedactivated..

CROSSCROSS--TALKTALK

CENTRAL CENTRAL SENSITIZATIONSENSITIZATION CHRONIC MASTCHRONIC MAST--CELL CELL

UPUP--REGULATIONREGULATION

ACTIVATEDMICROGLIA

FIRST NEURON

SECONDNEURON

ChronicChronic NeuropathicNeuropathicPelvicPelvic PainPain -- CPPCPP

NERVE LESIONNERVE LESION

Milligan ED & Watkins LR_2009 Nature Rev Neurosci.10(1):23-36

A.Graziottin, 2011

DepressionDepression

NEUROPLASTICITYNEUROPLASTICITY NEUROTOXICITYNEUROTOXICITY

PathwayPathway fromfrom InflammationInflammation totoDepressionDepression


PSYCHOGENIC STIMULIPSYCHOGENIC STIMULISPINALSPINAL--CORD CORD NEUROINFLAMMATIONNEUROINFLAMMATION

Blood-brain barrier

Neuroprotectivemicroglia

Activatedmicroglia

McNally L et al Review Article_2008 CNS Spectr.13(6):501-510

Conclusion 1

•The mast-cell is the director of the inflammatory process

•There is a close dialogue between mastcells and pain fibers

•They are intimately connected and use a common language: neurotransmitters and cytochines in the tissue and in the spinal cord/brain

Question 2.

Chronic Pelvic Pain

and mastcellsand mastcellsWhat is the evidence

on the key role of Mastcells in

chronic pelvic pain syndromes?

Chronic Pelvic Pain: Medical & sexual comorbidities

deep dyspareunia Endometriosis dysmenorrhea

infertility

Pelvic inflammatory disease infertilitydeep dyspareuniadeep dyspareunia

Vulvar vestibulitis introital dyspareunia

vulvodynia post-coital cystitis

Interstitial cystitis bladder pain, dysuria introital dyspareunia

Irritable bowel syndrome abdominal pain dyspareunia

www.fondazionegraziottin.orgwww.fondazionegraziottin.org

Heterogeneity of CPP.

Predictors of CPP include different factors:• Biological: endometriosis, PID, CS, pelvic adhesions • Affective: anxiety, depression, PTSD, Psychosomatic• Context dependent: sexual and emotional abuse

Comorbidity is frequent and underdiagnosed


What is the common denominatorof chronic pelvic pain?

CHRONIC INFLAMMATIONCHRONIC INFLAMMATIONMediatedMediated byby the MASTthe MAST--CELLSCELLS

and and hyperactivationhyperactivation ofof painpain fibersfibers

AnafAnaf etet al; al; FertilFertil SterilSteril 20062006

ObjectiveObjective: : To detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating To detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating

endometriosis and to study the relationship between mast cells and nerves in endometriosis and to study the relationship between mast cells and nerves in

endometriosis.endometriosis.

TryptaseTryptase--Positive Mast Cells CountPositive Mast Cells Count

Anaf et al; Fertil Steril 2006Anaf et al; Fertil Steril 2006

Number of Number of degranulatingdegranulating Mast Cells/mmMast Cells/mm22



Mast Cells Located < 25 µm from Nerve StructuresMast Cells Located < 25 µm from Nerve Structures

WangWang,, HumanHuman Reproduction,Reproduction, 20092009

ThereThere werewere significantlysignificantly moremore nervenerve fibresfibres inin

DIEDIE ((6767..66++6565..11/mm/mm22)) thanthan inin peritonealperitoneal

endometrioticendometriotic lesionslesions ((1616..33++1010..00/mm/mm22)) (P(P ,,

00..0101))..

DIEDIE waswas innervatedinnervated abundantlyabundantly byby sensorysensory

AAγγ,, sensorysensory C,C, cholinergiccholinergic andand adrenergicadrenergic

nervenerve fibresfibres;; NGF,NGF, TrkTrk--AA andand pp7575

werewere stronglystrongly expressedexpressed inin endometrioticendometriotic

glandsglands andand stromastroma ofof DIEDIE..

MastcellsMastcells in in endometriosisendometriosisConclusionsConclusions

The presence of increased activated The presence of increased activated and and degranulatingdegranulating mast cells mast cells

in deeply infiltrating endometriosis in deeply infiltrating endometriosis and the close histological relationship and the close histological relationship

between mast cells and nerves between mast cells and nerves between mast cells and nerves between mast cells and nerves strongly suggest that mast cells strongly suggest that mast cells

could contribute to the development of pain could contribute to the development of pain and and hyperalgesiahyperalgesiain endometriosis, in endometriosis,

possibly by a direct effect on nerve structures. possibly by a direct effect on nerve structures.

Mastcellsand Vulvar Vestibulitis

The chronically damaged introital tissueactivates the up -regulation of the :• mastcells, with increased production of pain factors and • mastcells, with increased production of pain factors and

NGF • nervous/pain system leading to vestibulitis/vulvodynia• muscular system, with defensive contraction of the

levator ani and myalgia

BertolasiBertolasi etet Al, 2004; Al, 2004; BohmeBohme--StarkeStarke etet Al, 1998, 2000, 2001;Al, 1998, 2000, 2001;BornsteinBornstein etet Al, 2001, 2004; Al, 2001, 2004; GlazerGlazer etet Al, 1995; Al, 1995; Graziottin 2001, 2004; Mc Kay Graziottin 2001, 2004; Mc Kay etet al. 1998, 2004al. 1998, 2004BertolasiBertolasi etet Al, 2008; Al, 2008; BornsteinBornstein, 2004, 2008, 2004, 2008


Symptoms: Dyspareunia and Symptoms: Dyspareunia and postcoital cystitispostcoital cystitis

Signs: vulvar vestibulitis and Signs: vulvar vestibulitis and hyperactive pelvic floorhyperactive pelvic floor


increased concentration of increased concentration of mastcellsmastcellshigher (p<0.001) in the superficial layers higher (p<0.001) in the superficial layers vsvs

the deep (0.05)the deep (0.05)(Bornstein et al, 2001, 2004, 2008)(Bornstein et al, 2001, 2004, 2008)

NormalNormal mucosamucosa

Increase of Mastcells Increase of Mastcells in the Vestibular mucosa in the Vestibular mucosa

MastcellsMastcellsNormalNormal mucosamucosa

Mucosa in VVSMucosa in VVS

MastMast--cell cell produceproduce NGF with NGF with proliferation of the free pain nerve proliferation of the free pain nerve

terminals = increase of nociceptorsterminals = increase of nociceptors X X 10 times 10 times

(Bohme(Bohme-- Starke et Al, 2001, Bornstein, 2004Starke et Al, 2001, Bornstein, 2004 ) ) Graziottin & Vincenti, 2004Graziottin & Vincenti, 2004

MastcellsMastcells

MastcellsMastcells and and vestibulitisvestibulitis//vulvodiniavulvodiniaConclusion 1.Conclusion 1.

HeparanaseHeparanase, which is , which is degranulateddegranulatedfrom mast cells,from mast cells,

is capable of degrading the vestibular is capable of degrading the vestibular stromastromaand epithelial basement membrane,and epithelial basement membrane,thus permitting thus permitting stromalstromal proliferation proliferation thus permitting thus permitting stromalstromal proliferation proliferation

and intraepithelial extension of nerve fibers. and intraepithelial extension of nerve fibers. The The hyperinnervationhyperinnervation

has been thought to cause has been thought to cause the vestibular hyperesthesia the vestibular hyperesthesia

distinctive of localized distinctive of localized vulvodyniavulvodyniaBornsteinBornstein etet Al, 2008Al, 2008

MastcellsMastcells and and irritableirritable bowelbowel syndromesyndrome

The colon The colon isis the the mostmost importantimportant immunitaryimmunitaryorganorgan ofof humanhuman bodybody

ColonicColonic mastcellsmastcells permanentlypermanently controlcontrol the the mucosalmucosal boundaryboundary and and “set the “set the levellevel” ” ofof the the generalgeneral immunitaryimmunitary, , inflammatoryinflammatory and and painpainresponseresponseresponseresponse

HyperactivatedHyperactivated coloniccolonic mastcellsmastcells increaseincrease painpain vulnerabilityvulnerability in colon in colon AND AND differentdifferent organsorgans, in the , in the abdomenabdomen//pelvispelvis suchsuch asas bladderbladder, , vestibulumvestibulum, and , and distantdistant, , ieie brainbrain

FoodFood allergiesallergies increaseincrease painpain vulnerabilityvulnerability in in differentdifferent painpain syndromessyndromes, , suchsuch asas endometriosisendometriosis

StanghelliniStanghellini etet Al, 2006, 2008; Barbara Al, 2006, 2008; Barbara etet Al, 2004; Al, 2004; AbarAbar etet Al, 2008Al, 2008

Barbara et al; GastroenterologyBarbara et al; Gastroenterology 2004 2004

MastcellsMastcells in the in the bladderbladder painpain syndromesyndromeBPS/IC (“BPS/IC (“interstitialinterstitial cystitiscystitis”)”)

RecurrentRecurrent bladderbladder inflammationinflammation leadsleads toto::

••HyperactivationHyperactivation ofof mastcellsmastcells in the in the bladderbladder wallwall withwith chronicchronicdetrusorialdetrusorial inflammationinflammation and progressive and progressive scarringscarring

••IncreasedIncreased production production ofof painpain signalssignals

••ProliferationProliferation ofof painpain fibersfibers

••DefensiveDefensive contractioncontraction ofof the the levatorlevator ani ani

A.Graziottin, 2010

BJU Int. 2008 :204BJU Int. 2008 :204--7 7

Question 3.

What bridges

Endometriosis & Chronic Pelvic Pain

What bridgesendometriosis, chronic inflammation and pain

to depression?

CourtesyCourtesy ofof G. Biggio, 2009G. Biggio, 2009

Somatic Symptoms of Depression

• “Unexplained” pain – CPP, Backache, Chest pain, Chronic join pain, Limb pain,

Headache, Bodily aches and Fibromyalgia

• Fatigue/loss of energy • Insomnia• Insomnia• Gastrointestinal symptoms

– Abdominal cramping, bloating, heartburn, diarrhea and/or constipation

• Change in sexual desire & Female Sexual Disorders• Weight loss or gain

– Loss or increase in of appetite • Dizziness & Palpitations

RakelRakel RERE.. DepressionDepression.. PrimPrim CareCare 19991999;;2626((22))::211211--224224,, TrivediTrivedi MHMH.. TheThe linklink betweenbetween depressiondepression andand physicalphysicalsymptomssymptoms.. PrimPrim CareCare CompanionCompanion JJ ClinClin PsychiatryPsychiatry 20042004;;66((SupplSuppl 11))::1212--1616,, BurtBurt VKVK.. PlottingPlotting thethe coursecourse toto remissionremission::thethesearchsearchforfor betterbetteroutcomesoutcomesinin thethetreatmenttreatmentofof depressiondepression.. JJ ClinClin PsychiatryPsychiatry 20042004;;6565SupplSuppl1212::2020--2525.. ©JLA’06©JLA’06

Major brain changes in depression• Down-regulation of the

* serotoninergic system:

§ in the brain

§ in the body (95% of serotonin is outside the brain!)

* dopaminergic system* dopaminergic system

1) seeking-appetitive-lust system

2) motor system (nigro-striatal)

3) logic linear thinking

* opiatergic system


and and increaseincrease ofof inflammatoryinflammatory mediatorsmediators

NEW READINGS OF DEPRESSION

••asas a a systemicsystemic diseasedisease

asas anan inflammatoryinflammatory

RakelRakel RE.RE. DepressionDepression.. Prim CarePrim Care 1999;26(2):2111999;26(2):211--224, 224, TrivediTrivedi MH.MH. The link between depression and physical symptomsThe link between depression and physical symptoms.. Prim Care Companion J Prim Care Companion J ClinClin PsychiatryPsychiatry

2004;6(2004;6(SupplSuppl 1):121):12--16, 16, Burt VK.Burt VK. Plotting the course to remission: the search for better outcomes in the treatment of depressionPlotting the course to remission: the search for better outcomes in the treatment of depression.. J J ClinClin

PsychiatryPsychiatry 2004;65 2004;65 SupplSuppl 12:2012:20--25.25.Graziottin & Serafini, Graziottin & Serafini, Menop.IntMenop.Int, 2009;, 2009;

DinanDinan TG, TG, CurrCurr OpinOpin Psychiatry 22(1):32Psychiatry 22(1):32--6, 2009.6, 2009.

asas anan inflammatoryinflammatoryconditioncondition

withwith significantsignificant increaseincrease ofof inflammatoryinflammatorymoleculesmolecules producedproduced byby the the mastcellsmastcells

Inflammatory markers in depression

• Major depression is associated with a proinflammatory response, as indexed by elevation in C-reactive protein and cytokines such as interleukin 6 and tumor necrosis factor-alpha.

• Most studies support a link between depression, inflammation and cardiovascular events.

• Antidepressants suppress the inflammatory response. Whether or not the immune system is an appropriate target for antidepressant development has yet to be established.

Dinan TG, Curr Opin Psychiatry 22(1):32-6, 2009.

DepressionDepression is an is an inflammatory state inflammatory state that may increase the risk of cardiac diseasethat may increase the risk of cardiac disease. .

Inflammation & depression

.

InflammationInflammation PainPain

Depression is (also) a systemic Depression is (also) a systemic

inflammatory stateinflammatory state


EstrogensEstrogens -- and testosterone!and testosterone!--havehave anan antianti--inflammatoryinflammatory activityactivity

in the in the brainbrainHalbreichHalbreich etet Al, 2001; Begliuomini Al, 2001; Begliuomini etet Al, 2007; Al, 2007; BrannBrann Al, 2007; Al, 2007; DheenDheen etet Al, 2007; Al, 2007; FoyFoyetet Al, 2007; Al, 2007; HajszanHajszan etet al, 2008; al, 2008; RazRaz etet Al, 2008; Vegeto Al, 2008; Vegeto etet Al, 2008; Al, 2008; DinanDinan, 2009 , 2009

Conclusion 3.

Depression:

• is a systemic disease

• is an inflammatory condition• is an inflammatory condition

• “somatizations” are the biological correlates of a systemic inflammatory state and of the widespread diffusion on neurotransmitters

The protagonists of the Chronic Pain scenario

ChronicChronicinflammationinflammation

PeripheralPeripheral NervousNervousPeripheralPeripheral NervousNervousSystem System

PAIN FIBERS PAIN FIBERS

MastMastcellcell

CentralCentral NervousNervousSystemSystem

PAIN CENTERSPAIN CENTERS


The The MastcellMastcell isis the the directordirectorofof painpain & & depressiondepression orchestraorchestra

“Immunologic abnormalities, especiallyindices of excess inflammation, are acommon finding in patients withdepression.

There is increasing evidence suggesting

By Leah McNally, Zubin Bhagwagar and Jonas Hannestadin Inflammation, Glutamate, and Glia in Depression: A Literature Review

2008 CNS Spectr.13(6):501-509

There is increasing evidence suggesting

that inflammation could, in a subgroup

of patients and in some medical conditions

contribute to thepathogenesis of depression.”

CRHCRH

CENTRAL CENTRAL NEUROINFLAMMATIONNEUROINFLAMMATION


PSYCHOGENICPSYCHOGENICSTIMULISTIMULI

HORMONAL STIMULIHORMONAL STIMULI

NEUROGENIC NEUROGENIC STIMULISTIMULI

vagina uterus

Peritoneum

PelvicPelvic PainPain((NeurogenicNeurogenic//NociceptiveNociceptive))

PelvicPelvic TissueTissueDamageDamage

IMMUNOGENIC IMMUNOGENIC STIMULISTIMULI

CROSSCROSS--TALKTALK

ChronicChronic (Neuropathic ?)(Neuropathic ?)PelvicPelvic Pain Pain -- CPPCPP

bladdercolon

Conclusion

CPP and comorbidities, such as Endometriosis, Vulvodynia, Bladder PainSyndrome and IBS, are characterized by

Mastcell mediated:Mastcell mediated:

• inflammation

• depression

• pain

New perspectives

Down-regulation of the hyperactive mastcells / microglia is the new frontier

• in endometriosis & chronic • in endometriosis & chronic inflammation

ImmunologicalImmunological reviewreviewJuneJune 2007 2007 volvol 217 pag 5217 pag 5--337337

•• in in chronicchronic pelvicpelvic painpain

RenRen & & DubnerDubner, Nature medicine, , Nature medicine, OctoberOctober 14, 201014, 2010

•• and in and in depressiondepression associatedassociated toto

chronicchronic diseasesdiseases A.Graziottin, 2011

thanksthanks forfor youryour attentionattentionwww.alessandragraziottin.itwww.alessandragraziottin.it

Documents

Chronic pelvic pain: mastcells, medical and psychological ... · Chronic pelvic pain: mastcells, medical and psychological comorbidity Alessandra Graziottin MD Center of Gynecology