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Association Between Periodontal Disease and Prostate-Specic Antigen Levels in Chronic Prostatitis Patients
Nishant Joshi,* Nabil F. Bissada,* Donald Bodner, Gregory T. MacLennan, Sena Narendran, Rick Jurevic,i and Robert Skillicorn*
Background: Prostate-specic antigen (PSA) is an inammatory marker produced by the epithelial cells of the prostate acini. In the presence of inammation or malignancy of the prostate, PSA levels are 4 ng/ml. This preliminary study was conducted to evaluate any association between periodontitis and PSA levels in chronic prostatitis patients. Methods: Thirty-ve subjects who underwent prostate biopsy because of abnormal ndings on digital rectal examination or elevated PSA (4 ng/ml) participated in the study. Plaque and gingival indices, bleeding on probing, probing depth, and clinical attachment level (CAL) were determined. Two-sided independent sample t tests assessed any signicant differences in the PSA levels between and among the groups of prostatitis and periodontitis. Results: Mean PSA levels were signicantly higher (P = 0.04) in subjects with moderate/severe prostate inammation than those with none/mild (8.8 5.8 versus 5.7 3.1 ng/ml). Subjects with CAL 2.7 mm had higher but not statistically signicant PSA levels than those with CAL <2.7 mm (7.7 5.2 versus 5.7 3.2 ng/ml), respectively. Individuals having both moderate/severe prostatitis and CAL 2.7 mm (10.8 7 ng/ml) had signicantly higher mean PSA levels (P = 0.05) than those with neither condition (5.6 3.7 ng/ml) nor only CAL 2.7 mm (5.7 2.4 ng/ml) or moderate/severe prostatitis (6 1.9 ng/ml). Conclusion: Subjects having comorbidity of CAL 2.7 mm and moderate/severe prostatitis have higher PSA levels than those with either condition alone. J Periodontol 2010;81:864869. KEY WORDS Inammation; periodontitis; prostate-specic antigen; prostatitis.
* i Department of Periodontics, Case Western Reserve University, Cleveland, OH. Department of Urology, University Hospitals Case Medical Center, Cleveland, OH. Institute of Pathology, University Hospitals Case Medical Center. Department of Community Dentistry, Case Western Reserve University. Department of Biological Sciences, Case Western Reserve University.

rostate-specic antigen (PSA) is a 33-kDa serine protease enzyme, which is synthesized in the epithelial cells of the prostatic acini, secreted into the lumen, and then transmitted through the prostatic ducts into the semen.1 The primary physiologic function of PSA is to liquefy the major gel proteins in the semen (seminogelin I and II and bronectin) and hence lyses the seminal clot, which releases motile sperm needed for fertilization.2,3 In healthy conditions, <4 ng/ml of PSA are released into the bloodstream. PSA levels are 4 ng/ml in the presence of inammation or malignancy. Serum PSA can be quantied by a number of chemical assays, and is used to track response to therapy for prostate cancer. PSA is prostate specic although not necessarily cancer specic. Many other conditions also can lead to elevated PSA levels, such as benign prostate hyperplasia, prostatitis, urinary retention, and instrumentation.4 Prostatitis is the inammation of the prostate gland, a phenomenon not very well understood despite a prevalence of 8%.5 The National Institutes of Health classied prostatitis into four clinical categories:6 category I, acute bacterial prostatitis; category II, chronic bacterial prostatitis; category III, chronic pelvic pain syndrome either inammatory (IIIa) or non-inammatory (IIIb); and category IV, asymptomatic inammatory prostatitis. Gram-negative bacteria, such as
doi: 10.1902/jop.2010.090646

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Escherichia coli and Klebsiella spp, have been implicated in the etiology of prostatic infection. Substantial evidence supports the role of the immune system in the pathogenesis of prostatitis, which is likely to be mediated through proinammatory cytokines, such as interleukin (IL)-1b and tumor necrosis factor-a (TNF-a).7,8 Numerous studies have examined the association between inammation of the prostate through needle biopsies and serum PSA levels and concluded that prostatic inammation signicantly contributes to increased serum PSA levels.9-11 Gram-negative bacteria have been suggested as etiologic agents for periodontitis and category I and II prostatitis. Bacterial etiology for categories III and IV prostatitis, however, has not yet been identied.6 Cytokine imbalance toward increased proinammatory and decreased anti-inammatory cytokines has been implicated in the pathogenesis of both periodontitis12 and prostatitis.13 Given the similarity in etiopathogenesis of prostatitis and periodontitis, it is possible that an association between the two conditions exists, which may manifest elevated PSA levels in the circulating blood. The purpose of this study is to evaluate any association between periodontitis and PSA levels in chronic prostatitis patients. MATERIALS AND METHODS This pilot study is a collaborative effort between the Department of Periodontics at the Case School of Dental Medicine and the Department of Urology and Institute of Pathology at the University Hospitals Case Medical Center, Cleveland, Ohio. The protocol for the study was approved by University Hospitals Institutional Review Board (No: 07-08-23 on February 3, 2009). Transrectal ultrasound database of the Department of Urology, University Hospitals Case Medical Center, was used to screen patients that had prostate needle biopsy between August 2008 and January 2009. The database identied 150 patients meeting initial eligibility criteria and gathered the following information: age, ethnicity, date, reason for prostate needle biopsy, serum PSA levels, and pathology results. These patients subsequently were screened by telephone using an institutional review boardapproved screening protocol to determine subjects eligibility and interest in the present study. Inclusion criteria for the study were 1) age 21 years; 2) prostate needle biopsy performed within the last 6 months because of abnormal digital rectal examination or elevated serum PSA levels (4 ng/ ml); 3) no dental prophylaxis within the last 3 months; 4) 12 teeth present; and 5) able and willing to understand the protocol and sign a consent form. Exclusion criteria were 1) age <21 years; 2) periodontal treatment within the last 3 months; and 3) history of

myocardial infarction, stroke, or organ transplant during the last 6 months. After the screening and application of criteria to participate in the study, 35 subjects were enrolled in the study. Once the subject consented to participate in the study, periodontal examination was performed by a trained and calibrated examiner (NJ). Periodontal assessment included 1) probing depth (PD) and clinical attachment level (CAL) at six sites per tooth, e and Silness,14 3) plaque index 2) gingival index of Lo 15 e, 4) gingival recession, and 5) percentage of of Lo sites with bleeding on probing (BOP). A pathologist (GTM) examined the prostate needle biopsy slides of the participants based on previously described criteria used to classify prostate inammation.16 Subjects then were divided into two groups: 10% inammation indicating none/mild prostatic inammation (group A) and >10% for moderate/ severe inammation (group B) (Fig. 1). Presence or absence of malignancy on prostate needle biopsy was coded as 1 or 2, respectively. Results were coded so that the pathologist was not aware of the periodontal ndings and vice versa. Statistical Analyses The mean and standard deviation for age, PSA levels, and periodontal parameters, and the frequencies for prostate inammation and CAL, were calculated. Two-sided independent sample t tests were used to compute 1) the P values for the differences between prostatitis and CAL groups; 2) difference in PSA levels between those with CAL <2.7 mm versus CAL 2.7 mm and those with none/mild versus moderate/severe prostatitis; and 3) pair-wise comparison among the four groups of patients (moderate/severe prostatitis and CAL 2.7 mm; moderate/severe prostatitis only or CAL 2.7 mm only; or neither). Pearson chi-square test and Fisher exact test assessed the association between periodontitis and prostate inammation and between prostate inammation and malignancy. The Pearson correlation coefcient was calculated to assess the relationship between PSA and individual periodontal parameters. A P value of 0.05 was considered as statistically signicant. All statistical analyses were carried out using software. RESULTS Among the study sample, 12 patients (34.3%) had moderate/severe prostate inammation and 11 patients (31.4%) showed malignant changes (data not shown). Only three patients had both severe prostate inammation and malignancy. There was no
Statistical Analysis System 9.1, Cary, NC.

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signicant association between the level of prostate inammation and malignancy (P = 0.71). Subjects were divided into two groups based on the median CAL of 2.7 mm: group I, CAL <2.7 mm; and group II, CAL 2.7 mm. Approximately 52% of the subjects had CAL 2.7 mm, whereas 20% (seven out of the 35) patients had both CAL 2.7 mm and moderate/severe prostatitis. No signicant association was detected between CAL and prostate inammation (P = 0.55). The difference in PSA levels between patients with moderate/severe prostate inammation and those with none/mild inammation are illustrated in Figure 2. Subjects with moderate/severe prostatitis had signicantly higher (P = 0.04) PSA levels (8.8 5.8 ng.ml) than those with none/mild prostatitis (5.7 3.1 ng/ml). Subjects with CAL 2.7 mm had higher PSA levels (7.7 5.2 ng/ml) than those with CAL

<2.7 mm (5.7 3.2 ng/ml), also shown in Figure 2. The difference between the two groups, however, was not signicant (P = 0.19). No signicant difference in the mean periodontal parameters was detected among subjects with different levels of prostate inammation: none/mild versus moderate/severe (Table 1). The means for periodontal parameters between the two groups of prostate inammation were similar except for CAL and PD. Between the groups, the difference in CAL and PD was only 0.1 mm. Subjects having CAL 2.7 mm had signicantly higher probing depth (2.7 0.5 versus 2.2 0.2 mm) and gingival recession (0.7 0.5 versus 0.2 0.1 mm) compared to those with CAL <2.7 mm. There was no signicant difference in the means of other periodontal parameters between these two groups (Table 1). A weak correlation was observed between age and PSA value (r = 0.23; P = 0.14), and no signicant association was detected among any of the periodontal parameters and PSA levels (Table 2). Although CAL, gingival index, gingival recession, and BOP showed weak positive correlation with the PSA levels, PD, and plaque index showed weak negative correlations. The strength of the association, or coefcient correlation (r), ranged from -0.18 for PD Figure 1. to 0.29 for BOP. Photomicrograph of a histologic section to illustrate (A) none/mild prostatitis (10% inammatory inltrate) Depending on the presence and (B) moderate/severe prostatitis (>10% inammatory inltrate) (Hematoxylin and eosin; original or absence of prostatitis and magnication 100). CAL of 2.7 or <2.7 mm, subjects were divided into four groups: group 1A, CAL <2.7 mm and none/mild prostatitis (control); group IIA, CAL 2.7 mm and none/ mild prostatitis; group IB, CAL <2.7 mm and moderate/severe prostatitis; and group IIB, CAL 2.7 mm and moderate/severe prostatitis. Subjects having moderate/severe prostatitis and CAL 2.7 mm (group IIB) had signicantly higher PSA levels (10.8 7 ng/ml; P <0.05) than group IA (5.6 3.7 ng/ml), group IB (6.0 1.9 ng/ml), or group IIA (5.7 2.4 ng/ml), as shown in Figure 3. There was no statistically signicant (P >0.05) difference in PSA Figure 2. levels when comparing group IA PSA levels in subjects with none/mild versus moderate/severe prostatitis and CAL <2.7 mm versus versus IIA, IA versus IB, and IIA CAL 2.7 mm. versus IB.

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Table 1.

Relationship of Periodontal Parameters to Level of Prostate Inammation and Periodontal Clinical Attachment Loss
Prostate Inammation Parameter CAL Gingival index PD Plaque index Gingival recession BOP Number of teeth None/Mild (n = 23) 2.9 0.7 mm 1.7 0.6 2.5 0.4 mm 1.4 0.4 0.4 0.5 mm 0.9 0.2 23.3 6.1 Moderate/Severe (n = 12) 2.8 0.6 mm 1.7 0.6 2.4 0.5 mm 1.4 0.5 0.4 0.4 mm 0.9 0.1 23.9 5.9 P Value 0.61 0.76 0.67 0.96 0.81 0.39 0.79 1.54 0.5 2.2 0.2 mm 1.2 0.4 0.2 0.1 mm 0.9 0.2 25.5 3.9 1.8 0.6 2.7 0.5 mm 1.6 0.6 0.7 0.5 mm 0.9 0.2 21.6 7.0 0.17 0.004 0.03 <0.001 0.28 0.047 <2.7 (n = 17) CAL 2.7 (n = 18) P Value

Table 2.

Relationship Between Periodontal Parameters and Prostate Antigen Levels

Parameter CAL Gingival index PD Plaque index Gingival recession BOP Correlation Coefcient (r) 0.04 0.12 -0.18 -0.07 0.22 0.29 P Value 0.8 0.61 0.47 0.59 0.27 0.12

DISCUSSION This present study explores the association between periodontitis and PSA levels in chronic prostatitis patients. The higher PSA levels found in the patients with moderate/severe compared to no/mild prostatitis are in agreement with Kandirali and colleagues,17 who reported a positive correlation between the serum PSA levels and the extent and aggressiveness of prostate inammation in biopsy specimens. Hasui et al.11 and Irani et al.18 also conrmed this same nding and attributed the increased serum PSA to disruption of epithelial integrity of the prostate gland rather than an absolute increase in PSA production. Using immunohistochemistry, Kuznar19 found similar number and gland sizes in the inamed and non-inamed tissues and signicantly less PSA staining in inamed areas compared to non-inamed areas. The authors concluded that increased serum PSA levels in prostatitis was caused by

inammatory response disrupting the glandular epithelium causing leakage of PSA into the bloodstream rather than local increase in PSA production because of glandular hyperactivity or hyperplasia.19 Morote et al.20 showed that serum PSA levels were directly related to the prostate volume and not the extent or type of inammatory inltrate. Because of this uncertainty in the increase in PSA levels, it may be possible that another non-prostatic source of PSA, such as the periodontium, similar to the PSA from breast in females,21 may be responsible for this increase in PSA levels. In our study, a trend toward higher PSA levels was observed in subjects with CAL 2.7 mm compared to those with CAL <2.7 mm. A weak correlation among each of the periodontal parameters and the elevated PSA levels was found in the present study implying that individual parameters of periodontal disease were not signicantly associated with PSA levels. The PSA levels, however, were higher in patients with CAL 2.7 mm than those with CAL <2.7 mm. More importantly, patients having both CAL 2.7 mm and moderate to severe prostatitis had the highest PSA levels compared to those with either condition alone, or neither, suggesting that comorbidity of CAL 2.7 mm and chronic prostatitis may have an effect on serum PSA levels. Although the precise phenomena demonstrating any relationship between periodontitis and prostatitis resulting in an increase in serum PSA levels are yet to be investigated, we propose the following potential mechanisms. The role of proinammatory cytokines is well-documented in the pathogenesis of periodontitis and prostatitis.22-24 Current evidence supports that periodontal disease contributes to an inammatory burden on the host through increased
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Figure 3.
Mean and SD of PSA levels in the four groups. *Statistically signicant (P <0.05) when compared to groups IA, IIA, and IB.

levels of C-reactive protein22 and proinammatory cytokines, such as TNF-a,24 IL-1, and IL-6.23 Elevated levels of IL-1 and TNF-a in serum of men with prostatitis compared to that of healthy individuals has also been documented.7 Therefore, it is possible that periodontitis indirectly contributes to the inammation of the prostate gland through dissemination of cytokines that exaggerate pre-existing inammation of the gland by increasing inammatory response in the prostate. Another possibility is that inammatory responses disrupt the integrity of the prostate glandular epithelium and cause greater leakage of PSA into the bloodstream. A third possibility is that inammatory responses associated with prostate gland enlargement lead to increased local production of PSA, which would then leak into circulation. A distant, non-prostatic source of PSA, such as the periodontium, may also be responsible for increased serum PSA levels. Research is warranted to assess the impact of inammatory mediators on the prostate gland, the integrity of the prostate epithelium, and whether non-prostatic sources of PSA impact serum PSA levels. Findings ought to be considered in terms of the present study sample size, which was small, and the cross-sectional nature, which did not permit either a temporal or cause and effect relationship to be established between periodontitis and high PSA levels. Because the sample size of this pilot study was small, it did not allow for appropriate control groups nor did it allow for controlling confounders, such as race, age, and smoking. In future large studies, the impact of confounders should be assessed along with determination of the level of other systemic markers of inammation, such as C-reactive protein. Because PSA
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values were taken at a specic point rather than over a longer period of time, change in PSA levels was not evaluated or measured according to PSA velocity. Prostatic volume also was not estimated by transrectal ultrasound in this study. Therefore, PSA density (PSA value divided by prostate volume) could not be determined. Assessment of prostate size is another important phenomenon in interpreting elevated PSA levels (PSA density). Interpreting elevated PSA levels and density may expose variations related to prostate gland enlargement. However, prostate needle biopsy specimens represent only a small part of the gland. It may or may not epitomize the entire prostate gland. Well-controlled longitudinal studies with larger sample size are warranted to further clarify any association between periodontitis and PSA levels. CONCLUSION Subjects having comorbidity of CAL 2.7 mm and moderate/severe prostatitis have higher PSA levels than those with either condition alone. ACKNOWLEDGMENTS This study was sponsored by the Department of Periodontics, Case Western Reserve University, Cleveland, Ohio. The authors report no conicts of interest related to this study. REFERENCES
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e H. The gingival index, the plaque index and the 15. Lo retention index systems. J Periodontol 1967;38 (Suppl.): 610-616. 16. MacLennan GT, Eisenberg R, Fleshman RL, et al. The inuence of chronic inammation in prostatic carcinogenesis: A 5-year followup study. J Urol 2006;176: 1012-1016. 17. Kandirali E, Boran C, Serin E, Semercioz A, Metin A. Association of extent and aggressiveness of inammation with serum PSA levels and PSA density in asymptomatic patients. Urology 2007;70:743-747. B, Aubert 18. Irani J, Levillain P, Goujon JM, Bon D, Dore J. Inammation in benign prostatic hyperplasia: Correlation with prostate specic antigen value. J Urol 1997;157:1301-1303. 19. Kuznar W. Leak phenomenon explains PSA rise in prostatitis. Urology Times 1995;23:11. 20. Morote J, Lopez M, Encabo G, de Torres IM. Effect of inammation and benign prostatic enlargement in total and percent free serum prostatic specic antigen. Eur Urol 2000;37:537-540. 21. Diamandis EP, Yu H. Nonprostatic sources of prostatespecic antigen. Urol Clin North Am 1997;24:275282. 22. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 2001;72:1221-1227. 23. Loos BG, Craandijk J, Hoek FJ, Wertheim-van Dillen PM, Van der Velden U. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 2000;71: 1528-1534. 24. Nishimura F, Iwamoto Y, Mineshiba J, Shimizu A, Soga Y, Murayama Y. Periodontal disease and diabetes mellitus: The role of tumor necrosis factor-alpha in a 2-way relationship. J Periodontol 2003;74:97-102. Correspondence: Nabil F. Bissada, Department of Periodontics, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 441064905. Fax: 216/368-3204; e-mail: nabil.bissada@case.edu. Submitted November 18, 2009; accepted for publication January 29, 2010.

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