© 2004 by Oxford University Press
© 2004 Oxford University Press
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Prostate-specific Antigen and All-Cause Mortality: Results From the Baltimore Longitudinal Study On Aging
Affiliations of authors: Department of Urology, The Johns Hopkins University School of Medicine, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland (HBC, JW, PL); The Johns Hopkins Bloomberg School of Public Health (EP); National Institute on Aging, Gerontology Research Center (EJM), Baltimore, MD.
Correspondence to: H. Ballentine Carter, Department of Urology, 403 Marburg, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287-2101 (e-mail: hcarter{at}jhmi.edu)
Benign prostatic hyperplasia (BPH) and prostate cancer are two common diseases in aging males. Age is the strongest known risk factor for the development of both diseases. The prevalence of BPH and prostate cancer increase exponentially with age (1,2).
Prostate-specific antigen (PSA) is a protein product of the prostate that is a recognized marker of both BPH and prostate cancer. Cross-sectional data suggest that PSA increases 4% per milliliter of prostate volume and that 30% and 5% of the variance in PSA can be accounted for by prostate volume and age, respectively (3). The risk of a prostate cancer diagnosis in the 10 years after a baseline PSA measurement increases incrementally with increasing PSA levels (4).
Because PSA is a marker of two diseases that are closely related to aging, we wondered if PSA levels might serve as a proxy for the aging process. Our hypothesis was that men in whom prostate disease is present might be biologically more advanced in age than those without prostate disease. If so, all-cause mortality, as a surrogate for aging, should be directly related to PSA.
To investigate this relationship, we reviewed death records and autopsy data of men who were participants in the Baltimore Longitudinal Study of Aging (BLSA), a long-term, prospective study of aging conducted by the National Institute on Aging (5). This study on aging has institutional approval (MedStar Research Institute, Harbor Hospital - Johns Hopkins Hospital), and all human subjects give written informed consent for the study prior to participation. There were 1201 male subjects in the BLSA who had PSA measurements from frozen sera over three decades. After excluding all men who had undergone a simple prostatectomy before their first PSA measure (n = 61), men who had used finasteride (n = 42), and all men with a diagnosis of prostate cancer (n = 169), we were left with a cohort of 929 men who had no history of prostate cancer. Associations between PSA and mortality, and PSA and the development of cancer were evaluated by proportional hazards analysis.
We demonstrated a statistically significant direct relationship between PSA and all-cause mortality, cancer mortality, and the development of cancer (Table 1). For each ng/mL increase in PSA, there was a 3%–5% increase in the risk of an event. There was no statistically significant relationship between PSA and cardiovascular mortality, and this finding was not the result of the lack of events in the cardiovascular group because most deaths were from a cardiovascular event.
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The inclusion of body mass index, testosterone, and free testosterone index as covariates in the analysis did not alter the findings in this study (data not shown). We cannot exclude the possibility that some men in our cohort may have had undiagnosed prostate cancer that could have resulted in elevated PSA levels. However, it is not likely that the cause of death was misclassified because of the careful review of death records and autopsy data. Therefore, it seems unlikely that the relationship between PSA and mortality from all cancers other than prostate could have been driven by the presence of occult prostate cancer.
A relationship between PSA and mortality from cancer other than prostate has not previously been reported. One possible explanation for our findings is that the development of prostate disease with age reflects a loss of growth-control mechanisms within the prostate that also occurs simultaneously in other tissues within the body. If so, men with prostate disease (and elevated PSA levels) would be at greater risk of non-prostatic neoplasia. Although we do not know why men with the highest PSA levels are at an increased risk of development and death from cancer other than prostate, the relationships between PSA and cancer mortality and between PSA and cancer development suggests that the events that lead to PSA elevations with age may be related to the development of cancer in non-prostate tissues.
NOTES
Supported by Prostate Spore NCI-CA58236, NIA Intramural Research Program.
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