Diagnosis and treatment of male accessory gland infections - eshre

Department of Urology, Pediatric Urology and AndrologyJUSTUS- LIEBIGUNIVERSITYGIESSENDIAGNOSIS AND TREATMENTOFMALE ACCESSORY GLANDINFECTIONSW. WeidnerKlinik und Poliklinik für Urologie, Kinderurologie und AndrologieUniversitätsklinikum Gießen und Marburg GmbH- Standort Gießen -Justus-Liebig-Universität Gießen(Direktor: Prof. Dr. W. Weidner)

Andrological Causes forInfertile PartnershipO +O + OO20 %30 %AndrologicalFactoridiopathicOAT-S.hypogonadismtesticular failureobstructioninfectionvaricoceledisorders ofejaculationDe Kretser, Baker, J Clin End Met 84: 3343 (1999)Weidner et al., Eur Urol 42: 313 (2002)JLU GIESSEN

Causes of Male InfertilityTumors2.3%Immunologic4.2%Systemic5%Obstruction1.5%Malformations 5.8%Cryptorchidism8.5%Hypogonadism8.9%Others6.5%Infections9%Idiopathic31.7%Varicocele16.6%n = 7802 patientsE. Nieschlag et al., 1997; Andrology, Springer-VerlagJLU GIESSEN

Diagnosis of consecutive 1834 Men with Fertility Problemscryopreservation(n=2)OAT-syndrome(n=635)34.6%general diseases(n=35)1.9%0.1%gynecomastia(n=28)normal1.5% (n=52)2.8%endocrine disorders0.8% (n=14)testicular disorders(n=449)24.5%ejaculatorydisorders /sexualdysfunction(n=34)1.9%3.3%immunologicaldisorders(n=61)8.5% 6.9%infections /inflammation(n=155)obstructiveazoospermia(n=126)13.2%varicocele(n=243)Andrological Outpatient DepartmentUrology Giessen (2008)

Infections and Male Infertilityacute and chronic urogenital infections(frequent) Orchitis and Epididymitis Prostatitis, Chronic Pelvic Pain Syndrome MAGI (Urethritis)generalized systemic infections (rare)JLU GIESSEN

Epididymo-OrchitisSwelling, STD and UTI, chronic inflammationUltrasonographyBiopsyRecent results: 100 consecutive patients -> 70% positive microbiologyJLU GIESSENPilatz et al., 2009in press

Testicular Inflammmation and Spermatogenesisspermdensitynormozoospermiaoligozoospermiaazoospermia3 - 12 weekstimeJLU GIESSEN

Spermatological Outcome ofAcute Epididymo-OrchitisOAT - SyndromTesticularazoospermiaObstructive(Epididymal)azoospermia50 % < 1 % < 5 %Weidner et al., Human Reproduction Update, 1999Diemer and Desjardins, Encyclopedia of Reproduction, 1999Paavonen and Eggert-Kruse, Human Reproduction Update, 1999JLU GIESSEN

Chronic Inflammation in Testicular BiopsiesAzoospermiaUp to 14% peritubular lymphocyte-inflammation¹ Mast-cell increase 1,2Interaction to dendritic cells²Association to spermatogenetic failure²- Direct association to bacterial origin is lacking -JLU GIESSEN¹ Schuppe and Meinhardt, 2008² Bhushan et al., 2008

ProstatitisNIDDK / NIH ClassificationIIIIIIABIVAcute Bacterial Prostatitis (ABP)Chronic Bacterial Prostatitis (CBP)Chronic Pelvic Pain Syndrome (CPPS)Inflammatory (EPS, VB III, Semen)Non - inflammatoryAsymptomatic (inflammatory)JLU GIESSENKrieger et al., JAMA 292: 236 (1999)

GIESSEN COHORT STUDIESNIH IIIA31.5% ( n=53)NIH IIIA31.0%(n=203)NIH II4.2%(n=7)NIH II7.0%(n=46)NIH IIIB50.0% (n=84)UP14.3%(n=24)NIH IIIB51.0% (n=335)UP11.0%(n=72)Study 20022001-2002n = 168Study 19921985-1990n = 656

4 - SPECIMEN - TECHNIQUE1 : 101.UrineMidstreamUrineEPSUrineafterprostaticmassageJLU GIESSEN

DIAGNOSTIC MANAGEMENTINFECTIONSNIH INIH IINIH IIIurine analysis, culture4 and 2 glass test,semen culture,(significant bacteriospermia in about 50%)4 and 2 glass test are an indicator forinflammation and infectionNIH IVJLU GIESSENno suggestionParis, 2005Consensus ConferenceNIH, EAU, WHO

INFLUENCE OF LEUKOCYTES IN THE EJACULATEON CP / CPPS CLASSIFICATIONTraditional• EPS, VB3 •n=140NIH IIIA 28 %NIH IIIB 72 %New: EPS, VB3 + SemenNIH IIIA 52 %NIH IIIB 48 %1.9 fold more patients to haveinflammatory CP / CPPSJLU GIESSENKrieger et al., 2003

Bacteriospermia in CBP(≥10³ cfu/ml)CBP/NIH II(N= 32)NIH IIIa(N= 102)NIH IIIb(N=142)Controls(N=42)JLU GIESSENWeidner et al., Arch. Androl., 26: 173 (1991)

DIAGNOSTIC PROCEDURESNIH III / CP-CPPSEjaculateEjaculate qualityno influenceEvidence of leukocytesAutoimmune markers(complement, T-cells)ImmunoglobulinescytokinesImproves the accuracy for classificationin category IIIa and IIIbonly researchJLU GIESSENParis, 2005Consensus ConferenceNIH, EAU, WHO

Cutpoints for EPS, urine after P.M. (VB3) andejaculate/seminal plasma parameters indicative for inflammationparametercutpointEPS leukocytes ≥ 10-20/1000 xVB3 leukocytes ≥ 10/mm³Semen PPL ≥ 0.113 x 10 6 /mlSeminal plasma Elastase ≥ 280 ng/mlSeminal plasma IL-8 > 10600 pg/mlJLU GIESSENWagenlehner and Weidner, 2008

Inflammatory Parameters inCP/CPPS and Infertile MenNIH IIIaN34NIH IIIbN140Infertile MenN77Age 45 (19-69) 42 (18-69) 40 (15-71)PPL (mill./ml) 0.23 (0-8.24) 0.04 (0-12.08) 0.07 (0-23.04)Elastase (ng/ml) 188 (7-1.708) 95 (4-1001) 91 (2-400)IL-8 (pg/ml) 2,969 (27-10,001) 1,588 (7 – 10,001) 1,602 (13-10,001)JLU GIESSENongoing studyWagenlehner et al.Dresden 2009

Altered Sperm Parameters and„Prostatitis“Sperm Parameter Proven Questionable No hintBacteriospermiaOAT-S. +Leucocytospermia +Cytokine response +ROS formation ++CommentCBPtotally unclearCBP, NIH IIIaNIH IIIano new dataSperm antibodiesInflammatoryobstruction(+)-recentlyreconfirmedrareJLU GIESSEN

Male Accessory Gland Infection• Asymptomatic (silent ejaculate infection)• LeukocytospermiaWBC > 1 x 10 6 /mlPeroxidase StainingUnsolved Problemsof LeukocytospermiaOnly associated withbacterial infections in 20 %high rate of spontaneousresolution in infertile menWHO, WHO ManualCambridge University Press, 1992JLU GIESSEN

MAGI – CLASSIFICATION SYSTEMGroup AGroup BTypical History/ Urine afterPhysical Signs P-MassageGroup CEjaculate signse.g. UTI,Epididymitis, STDEpididymal swellingAbnormal prostateIncreased PMLPPLC. trachomatis BacteriospermiaC. trachomatisBiochemistryInflammationC. trachomatis PCRPPL > 1 Mill./mlBacteriospermia > 1000 cfu/mlElastase > 250 ng/mlMAGI =a) 2 signs,each from a different groupb) at least 2 ejaculate signsJLU GIESSEN(WHO 1993, 2000)

PATIENTS / METHODS258 infertile men (age 24-69 years)Ejaculate analysis according to WHO analysis of PPL (1 Mill./ml), bacteria (10³ cfu/ml), elastase (250 ngl/ml)Exclusion of urethritis (1. voided urine: PML, C. trachomatis, N. gonorrhoeae)Diagnosis of NIH II prostatitis and CP/CPPS NIH-CPSI, 4-glass-techniqueDiagnosis of chronic epididymitis palpation, scrotal ultrasonographyJLU GIESSEN

RESULTSDIAGNOSIS OF UROGENITAL INFECTION / INFLAMMATIONn 258MAGINIH63 (24.4 %) 101 (39.1 %)including25 epididymitis14 urethritisJLU GIESSEN

RESULTSDIAGNOSIS OF PROSTATE RELATED INFECTION / INFLAMMATIONn 258MAGINIH24 (9 %) 62 (24 %)excluding25 epididymitis14 urethritis“prostatitis“NIH II 26 (10 %)NIH IIIa 36 (14 %)JLU GIESSEN

RESULTSEJACULATE DIAGNOSIS OF UROGENITAL INFECTION / INFLAMMATIONIN DEFINED ENTITIESnEvidence ofBacteriospermia PPL Elastase C. trachomatisNIH II 26 x none xx 12 15 noneNIH IIIa36 none 24 20 noneEpididymitis 25 9 9 8 2Urethritis 14 1 4 4 12x15 x E. Colixx> 10³ cfu/mlJLU GIESSEN

CONCLUSIONSThe WHO diagnosis „MAGI“ detects urogenital infection/inflammationin about 20% of patients.In this figure, cases of epididymitis and urethritis are included.Prostate related infections (NIH II) are detectablein 10% of infertile men.Questionable prostate-related inflammatory changes (NIH IIIa)have to be noted in further 14%.Ejaculate analysis demonstrates leukocytal activity in about two thirds ofthese cases.The MAGI classification of the WHO clearly underestimates thepercentage of infections/inflammatory prostatitis and/or CP/CPPS in maleinfertility.JLU GIESSEN

CONCLUSIONSTo exclude male urogenital infections and inflammationin infertile menejaculate analysisclinical investigation of the epididymisa 4 glass test for prostatitis diagnosisare mandatory.JLU GIESSEN

THERAPEUTIC DILEMMAAntibacterial therapy works in about 70%The persistence of inflammation can not be predicted.JLU GIESSEN

SUGGESTED ANTIBIOTIC IN CBP (NIH II)fluoroquinolonestrimethoprim /sulfamethoxazole1. choicein FQ resistence (2-3 months)macrolides gram positives, atypical m.tetracyclines atypical m.aminoglycosidesnot suggestedJLU GIESSENEAU guidelines 2009

Fluoroquinolones in CBPDosage/day Days(mg)n Eradication Follow(%) up (mo)NorfloxacinSchaeffer et al800 28 14 64 6 1990NorfloxacinPetrikkos et al4-800 174 42 60 8 1991OfloxacinPust et al400 14 21 67 12 1989CiprofloxacinWeidner et al1000 14 15 60 12 1987Ciprofloxacin Weidner et al1000 28 16 63 21-36 1991CiprofloxacinPfau1000 60-150 7 86 12 1987,1991CiprofloxacinNaber et al1000 28 34 76 6 2000Ciprofloxacin vs. 1000 28 78 72 6 2001Lomefloxacin 400 28 75 63 6 2001Naber et alLevofloxacin 500 28 136 53 6 2003Bundrick et alNaber et al 500 28 116 84 6 2008JLU GIESSENMeares & Stamey - Diagnosis

NIH IINIH IIantibiotics, α-blockers (4 weeks)63-76% bacteriological curefailure - intermittent antimicrobial therapy(acute symptomatic)- low dose suppression- radical TUR-P or prostatectomyJLU GIESSENParis 2005

Sperm Preparation: GlasswoolHenkel und Schill, Andrologia 30 (Suppl 1): 91 (1998)JLU GIESSEN

TARGETS OF THERAPY• Eradication of Microorganisms• Normalization of Inflammatory Parameters ?Normalization of SymptomsJLU GIESSEN

Bacteria - Sperm - InteractionMotility and MorphologyAgglutinationAdhesionMembranedamageJLU GIESSENDiemer, Weidner et al.,Int J Androl 19: 271 (1996)Int J Androl 23: 178 (2000)Andrologia 35: 100 (2003)

Bacteria - Sperm - InteractionMotility and MorphologyDepending uponSpecies+ E. coli, C. trachomatis- E. faecalis, Staphylococcus spp.NumberTimeDiemer, Weidner et al.,Int J Androl 19: 271 (1996)Int J Androl 23: 178 (2000)Andrologia 35: 100 (2003)JLU GIESSEN

Bacteriospermiacfu/mlfrequency of ejaculationJLU GIESSEN