Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95, 1 REVIEW INTRODUCTION The term Chronic Prostatitis (CP) Refers to a group of syn- dromes of various etiology characterized by subacute and persistent prostatic inflammation although a large pro- portion of patients with prostatic inflammation don’t have any symptoms (category IV, asymptomatic inflam- matory prostatitis). The remaining patients, affected by category II chronic bacterial prostatitis (CBP) or by catego- ry III chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may experience pelvic pain, including supra- pubic pain, pain in the penis, testicles or perineum, pain during sexual intercourse or during ejaculation, dysuria (painful urination), nocturia and/or urinary urgency. The duration and severity of pain and discomfort varies among patients. Chronic pain may be accompanied by several voiding disturbances mainly urgency and nocturia sexual dysfunction as well (1). However pelvic pain is the most prominent symptom (as compared with patients with BPH and those with erectile dysfunction (2). Stress and a spectrum of various psychological problems are commonly found in CP patients, but it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological distur- bances (3). Moreover, the exact incidence of individual psychological problems remains unspecified. In this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. Introduction/Aim: A spectrum of psychologi- cal problems is commonly found in CP/CPPS patients, though it is not yet clear whether, a priori, psychologi- cal dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psycholog- ical disturbances. In this article we present the current perspec- tive on the impact of psychological problems in chronic prostati- tis syndromes and we discuss the implications thereof from a clinical perspective. Materials and Methods: A database and a manual search were conducted in the MEDLINE database of the National Library of Medicine, EMBASE, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, in various combinations with the terms “psycholog- ical issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status” and “personality”. Two independent reviewers performed data extraction. We included clinical studies with available information on chronic prostatitis and related psycho- logical conditions. We considered full-text written papers. We excluded reviews and case reports. In order to reduce the risk of bias we analyzed only studies including patients with confirmed CBP or CP/CPPS. Bibliographic information in the selected pub- lications was checked for relevant records not included in the initial search. Results: Database search allowed us to retrieve 638 studies to which we added to 16 additional studies retrieved by hand- searching. After screening, 34 relevant papers were identified for thorough review. Most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically con- firmed CP/CPPS including studies with a microbiologically con- firmed diagnosis of CBP. The psychosocial factors examined in the selected studies include pain, catastrophizing, stress, person- ality factors and social aspects. Comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trau- ma-related disorders, somatization disorders, and substance abuse. Some studies investigated the association of pain with each individual psychological disturbance, while others exam- ined the impact of pain in association with the overall quality of life. Sample size, study design and diagnostic measures varied among studies. Conclusions: Despite limitations and variations in sample size, study design and diagnostic measures in all included studies, a relation between chronic prostatitis and psychological problems Chronic prostatitis and related psychological problems. Which came first: The chicken or the egg? A systematic review Konstantinos Stamatiou 1, Margherita Trinchieri 2, Martina Trinchieri 3, Gianpaolo Perletti 4, Vittorio Magri 5 1 Department of Urology, Tzaneio Hospital, Pireus, Greece; 2 Psichiatry Unit, ASST Rhodense, G. Salvini Hospital, Garbagnate, Milano, Italy; 3 Società Italiana di Psicoanalisi della Relazione SIPRe, Milano, Italy; 4 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 5 Urology Unit, ASST Fatebenefratelli Sacco, Milano, Italy. DOI: 10.4081/aiua.2023.11300 Summary is a consistent finding. The existing evidence does not permit to definitely conclude whether psychological problems are a risk factor for CP/CPPS or whether they represent an array of symptoms that are associated with the exacerbation of this dis- ease. KEY WORDS: Prostatitis syndromes; Chronic bacterial prostatitis; Chronic pelvic pain; Psychological issues: Depression; Anxiety; Stress; Unhappiness; Cognitive status; Personality. Submitted 21 January 2023; Accepted 25 February 2023 Archivio Italiano di Urologia e Andrologia 2023; 95, 1 K. Stamatiou, M. Trinchieri, M. Trinchieri, G. Perletti, V. Magri MATERIALS AND METHODS A database and a manual search were conducted in the MEDLINE database of the National Library of Medicine, EMBASE, and other libraries using the key words “prosta- titis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, “males” in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status”, “personality”. Two inde- pendent reviewers performed data extraction by using identical extraction tables. The search was carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology (4) and were extended from first records up to 15th December 2022. Titles were screened and any duplicates removed before abstracts and finally full-text articles were assessed for rel- evance (Figure 1). Reference lists were also checked. Relevant studies were evaluated by all authors and included in the narrative data synthesis. We included clinical studies with available information on chronic prostatitis and related psychological prob- lems. We considered full-text written papers. We exclud- ed reviews and case reports. In order to reduce the risk of bias we analyzed only studies including patients with confirmed CBP or CP/CPPS. Bibliographic information in the selected publications was checked for relevant records not included in the initial search. The methodological quality of included studies was assessed independently by 2 authors. Case-control and cohort were evaluated using the Newcastle-Ottawa Scale (NOS) as bias assessment tool (5). RESULTS The initial search of the databases retrieved 668 studies. Title/abstract screening led to select 60 papers after exclu- sion of 618 papers that were judged as not directly rele- vant to the research question. Out of these 60 papers, 19 duplicates were removed. Sixteen additional studies were retrieved by handsearching. Review of the abstracts led to exclusion of 23 papers due to several reasons (review papers, papers reporting the same series described in other selected papers, congress reports/abstracts with lim- ited information). Finally, 34 relevant papers were identified for systematic review (6-39). Specifically, 15 records reported case series, 13 were case- control studies and 6 were cross-sectional cohort studies. According to the quality assessment of Newcastle-Ottawa Scale, 11 studies out 19 were characterized by high quali- ty with scores ranging between 7 and 9 (Supplementary Materials). Data synthesis Most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically con- firmed CP/CPPS including studies with a microbiologi- cally confirmed diagnosis of CBP. The psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. Comorbid psychiatric disorders evi- denced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. Some studies investigated the associa- tion of pain with each individual psychological distur- bance, while others examined the impact of pain in asso- ciation with the overall quality of life. Sample size, study design and diagnostic measures varied among studies. Several studies showed that this disease has a significant negative impact on mental and physical quality of life domains (6-9). Men with CP/CPPS have significantly more disturbances in their psychological profile com- pared to both healthy control patients (10-12) and patients with chronic pain of different etiology (13). In CP/CPPS patients, pain has an impact in different domains of life (viz., sexual relationships) compared with patients with chronic pain of different etiology (viz., work and professional activity) (13). Aubin and coworkers, compared self-report questionnaires measuring demo- graphic, pain, and sexual function of men with CP/CPPS with those of men without any pain condition. According to their findings, patients affected by CP/CPPS differed from controls in the domains of sexual desire, frequency of sexual intercourse, and in the quality of erectile and orgasm functions (14). Erectile dysfunction and decreased libido were reported by 43% and 24% of men with CP/CPPS, respectively (15). One key difference between the populations investigated was the presence of depression and anxiety. Smith et al. compared (a) the sexual and relationship functioning of 38 male patients with CP/CPPS with those of their female partners, and (b) the sexual and relationship functioning of both CP/CPPS men and their partners with the same items assessed in 37 control couples. Compared to con- trol males, men with CP/CPPS reported significantly more sexual dysfunction and symptoms of depression. Furthermore, the symptoms of depression mediated the relationship between some aspects of sexual function and male participant status as a patient or control (16). Therefore, in CP/CPPS subjects, the frequency of sexual activity decreased with increasing depression, the orgasm function decreased with increasing depression, and the quality of erectile function decreased with increasing pain symptoms. In addition, overall sexual satisfaction decreased with increasing pain symptoms (14). Thus, from these data it appears that the psychological profile of patients can deteriorate in function of the kind and sever- ity of symptoms of CP/CPPS. The severity of erectile dysfunction also correlates signifi- cantly with anxiety. Moreover, both depression and anx- iety are closely correlated with chronic pain and urinary symptoms and contribute to the recurrence, refractori- ness, and outcome of the disease (17, 18). The incidences of depression and anxiety in patients with CP/CPPS are estimated to be approximately 20-50% and 40-60%, respectively. Besides depression and anxiety, a variety of somatic and psychological conditions were detected among CP/CPPS patients, including distur- bances of several personality traits, mental distress, psy- chological stress, somatization, obsessive-compulsive dis- order and interpersonal sensitivity (12, 19). A large population-based cross-sectional survey demon- strated a significantly high occurrence of mental distress Archivio Italiano di Urologia e Andrologia 2023; 95, 1 Chronic prostatitis and related psychological problems and psychological stress related to CP/CPPS in Finnish men: suicidal thinking and fear of undetected prostate cancer or of having a sexually transmitted disease was reported by 17% of partients (15). Psychological stress has a major impact on the sexuality of CP/CPPS patients. In fact, the frequency of sexual activity decreased with increasing depression, arousal/erectile function decreased with increasing pain symptoms and orgasm function decreased with increasing depression. Moreover, sexual satisfaction decreased with increasing pain symptoms, stress appraisal, and decreasing belief of a relationship between emotions and pain (14). Male participants of the MAPP study (National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, USA) had a significant rate of non-uro- logical associated somatic syndrome (31%) associated with longstanding disease, more severe urological symp- toms and higher rates of depression and anxiety (20). A Chinese study compared the demographics, character, leukocyte counts in EPS, disease course, NIH chronic pro- statitis syndrome index (NIH-CPSI), self-rating anxiety scale (SAS) and self-rating depression scale (SDS) of 291 CP/CPPS patients and 100 normal controls, in order to establish the psychological factors related with CP/CPPS. All patients were treated with the same protocol and fol- lowed-up for 6 weeks. According to this study, the rate of introversion was significantly higher while that of extro- version was significantly lower in the CP/CPPS group compared to the control group. Univariate and multivari- ate analyses with Cox regression revealed that anxiety, depression and disease course were the definite factors that negatively affected the prognosis of CP/CPPS, while other factors such as age, NIH-CPSI, character and leuko- cyte counts in EPS had no influence (12). A Korean study investigated the association of personali- ty traits with the baseline clinical characteristics and treat- ment outcomes of patients with CP/CPPS. According to this study, although extraversion, agreeableness, and con- scientiousness can influence the clinical characteristics of patients with CP/CPPS, they do not affect the overall symptoms or the treatment response in those patients. In contrast, neuroticism is associated with a significantly poorer treatment response and with higher levels of depression and somatization (21). A small study conducted in the USA measured the per- ceived stress, pain intensity, and pain-related disability 1, 3, 6, and 12 months after a health care visit resulting in a new diagnosis of nonbacterial prostatitis/pelvic pain. According to this study, greater perceived stress during the 6 months after the health care visit was associated with greater pain intensity and disability at 12 months (22). Another Chinese study compared anxiety, depression, erectile function and the scores of the NIH-CPSI among refractory CPPS patients who had never received any psy- chotherapy and non-refractory CPPS patients. No signifi- cant differences were observed in the chronic prostatitis symptom scores between the two groups, while anxiety and depression scores were significantly higher and that on erectile function was significantly lower in the refracto- ry than in the non-refractory CPPS patient group (23). A study based on the Taiwan Longitudinal Health Insurance Database, compared 8,088 subjects with CP/CPPS with 24,264 randomly matched controls and found that CP/CPPS is consistently and significantly associated with prior anxiety disorder in all age groups. In particular, subjects aged 40-59 years had the highest rates of prior anxiety disorder among cases compared to controls (24). These results reflected those of a previous study which found that men who experienced severe stress were 1.2 and 1.5 times more likely to report prostatitis than those whose lives were relatively stress-free (25). Similarly, a cross-sectional study from Estonia revealed a familial pre- disposition to CP/CPPS that may be associated also with susceptibility to respiratory tract infections (26). DISCUSSION Chronic prostatitis is a relatively common male chronic pain condition. It is characterized by recurrent sympto- matic episodes, or flare-ups. Between flare-ups, some patients are asymptomatic, while others complain of mild symptoms. Patients usually have a long history of persist- ent symptoms. It isn’t clear what causes chronic pain in CP/CPPS, and the etiology of this disease is still uncertain. Various theories have been hypothesized, such as auto- immunity, persistent inflammatory statuses, neuroinflam- mation oxidative stress, pathogen and host-specific fac- tors, pelvic floor tension myalgia, and differences in sys- temic pressure sensitivity (40-42). In addition, there is evidence that CP/CPPS patients show alterations of the hypothalamic-pituitary adrenal axis function in response to acute stress (9). Moreover, it has been suggested that stress is a potent factor in the development of CP/CPPS; for this reason the term “stress prostatitis” was proposed as an appropriate label for this condition (43). Currently, psychological factors are considered to play an important role in CP/CPPS and the possible association between personality disorders and chronic pelvic pain develop- ment has garnered increasing attention. For example, the validated UPOINT diagnostic-therapeutic algorithm, in its original or modified version (i.e. UPOINTS, including a sexual function domain), acknowledges the importance of psychological factors in CP/CPPS and includes a domain specifically focusing on the psychosocial func- tioning of patients (44, 45). In the UPOINT/UPOINTS system, items such as a history of clinical depression, ongoing antidepressant therapy, a history of abuse, mal- adaptive coping mechanisms (for example, catastrophiz- ing), anxiety, or a high score of a depression scale such as HADS qualifies a patient as having a positive psychosocial phenotype. Stress can have a significant impact on CP/CPPS, as it can worsen the symptoms and significantly affect the emo- tional state of patients by causing extreme overwhelming or distress (36). On the other hand, it was shown that the development of stress in CP/CPPS is time-dependent and is associated with subsequent pain and disability (23, 25). The severity of stress has been reported to depend on individual perception or subjective interpretation of causative factors rather than on the contents or frequen- cy of factors causing stress (37). In a such a case, pain and disability are causative factors of stress while stress is a potent factor in the prolongation and perpetuation of the symptoms. In fact, psychological stress can lead to the Archivio Italiano di Urologia e Andrologia 2023; 95, 1 K. Stamatiou, M. Trinchieri, M. Trinchieri, G. Perletti, V. Magri worsening of symptoms, and particularly to pain and dis- comfort during sexual intercourse, thus making patients more anxious and irritated. In turn, these negative emo- tions can worsen CP/CPPS, thus triggering a vicious cir- cle (14). As a consequence, the quality of life of men with CP/CPPS can decrease to levels comparable to patients with severe illnesses (38, 39). Existing data suggest that the experience and perception of pain is complex, and is maintained by educational, psychosocial, and behavioral variables (46). For this rea- son, the rate of introversion is significantly higher than that of extroversion in CP/CPPS patients (21), and this evidence may also explain the association of CP/CPPS with lower educational levels, poor emotional health and a lack of social support (44). Therefore, several patients are more prone to develop persisting diseases, especially in the presence of exaggerated media-reported informa- tion, describing chronic prostatitis as a very serious con- dition. In addition, because of the lack of correct under- standing about this disease, many patients can feel anx- ious and worried, fearing that the sexual function and fer- tility will be affected by CP/CPPS. Other patients may fear of having undetected prostate cancer or of having a sexu- ally transmitted disease (15). In certain patients, persist- ent urinary symptoms may lead to weak masculine iden- tity disorder (47). Given that depression and anxiety are closely correlated with chronic pain, urinary symptoms, sexual dysfunction and weak masculine identity (14, 37), it could be assumed that, in addition to stress perception, psychological problems, personality traits, educational and behavioral variables can be considered as factors causing or deteriorating symptoms in patients with CP/CPPS. This hypothesis explains the high incidence of anxiety and depression in treatment–resistant chronic bacterial prostatitis (24). Given the familial predisposition to CP/CPPS, the high incidence of CP/CPPS among men who experience severe stress and the fact that CPPS is consistently and signifi- cantly associated with prior anxiety disorders (24, 26), several researchers suggested CP/CPPS patients to be psy- chologically seriously ill. In fact, studies on quality-of-life outcomes suggest that psychiatric disorders strongly coexist with CP/CPPS (48). However, in a study by de la Rosette and coworkers, it was shown that differences in scores of personality inventory (NVM), symptom check- list (SLC-90), and depression inventory (IDD) between CP/CPPS patients and controls were not of a great magni- tude, and in any case of lesser extent compared with dif- ferences in scores from psychiatric patients (10). In addi- tion, Fishbain et al. showed that some trait tests and inventories may not be pain state-independent, and therefore may interpret post-pain development personal- ity profiles as being indicative of the true pre-pain per- sonality structure (49). CONCLUSIONS Despite limitations and variations in sample size, study design and diagnostic measures shown by the studies included in this review, the relation between chronic pro- statitis and different psychological conditions is a consistent finding. 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Correspondence Konstantinos Stamatiou, MD stamatiouk@gmail.com Department of Urology, Tzaneio Hospital 2 Salepoula str., 18536 Piraeus, Greece Margherita Trinchieri, MD margherita.trinchieri@gmail.com Psichiatry Unit, ASST Rhodense, G. Salvini Hospital, Garbagnate, Milano, Italy Martina Trinchieri, MD martinatrinchieri90@gmail.com Società Italiana di Psicoanalisi della Relazione SIPRe, Milano, Italy Gianpaolo Perletti, Dr. Biol. Sci. M. Clin. Pharmacol. gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy Vittorio Magri, MD vittorio.magri@asst-fbf-sacco.it Urology Unit, ASST Fatebenefratelli Sacco, Milano, Italy Conflict of interest: The authors declare no potential conflict of interest.