대한요로생식기감염학회지 : 제 7 권제 1 호 2012년 4월 Korean J UTII Vol. 7, No. 1, April 2012 종설 전립선염에대한 UPOINT 개념의검토 전남대학교의과대학비뇨기과학교실 정승일 [Abstract] General Review of UPOINT Concept on Prostatitis Seung Il Jung From the Departments of Urology, Chonnam National University Medical School, Gwangju, Korea Traditional approach to manage chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has not been successful for many patients. There is no one unifying etiological mechanism or specific curative therapy for CP/CPPS. However, each of the proposed mechanisms may be important in some patients, and many of the treatments work in subgroups of patients. So, CP/CPPS patients are not a homogenous group, which suffers from a single disease entity, but rather a heterogeneous group of individual patients with widely different clinical phenotypes. Unique individuals with differing clinical phenotypes based on various etiological mechanisms with distinctive symptom complexes. A clinically practical phenotyping classification system for patients diagnosed with CP/CPPS has recently been proposed and validated in a CP/CPPS cohort. UPOINT is a 6-point clinical classification system that categorizes the phenotype of patients with CP/CPPS into one or more of 6 clinically identifiable domains: urinary, psychosocial, organ specific, infection, neurologic/systemic, and tenderness (muscle). It is proposed that patients be classified into one or more of these phenotypic domains, as a way to characterize them and direct specific therapy. There is a suggestion that phenotypically directed therapy will improve our clinical treatment outcomes. (Korean J UTII 2012;7:1-9) Key Words: Chronic prostatitis with chronic pelvic pain syndrome, Phenotype 교신저자 : 정승일, 화순전남대학교병원비뇨기과전남화순군화순읍일심리 160 번지 ( 서양로 322) 우 519-763 Tel: 061-379-7749, Fax: 061-379-7750, E-mail: drjsi@yahoo.co.kr Received: March 8, 2012 Revised: March 9, 2012 Accepted: March 16, 2012 1
2 대한요로생식기감염학회지 : 제 7 권제 1 호 2012 년 4 월 서 론 본 론 최근에보고된연구결과들에따르면 chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) 의원인기전에대한연구와치료방법의임상적시도들이공통적으로적용되는원인기전을밝히는데실패하였거나모든환자에게효과가있는단일치료법을밝히는데실패했음을알수있다. 1 이러한이유는 CP/CPPS가다양한증상과원인을가지는이질적인상황이기때문이다. 단일치료법들은이질적인환자군에서개개인의원인에대한치료가아니기때문에보통증상을경감하는데효과적이지못하다. 2,3 또한, CP/CPPS 환자들에서치료결정을내리는데도움을줄만한타당성있는예측인자나생물표지자가없다. 4 최근이러한문제를다루기위해 6가지임상표현형분류체계인 UPOINT (Urinary, Psychosocial, Organ-specific, Infection, Neurologic/systemic, and Tenderness domains) 개념이제시되었다. 5 Shoskes 등 5 에의해최초로제안이되었는데, UPOINT의이론적근거는 CP/CPPS의병인과증상이다양하고여러가지치료에따른반응이모두다르다는점에두고있다. 이들연구자들은 CP/CPPS 환자는비슷한환자들의균질한집단이아니며독특한개개인의집합체인이질집단으로제시하며, 개개인의환자들은다른원인기전, 질환특성, 증상집합, 질환의진행경과를가지고있고, 이러한차이를환자들의임상적표현형에따라기술할수가있다고하였다. 5 UPOINT 개념이제시된후지속적으로이러한개념이전립선염진료현장에서시험되었으며타당성여부가확인되었다. 4 최근 UPOINT 개념은 CP/CPPS 환자들의치료가이드역할을하는개개인의독특한임상표현형으로분류하는데이용된다. 2,4,5 CP/CPPS 환자에서 UPOINT 개념의적용은임상유형을정확하게구별할수있어원인규명과효율적인치료를할수있게도와주리라기대되고있다. 이에저자는전립선염의대부분을차지하는 CP/CPPS 환자에있어서 UPOINT 개념의진단, 분류, 그리고치료에있어서현주소를검토해보고자한다. 1. UPOINT 개념의도입배경 CP/CPPS 환자들을치료하는데근거중심의치료방법을사용하여왔으나결과가좋지못하였다. 실제임상상황에서효과가있어보이던다양한전통적치료법및새로운치료법들이대규모무작위위약통제연구에서임상적으로중요한효과를보이는데실패하였다. 6,7 그렇다면이러한좋지못한성과를보인연구들이전립선염을치료하는의사들에게뜻하는바가무엇일지생각해보면 CP/CPPS 증상을가지는모든환자들을치료할수있는단독방법은없다는뜻으로이해하는게좋을듯하다. 하지만이러한연구를다시재평가해보면일부환자들은이들다양한치료법에반응함을보여준다. 그래서우리는이러한특정치료법에반응을할수있는환자들을찾아야한다. 최근 CP/CPPS 환자는동일한원인, 동통, 배뇨증상, 정신및성문제를가지는균질한집단이아니라매우다른임상적표현형을가지는이질집단이라고인식되었다. 이러한이질집단환자들의 "phenotyping" 표현형화가동일하지않은치료결과들을설명해주고이러한개념이더나은치료방향을제시해주리라본다. 전립선염전문가들이광범위한임상연구경험과문헌고찰을통해새로운표현형분류체계를만들었으며임상에적용할수있고개개인의치료계획을짜는데에유용함을보여주었다. 5 2009년이러한비뇨기적만성골반동통증후군 (CP/CPPS와간질성방광염 ) 을가지는환자들을분류할수있는임상적으로실용적인방법이제시되었으며, 이들분류체계를 UPOINT 라고명명하였다. 4,5 2. UPOINT 개념 UPOINT는 urinary, psychosocial, organ-specific, infection, neurologic/systemic, 및 tenderness 도메인의 6개요소의첫글자를딴약자로서, CP/CPPS를전립선에만국한하지않고전립선이외의여러요소를포함하
정승일 : 전립선염에대한 UPOINT 개념의검토 3 Table 1. Evaluation of a man with chronic pelvic pain syndrome (CPPS) Evaluative steps Mandatory Recommended Optional (for specific indications) Description History Physical examination with DRE (includes pelvic floor assessment) Urine analysis and urine culture Pre- and post-massage two glass test for culture Symptom inventory or index (NIH-CPSI) Flow rate and residual urine determination Assessment for depression, maladaptive social and/or coping behavior Questions regarding associated conditions (e.g. irritable bowel syndrome, etc.) Urine cytology Semen analysis and culture Urethral swab for culture Pressure flow studies Videourodynamics (including flow-electromyography) Cystoscopy TRUS Pelvic imaging (ultrasound, computed tomography, MRI) PSA DRE: digital rectal examination, NIH-CPSI: NIH-chronic prostatitis symptom index, TRUS: transrectal ultrasound, MRI: magnetic resonance imaging, PSA: prostate specific antigen 여접근하는개념방법이다. 5 UPOINT는비뇨기적만성골반동통증후군을가진환자들을 urinary, psychosocial, organ-specific, infection, neurologic/systemic, 및 tenderness (muscle) 의 6개의도메인중에서환자에서확인되는하나또는그이상의도메인으로분류를한다. UPOINT는비뇨기과의사가개개인의환자에따른치료를하는데새로운임상적도구가될것이라고제시가되었고, 여성간질성방광염과남성만성골반통증후군에서평가되었으며타당성이입증이되었다. 4,8 UPOINT 분류는 CP/CPPS 환자들에서연구목적뿐만아니라임상에서도사용되고있다. 2,4 또한이들접근법은간질성방광염 / 방광통증증후군환자들의이질성을이해하는데에도유용함이보고되었다. 8,9 이들두가지의비뇨기과적만성골반동통증후군을위해각각의도메인은표준적인임상측정법을이용하여정의가되어있으며특정치료법과연결이되어있다. 3. UPOINT 분류를위해서필요한검사일반적인외래진료상황에서시행되는검사로 환자들이평가될수있다. 표 1에 CPPS환자들을평가하는방법이기술되어있으며이들검사로환자들을한개이상의도메인으로분류가가능하다. 10 기존 CPPS 검사방법과다른점이있다면기본검사에있어서직장수지검사를포함한신체검사에있어서신경학적도메인과근육압통도메인진단을위한골반저부위에통증 ( 골반근막동통, 근육연축 ) 이있는지확인할필요가있다. 또한추천검사에있어서정신사회적도메인진단을위한우울증, 부적응행동, 잘못된극복행동등을평가하여야하며신경학적 / 전신적상황도메인을위해과민성방광증후군, 섬유근육통 (fibromyalgia), 만성피로증후군과같은관련상황에대한질문이필요하다. 각각의도메인에대한임상적기술은표 2에정리하였다. 10 Urinary 도메인은방광자극증상, 폐색증상등이있는경우이다. CPPS에서통증이가장주된증상이지만저장및배뇨증상도흔하다. 일부환자에서는배뇨관련증상이없는경우도있다. 빈뇨, 급박뇨, 야간뇨가있는지확인이필요하며 NIH Chronic
4 대한요로생식기감염학회지 : 제 7 권제 1 호 2012 년 4 월 Table 2. Clinical descriptions of the six UPOINT domains Domain Clinical description Urinary NIH-CPSI urinary score >4 Bothersome urgency, frequency, or nocturia Flow rate <15 ml/s and/or obstructed pattern Postvoid residual urine volume >100 ml Psychosocial Organ specific Infection Neurological/systemic conditions Tenderness of skeletal muscles Clinical depression Poor coping or maladaptive behaviour, e.g. evidence of catastrophizing (magnification or rumination in regard to symptoms, hopelessness) or poor social interaction Anxiety/stress Specific prostate tenderness Leukocytosis in prostatic fluid Haematospermia Extensive prostatic calcification Lower urinary tract obstruction Exclude patients with clinical evidence of acute (acute infection) or chronic bacterial prostatitis (recurrent infection that is localized to prostate specimen between infections) Gram-negative bacilli or enterococcus localized to prostatic fluid Documented successful response to antimicrobial therapy Pain beyond abdomen and pelvis Associated medical conditions such as Irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, etc. Palpable tenderness and/or painful muscle spasm or trigger points in perineum or pelvic floor or sidewalls during DRE examination NIH-CPSI: NIH-chronic prostatitis symptom index Prostatits Symptom Index (CPSI) 가평가하는도구가되며, 배뇨후잔뇨측정, 요속측정이도움이되겠다. 잔뇨가 100ml 이상, CPSI urine score가 4점보다큰경우, 2회이상의야간뇨, 급박뇨, 빈뇨가있는경우등을 Urinary 도메인양성이라본다. Psychosocial 도메인은임상적우울증이있는경우, 잘못된극복방법과사회적상호작용문제, 파국화 라불리우는정신과적인상황 ( 증상을확대해석하고강박적으로사고하며결국무력증에빠짐 ) 등이있는경우이다. 병력청취도중정신사회적인문제가중요하다고생각되면우울증과불안을평가하는 patient health questionnaire (PHQ) 와통증과연관된부정적사고 ( 근심, 확대, 무력감 ) 를평가하는 pain catastrophizing scale (PCS) 이유용하다. 11,12 Organ specific 도메인은전립선을가볍게만지기만해도통증을호소하는경우, 전립선액에서염증 이확인된경우등이다. Infection 도메인은급성감염이있거나만성세균성전립선염환자들은배제되며과거에항생제치료에효과가있었던경우, 전립선액에서그람음성균또는장내구균이발견되는경우에 Infection 도메인양성이다. Infection 도메인에대한기술이문헌마다모호하게되어있어착각할소지가있다. 특히반복적요로감염은만성세균성전립선염의특징이므로배제되어야한다. 2 UPOINT 분류는만성세균성전립선염이아닌 CP/CPPS 환자를분류하는데사용되는개념이기때문이다. 통상의이배분법검사에서음성이나중합효소연쇄반응검사에서양성 ( 예, Ureaplasma, Chlamydia, Mycoplasma) 을보이는경우는 Infection 도메인양성으로해석할수있겠다. 5 Neurological/systemic conditions 도메인은과민성대장증후군, 섬유근육통, 만성피로증후군과같은설명
정승일 : 전립선염에대한 UPOINT 개념의검토 5 Table 3. Suggested therapies for the six UPOINT domains UPOINT domain Suggested therapies Urinary Psychosocial Organ specific Infection Neurological/systemic conditions Tenderness of skeletal muscles Anti-muscarinics α-blockers Counselling Cognitive behavioural therapy Anti-depressants Anti-anxiolytics α-adrenergic blockers 5-α-Reductase inhibitors Phytotherapy (Quercetin, Pollen extract) Prostate massage Surgery Antibiotics Neuromodulators: tricyclic antidepressants (amitriptyline), gabapentinoids Specific therapies for associated conditions Neuromodulation Skeletal muscle relaxants Focused pelvic physiotherapy General physiotherapy Exercises 되지않는신경병증이있는경우로복부및골반이외의부위에동통이있는경우가해당되겠다. Tenderness 도메인은회음부또는골반저에압통, 동통, 연축이있거나직장수지검사시회음부와골반부위에근막동통유발점이있는경우이다. 근막동통유발점의촉진은 4kg/cm 2 의힘으로근육을눌러서양성여부를평가한다. 13 이힘은우리가손톱을눌렀을때손톱하방의색이창백하게변하는정도의힘이라고생각하면되겠다. 14 4. UPOINT 표현형분류와증상중증도와의연관성한연구에서 CP/CPPS 환자들을 UPOINT 시스템을이용하여표현형을평가해보았고개개의도메인의빈도와증상의중증도에미치는영향을살펴보았다. 4 Urinary, psychosocial, organ-specific, infection, neurologic/systemic, 및 tenderness 도메인에양성을보인환자들의퍼센트는각각 52%, 34%, 61%, 16%, 37%, 그리고 53% 이었다. 환자들중단 지 22% 에서단하나의도메인을가지고있었으며, 도메인수가증가할수록전체만성전립선염증상지수점수가순차적으로증가하였다. 즉도메인의개수와증상의중증도는상관관계를가지고있었다. 이러한결과는다른기관에서도마찬가지로도메인의수와만성전립선염증상지수의총점수와상관관계가있다고보고하였다. 15,16 증상기간이길어질수록양성도메인개수도증가하며이것은표현형악화를의미하였다. 4 증상에가장영향을미치는도메인은 urinary, psychosocial, organ specific, 및 neurologic/systemic 도메인들이었다. 동통에대해서는 psychosocial, neurologic/systemic, 및 tenderness 도메인들이의미있게높은점수를보였으며, 반면에 psychosocial과 neurologic/systemic 도메인만이환자의삶의질에영향을미쳤다. 이러한소견은전립선이외의부위에작용하는도메인이동통증상과삶의질에영향을미친다는것을의미한다. 따라서이들도메인에대한확인과치료가 CP/CPPS 증상의더효과적인개
6 대한요로생식기감염학회지 : 제 7 권제 1 호 2012 년 4 월 선과삶의질을개선시킬거라고생각한다. 5. UPOINT 분류에따른치료적접근지금까지가장잘수행된연구들에근거해서이들새로운임상표현형에맞는치료법들이제시되고있다 (Table 3). 10 열거된치료방법은반드시근거가있는것은아니고현재까지의근거자료, 임상데이터분석, 임상적경험에바탕을두어제시되는치료법들이다. 특정표형현내의특정증상또는임상평가결과에초점을맞춘치료가시행되어야한다. 일부치료방법은특정표형형의하위범주에만효과가있고다른하위범주에는효과가없을수있다. Urinary 도메인에대한치료는알파차단제, 항콜린제, 식이생활조절등이있다. Psychosocial 도메인에대한치료는상담, 인지행동치료, 항우울제투약등이다. 만성통증이있는환자는부적절한동통대응기전을갖고있는경우가많고우울증, 불안, 스트레스, 성적또는육체적학대의과거력으로고통받고있을수있다. 이러한환자의경우상담, 인지행동치료, 항우울제등으로치료한다. Nickel 등 17 은동통파국화, 우울적사고, 통증의존적휴식 (pain contingent rest), 사회적지지여부에대한인지행동치료가 CPPS 환자에서삶의질개선을위해필요하다고보고 8주간의인지행동치료법을제시하였다. 통증의존적휴식이있는환자에서는오히려신체활동을장려해서걷기, 달리기와같은유산소운동을장려하는게도움이되겠다. 18 Organ specific 도메인에대한치료는알파차단제, 5-α 환원효소억제제, 생약치료 (Quercetin, Pollen 추출물 ), 전립선마사지가있다. 5-α환원효소억제제는전립선비대증이동반시에사용해볼수있겠다. 최근다모드의치료연구에서는생약제를이용한연구가시행되었고이들에대한국내관심도필요하겠다. 19,20 Infection 도메인에대한치료는항생제배양감수성에따르거나비특이균인경우에는알려져있는감수성패턴에따라처방이되어야한다. 그러나실질적으로는경험적항생제가처방되며, 적절한항생제처방에환자가효과가없다면 더이상의항생제는사용되지말아야하겠다. Neurological/systemic conditions 도메인에대한치료는 gabapentin, pregabalin, nortryptiline과 amitriptyline 같은신경이완제가있으며침술과같은보완신경조절치료가있겠다. 또한과민성대장증후군, 섬유근육통, 만성피로증후군과같은연관된질환이있으면이에대한치료가추가된다. Gabapentin, pregabalin 약제는국내에서 CP/CPPS 질환에대해서보험이적용되지않고있으며, 일차적으로 nortryptiline과 amitriptyline과같은약을우선적으로고려해볼수있겠다. 21 Nortryptiline이 amitriptyline에비해부작용이덜한것으로알려져있다. Tenderness 도메인에대한치료는골격근이완제, 골반집중물리치료, 일반물리치료, 운동등이거론된다. 골반근육물리치료에대해서는 Anderson 등 22,23 이근막동통유발점이완치료와이완훈련을병행한치료법의효과들을보고하고있으며이들결과에의하면동통과배뇨증상, 성기능개선에도효과가있었다. CP/CPPS 환자에서다모드치료가단일치료보다좋다 24,25 고보고되고있어개개인의환자의 UPOINT 도메인에따른다모드치료는치료효율을높일수있을것이다. Shoskes 등 19 은 CP/CPPS 환자 100명을대상으로하여 UPOINT에따른분류와 UPOINT 치료전략에따른치료를시행하였으며 6개월이상추적하였다. UPOINT에의한다모드의전향적인치료연구에서치료 6개월째 84% 의환자에서만성전립선염증상지수점수 6점이상의감소를보이는의미있는증상의호전을보고하였다. 19 이러한결과는상대적으로낮은치료효과를보였던단일치료법과비교하면상당히양호한편이라볼수있다. 26,27 현재이들연구자들은비뇨기과의사들이 6개의주요표현형을진단하는데임상적도구로사용할수있는특정설문을시험하고있다. 또한각각의특정도메인안에서유용할수있는소분류를연구중에있다. 원인, 질환및진행기전의이해, 및특정생물표지자발견은이러한표현형을더잘진단할수있게할것이며 CP/CPPS를치료함에있어서향상을가져오리라본다.
정승일 : 전립선염에대한 UPOINT 개념의검토 7 6. 성기능장애도메인 REFERENCES 비록발기부전은 UPOINT 표현형에는포함이되지않지만, 성기능장애는 CP/CPPS 환자들의 40-70% 에서존재한다. 28,29 다른 CP/CPPS 환자에비해성기능장애를갖는 CP/CPPS 환자들은상당히심한증상을앓으며특히삶의질에영향을미친다. 28 최근이탈리아와독일코호트를포함한대규모유럽연구에서이탈리아인에서는 UPOINT 도메인양성수와증상과상관관계를보이지만독일코호트에서는연관성을보이지않았고성기능도메인을첨가했을때두개의코호트자료와표현형분류간에상관관계를보인다고보고하였다. 15 Magri 등 15 은 UPOINT의기존 16 항목외에국제발기능지수가포함된수정 UPOINT를임상적으로사용하는것이보다효율적임을주장하였다. 한편북미코호트에서발기부전 (erectile dysfunction; ED) 도메인을추가한것이더효율적인가에대한연구결과에서 "S" (sexual dysfunction) 도메인의추가가증상과의상관관계를향상시키지못한다고하였다. 30 이들은비록발기부전증상에대한고려가필요하고적절한치료가필요하지만 ED ("S": sexual dysfunction) 도메인을독립적인 UPOINT 도메인으로사용하는데에는문제가있다고지적하였다. 결론 CP/CPPS 환자에서 UPOINT의개념은개개인의환자의표현형을잘묘사할수있었으며, 이러한개개인의독특한표현형을겨냥한다면적인치료는더욱향상된치료효과를보여주었다. UPOINT 개념은 CP/CPPS의병인에대한이해를돕고, 면역학적, 신경학적, 골반기능학적, 사회환경적및정신의학적인면을포함한새로운치료방식을제시하는데에밑바탕이되리라본다. 또한 CPPS를구성하고있는표현형을밝히기위한향후연구에중요한근간이되리라보며, 이들체계의수정및관련된향후연구를통해환자개개인에맞는맞춤치료가가능해지리라본다. 1. Nickel JC, Downey J, Ardern D, Clark J, Nickel K. Failure of a monotherapy strategy for difficult chronic prostatitis/chronic pelvic pain syndrome. J Urol 2004;172:551-4 2. Nickel JC, Shoskes D. Phenotypic approach to the management of chronic prostatitis/chronic pelvic pain syndrome. Curr Urol Rep 2009;10:307-12 3. Shoskes DA, Katz E. Multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome. Curr Urol Rep 2005;6:296-9 4. Shoskes DA, Nickel JC, Dolinga R, Prots D. Clinical phenotyping of patients with chronic prostatitis/chronic pelvic pain syndrome and correlation with symptom severity. Urology 2009;73: 538-42 5. Shoskes DA, Nickel JC, Rackley RR, Pontari MA. Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes. Prostate Cancer Prostatic Dis 2009;12:177-83 6. Schaeffer AJ. Chronic prostatitis and chronic pelvic pain syndrome. N Engl J Med 2006;355: 1690-8 7. Nickel JC. Treatment of chronic prostatitis/chronic pelvic pain syndrome. Int J Antimicrob Agents 2008;31:S112-6 8. Nickel JC, Shoskes D, Irvine-Bird K. Clinical phenotyping of women with interstitial cystitis/painful bladder syndrome: a key to classification and potentially improved management. J Urol 2009;182:155-60 9. Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK, et al. Psychosocial phenotyping of women with interstitial cystitis/painful bladder syndrome: a case control study. J Urol 2010; 183:167-72 10. Nickel JC, Shoskes DA. Phenotypic approach to the management of the chronic prostatitis/chronic pelvic pain syndrome. BJU Int 2010;106:1252-63
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