• prostate-specific antigen;
  • nonsteroidal anti–inflammatory drug;
  • acetaminophen;
  • inflammation;
  • epidemiology


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Inflammation has been implicated in prostate carcinogenesis; therefore, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has the potential of decreasing the risk of prostate cancer. However, to the authors' knowledge the precise correlation between oral NSAID use, serum prostate-specific antigen (PSA), and prostate cancer risk is unknown. To further characterize this association, the authors evaluated serum PSA levels with regard to NSAID and acetaminophen consumption in a large cross-sectional study of men in the US.


PSA levels were determined in 1319 men aged >40 years in the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Linear regressions were performed on log-transformed PSA levels, accounting for the complex survey design, to evaluate the relations between PSA and the use of NSAIDs and acetaminophen after adjusting for the effects of age, race, educational level, smoking status, body mass index, coexisting inflammatory conditions, and heart disease.


NSAID and acetaminophen consumption displayed a negative association with PSA levels, namely, individuals who reported using NSAIDs (19.8%) or acetaminophen (1.3%) regularly had lower PSA levels than individuals who did not take these drugs, although the impact of acetaminophen was not statistically significant. PSA levels among NSAID users were 0.9 times the levels among nondrug takers (P = .038), whereas PSA levels among acetaminophen users were 0.76 times the levels in nondrug takers (P = .14). Individuals who stated they took both NSAIDs and acetaminophen (0.99%) on a regular basis had higher PSA levels (1.8 times greater), although not statistically significantly so (P = .24), than individuals who stated they did not take either of these drugs regularly.


The findings of the current study suggest that regular NSAID consumption may reduce serum PSA levels. Whether this is indicative of a protective effect on prostate cancer risk or masks possible prostate injury resulting in reduced detection of prostate cancer is unclear. Given the widespread consumption of NSAIDs and the regular use of PSA for the assessment of prostate cancer risk, the potential implications of the current study's findings may be substantial and warrant further investigation. Cancer 2008. © 2008 American Cancer Society.

Prostate cancer is a significant burden on men's health. It is the most frequently diagnosed noncutaneous malignancy in the US, with 186,320 new cases and 28,660 deaths expected in 2008, making this the second leading causes of cancer-related mortality for American men.1 Although the nature of the risk factors contributing to the development of prostate cancer remains largely unknown,2–11 inflammation (via infection, hormonal changes, physical trauma, urine reflux, and dietary habits) has been postulated as a factor in prostate carcinogenesis.12–15 Consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen may impact prostate-specific antigen (PSA) levels and prostate cancer risk via their effects on inflammation. Because serum PSA levels are indicative of prostatic injury or inflammation and are also used to assess a man's risk for prostate cancer, we evaluated the association between the use of NSAIDs and acetaminophen and PSA values in the 2001-2002 National Health and Nutrition Examination Survey (NHANES).


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Study Population

To our knowledge, the 2001-2002 NHANES is the first of such surveys to determine PSA levels in men aged >40 years.16, 17 Levels of total and free PSA were measured in 1320 eligible men after excluding men who reported having any of the following conditions: current infection or inflammation of the prostate gland, rectal examination within the past week, prostate biopsy within the past month, cystoscopy within the past month, history of prostate cancer, or were missing data concerning any of these eligibility criteria.18 For the current analysis, we used total PSA levels.

Explanatory Variables

Medication history was characterized as current, regular (“nearly every day”) consumption of NSAIDS (including aspirin) or acetaminophen; both; or no current intake. Unfortunately, dosing information, indication for use, and chronicity were not available through the NHANES database. One participant was excluded from the analysis because of missing data regarding the consumption of NSAIDs or acetaminophen, resulting in a final dataset of 1319 men. Other covariates considered to be potential risk factors for elevated PSA levels include age (continuous or categorical; <60 years, 60-69 years, 70-79 years, and ≥80 years), race (white, black, and other), education (<high school, high school, and >high school), body mass index (BMI) (<25, 25-29, and ≥30), smoking status (dichotomous: ever vs never), history of any inflammatory disease (dichotomous: yes vs no; includes asthma, hay fever, arthritis, emphysema, and chronic bronchitis), and history of any heart disease (dichotomous: yes vs no; includes congestive heart failure, coronary heart disease, angina, heart attack, and stroke) (Table 1). Data regarding the use of 5-alpha reductase inhibitors such as finasteride and dutasteride, which are used in the medical management of benign prostatic hypertrophy and are known to decrease serum PSA values, were not available.19

Table 1. Study Population Demographics*
Characteristic%% Consuming NSAIDs onlyMean PSA Level, ng/mL
  • NSAIDs indicates nonsteroidal antiinflammatory drugs; PSA, prostate-specific antigen; GED, General Educational Development; BMI, body mass index.

  • *

    Not displayed: total acetaminophen consumption, 1.3%; total consumption of both NSAIDs and acetaminophen, 0.99%; no consumption of either, 77.9%.

  • Category-specific percentages add up to total percentage of NSAID consumption; proportion of all users in each category in parentheses (may not add up to 100% due to rounding).

Total10019.8 (100)1.56
Age, y   
 <6071.910.2 (52)1.14
 60-6914.55.2 (26)1.67
 70-7910.23.4 (17)2.90
 ≥803.41.2 (6)5.82
 White79.418.1 (91)1.48
 Black8.10.8 (4)1.85
 Other12.50.9 (5)1.85
Education level   
 <High school16.73.5 (18)2.10
 High school/GED24.44.2 (21)1.35
 > High school58.712.1 (61)1.49
Smoking history   
 Ever58.712.4 (63)1.50
 Never40.37.5 (38)1.64
 <2522.73.1 (16)1.70
 25-2945.89.7 (49)1.47
 30+31.57.1 (36)1.33
History of heart disease   
 Yes12.46.1 (31)2.22
 No87.613.8 (70)1.46
History of inflammatory disease   
 Yes32.28.2 (41)1.66
 No67.811.6 (59)1.50

Statistical Analysis

Linear regression was performed on log-transformed PSA levels (untransformed PSA levels displayed a left-skewed distribution) to evaluate the correlations between PSA and the use of NSAIDs or acetaminophen. Age, race, educational level, smoking status, BMI, coexisting inflammatory conditions, and heart disease were chosen a priori as covariates in our regression model. All statistical analyses were performed with SAS statistical software (version 9.2; SAS Institute Inc, Cary, NC) using the SURVEYMEANS and SURVEYREG procedures, which accounted for the complex survey design by incorporating appropriate sample weights (WTSHM2YR) and stratum and primary sampling unit variables (SDMVSTRA and SDMVPSU, respectively).


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The study population was predominantly white (79.4%) and aged <60 years (71.9%), with greater than a high school education (58.7%) (Table 1). The majority of PSA concentrations were <4.0 ng/mL (mean of 1.6 ng/mL; median, 0.9 ng/mL [95th percentile, 4.5 ng/mL]). Current, regular users of NSAIDs (19.8% of the sample population) had lower serum PSA concentrations than those who did not take any of the medications of interest (ie, NSAID, etc). Table 2 shows the results of the multiple linear regression analysis of log-transformed PSA concentrations. PSA levels in the NSAID group were 0.9 (ie, e−0.10) times the levels of nondrug takers (P = .038) (ie, average PSA levels were 10% lower in the NSAID group). Acetaminophen users (1.3% of the sample population) also had reduced serum PSA concentrations that were 0.76 times (ie, e−0.28) the levels of nondrug takers, but not to a statistically significant degree (P = .14). In other words, PSA levels were 24% lower among acetaminophen users compared with nondrug takers. Conversely, individuals who consumed both NSAIDs and acetaminophen regularly (1.0% of the sample population) appeared to have higher PSA values (1.8 times or 80% greater [ie, e0.60]) than individuals who took neither of these drugs (P = .24).

Table 2. Analysis of PSA Level in Relation to Current NSAID Use
Drug TypePSA Level: Crude AnalysisMultiple Linear Regression*
Mean (95% CI)Rangeβ (SE)95% CIP
  • PSA indicates prostate-specific antigen; NSAID, nonsteroidal antiinflammatory drugs; 95% CI, 95% confidence interval; SE, standard error.

  • *

    log(PSA) regressed as a function of NSAID use, age, race, educational status, smoking status, body mass index, history of inflammatory conditions, and history of heart conditions.

  • Interpretation: PSA level among NSAID user 0.9 (e−0.10) times the PSA level among those taking no medication.

None1.51 (1.27-1.74)0.1-202Reference 
NSAIDs1.59 (1.42-1.75)0.1-33.4−0.10 (0.045)−0.20 to -0.0067.0377
Acetaminophen1.20 (0.77-1.63)0.3-4.6−0.28 (0.18)−0.67 to 0.099.1355
NSAIDs plus acetaminophen5.35 (0.00-10.69)0.5-22.30.60 (0.50)−0.46 to 1.66.2433


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Chronic inflammation has been linked to a multitude of malignancies, including gastric, hepatic, biliary, colorectal, and bladder cancers.20, 21 Although to our knowledge the causal nexus is not as well established in prostate cancer, inflammation is also believed to play a role in prostate carcinogenesis through multiple mechanisms such as infection, hormonal changes, physical trauma, urine reflux, and dietary habits.12–15 Cyclooxygenase (COX) activity, via its inducible type-2 pathway and the subsequent conversion of arachidonic acid to prostaglandins, is a potent mediator of inflammation and is known to be inhibited by NSAIDs and aspirin.22 COX-2 activity has been shown to influence carcinogenesis by favoring cell proliferation, inhibiting programmed cell death, promoting neovascularization, and altering immune surveillance.23–26

Acetaminophen, not traditionally considered an NSAID, has also been recognized to possess some anti–inflammatory properties, although its exact mechanism remains unclear. Acetaminophen had been believed to act via inhibition of the COX-3 pathway,27 but later evidence refuted this theory.28 Recently, acetaminophen has been suggested to selectively inhibit the COX-2 pathway in ex vivo and in vitro studies involving humans.29

Several systematic reviews have examined the relation between NSAID/aspirin consumption and the risk of developing prostate cancer. In their meta-analysis of 12 reports, Mahmud et al30 found that aspirin use provided a 10% risk reduction for prostate cancer overall (summary odds ratio [OR] of 0.90; 95% confidence interval [95% CI], 0.82-0.99) and a 30% risk reduction for advanced disease (OR of 0.70; 95% CI, 0.52-0.94). Harris et al31 reported that daily NSAID use (which included aspirin) was associated with a 39% risk reduction for prostate cancer (relative risk [RR] of 0.61; 95% CI, 0.45-0.85). Jacobs et al32 demonstrated in their cohort study that daily long-term aspirin use was associated with an approximately 20% lower incidence of prostate cancer (OR of 0.81; 95% CI, 0.70-0.94).

The Baltimore Longitudinal Study of Aging, which also examined acetaminophen consumption in addition to NSAID/aspirin use, attempted to determine their effects on serum PSA and the risk of developing prostate cancer. This prospective study concluded that men aged <70 years who used NSAIDs had a lower risk of developing prostate cancer, although this result was not statistically significant (RR of 0.54; 95% CI, 0.27-1.03) (men aged >70 years did not experience a risk reduction).33 In addition, they detected no difference in serum PSA values between NSAID users and nonusers (1.01 vs 0.98 ng/mL, respectively; P = .56), and a nonstatistically significant decrease in PSA among users of acetaminophen and nonusers (1.01 vs 0.93 ng/mL, respectively; P = .09). Platz et al33 were reassured by the lack of clear correlation between NSAIDs and serum PSA, as reductions in PSA due to decreased inflammation may lower the number of men referred for prostate biopsy, thereby decreasing the number of men diagnosed with prostate cancer (incidence) without truly altering the natural history of the disease.

We are not aware of other publications directly reporting on the correlation between NSAID and acetaminophen use and serum PSA levels. However, several original observational studies and reviews of the literature have suggested that NSAIDs may have a role in the chemoprevention of prostate cancer.21, 34, 35 The results reported herein appear to stand in contrast to those found in the Baltimore Longitudinal Study of Aging. Although both studies document a nonstatistically significant decrease in serum PSA in men taking acetaminophen, to our knowledge only the results of the current study revealed a significant negative association between NSAID consumption and serum PSA concentration. The difference between these 2 studies is unclear.

The limitations of the current study include the use of cross-sectional data that does not provide information regarding temporality of association. In addition, the NHANES database does not have detailed descriptions of medication dosing and frequency, and acetaminophen users comprised a small percentage of the overall drug takers, thereby limiting the conclusions that can be drawn from its use. Consumption of medications known to decrease serum PSA, such as finasteride and dutasteride, were not recorded in by the NHANES instrument. Although the NHANES database lacks information regarding prostate biopsies (presence/absence of inflammation, adenoma, or adenocarcinoma) or the number of men eventually diagnosed with prostate cancer, NHANES does capture a nationally representative cross-section of American men and collects information on many potentially important covariates, such as those accounted for in Table 1 of our study. The unexpected finding that concomitant use of both NSAIDs and acetaminophen was associated with increased PSA levels, although not significantly so, may be because of the low number of subjects in those categories (<1% of the total study population) with a corresponding lack of statistical accuracy, and likely does not indicate a biologic effect.


The interplay between NSAID consumption and serum PSA is complex and may involve a variety of different pathways and variables. Nevertheless, the results of the current study are consistent with previous reports that NSAID use is a protective factor for the development of prostate cancer. Conversely, NSAIDs may reduce serum PSA levels without truly affecting the natural history of prostate carcinogenesis, and may result in the underdiagnosis of this condition. The widespread use of PSA screening and the high rate of consumption of NSAIDs in the general population suggest further study is warranted to clarify the potential impact of this class of drugs on prostate cancer development and diagnosis using large epidemiologic studies with a prospective design and collecting more detailed information regarding NSAID use.


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