Vol. 9, 517–521, May 2000 Cancer Epidemiology, Biomarkers & Prevention 517 Short Communication Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate and the Subsequent Risk of Developing Colon Cancer1 Anthony J. Alberg,2 Gary B. Gordon, Introduction Sandra C. Hoffman, George W. Comstock, and Colon cancer is the fourth most common cancer in the Kathy J. Helzlsouer United States and the second highest cause of cancer mortality Department of Epidemiology, The Johns Hopkins School of Hygiene and (1). The American Cancer Society estimates that during 1999, Public Health, Baltimore, Maryland 21205 [A. J. A., S. C. H., G. W. C., almost 95,000 persons will be diagnosed with colon cancer and K. J. H.], and The Johns Hopkins Oncology Center, Baltimore, Maryland that almost 48,000 people will die of the disease (1). One factor 21205 [A. J. A., G. B. G., K. J. H.] that can alter the risk of colon cancer is the hormonal milieu. For example, postmenopausal hormone replacement therapy reduces the risk of colon cancer among women (2). DHEA3 and Abstract its sulfate conjugate, DHEAS, are steroids produced primarily This purpose of this study was to evaluate whether serum by the adrenal gland. In humans, they circulate at high concen- dehydroepiandrosterone (DHEA) and its sulfate trations, but their specific physiological functions remain un- conjugate, dehydroepiandrosterone sulfate (DHEAS), are known, other than serving as precursors in the extra-adrenal associated with the likelihood of developing colon cancer. synthesis of androgens and estrogens (3). They have properties, A nested case-control study was conducted using the such as antioxidant capacity, inhibition of weight gain, and serum bank and cancer registry in Washington County, inhibition of cellular proliferation, that could enable them to Maryland. From a population of 20,305 county residents protect against cancer (4, 5). Specifically, DHEA has been who donated blood in 1974, incident cases of colon cancer proposed as a potential protective agent against colorectal can- were matched cer (5). The results of animal studies provide some support for (117 ؍ that occurred from 1975 to 1991 (n to one cancer-free control by age, race, and sex. Serum this hypothesis. The administration of DHEA to laboratory specimens that were stored at ؊70°C since 1974 were animals has been reported to inhibit tumor development in a assayed for DHEA and DHEAS. Compared with the number of anatomical sites (4). DHEA or DHEA analogues controls, the mean serum concentrations of cases were have been shown to reduce cancer incidence in various animal and 13% lower for models of colon cancer, including the dimethylhydrazine model (0.90 ؍ lower for DHEA (P 3% When DHEA levels were analyzed (6) and the rat azoxymethane model (7), but not all studies have .(0.60 ؍ DHEAS (P according to fourths, no noteworthy associations were demonstrated benefit (8). Because there is a lack of information observed. Compared with the lowest fourth, the highest concerning DHEA, DHEAS, and colon cancer among humans, fourth of serum DHEAS was nonsignificantly associated we conducted a nested case-control study to investigate whether with a halving in the risk of colon cancer (odds ratio, physiological concentrations of serum DHEA and DHEAS ؍ 0.50; 95% confidence limits, 0.18, 1.37; Ptrend 0.22), were associated with the risk of developing colon cancer. and further analyses showed the potential protective association was confined largely to males (highest-versus- Materials and Methods lowest fourth odds ratio, 0.26; 95% confidence limits, Study Design. This study was carried out using the serum ؍ 0.06, 1.16; Ptrend 0.06). This prospective study does not provide strong evidence that circulating DHEA and bank and cancer registry in Washington County, MD. The DHEAS concentrations are associated with the risk of serum bank was established in 1974, when 20,305 community volunteers donated blood samples for use in research studies. colon cancer. Among men, DHEAS was associated with a Ϫ decreased risk of colon cancer, but the association was After preparation of serum, the samples were stored at 70°C. within the bounds of chance. Further studies are needed Additional information was obtained from the study partici- to either support or refute the potentially promising lead pants during a brief interview, when demographic and health- hinted at by the results for DHEAS. related information (e.g., cigarette smoking history) were col- lected. Among the cohort of blood donors, cases of colon cancer that occurred from January 1, 1975 through September 30, 1991 were ascertained by linkage to the Washington County cancer Received 11/10/98; revised 1/10/00; accepted 1/24/00. registry. This registry has been maintained by the staff of the The costs of publication of this article were defrayed in part by the payment of Training Center for Public Health Research since 1968. Cancer page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cases are primarily ascertained from two sources: (a) discharge 1 Supported by research Grants CA 62988 from the National Cancer Institute and records from the Washington County Hospital; and (b) death DAMD17-94-J-4265 from the Department of Defense. A. J. A. is a recipient of certificates. A high proportion of cancer patients in the county Preventive Oncology Academic Award CA73790 from the National Cancer Institute. G. W. C. is a recipient of Research Career Award HL21620 from the National Heart, Lung, and Blood Institute. 2 To whom requests for reprints should be addressed, at Department of Epide- miology, The Johns Hopkins School of Hygiene and Public Health, 615 North 3 The abbreviations used are: DHEA, dehydroepiandrosterone; DHEAS, dehy- Wolfe Street, Baltimore, MD 21205. droepiandrosterone sulfate; OR, odds ratio; CL, confidence limit. Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2000 American Association for Cancer Research. 518 Short Communication: Serum DHEA and DHEAS and the Risk of Colon Cancer receive their care at Washington County Hospital because it is Table 1 Percentage distribution of selected characteristics among colon the only general hospital in the county and has an excellent cancer cases and matched controls at study baseline, Washington County, Oncology Service. As a branch of the Washington County Maryland, 1974 Health Department, the Training Center for Public Health Re- Cases (n ϭ 117) Controls (n ϭ 117) search has access to death certificates. Linkage between the Washington County Cancer Registry and the Maryland State Sex Cancer Registry showed that for 1993, the county registry Male 41.9 41.9 Female 58.1 58.1 ascertained 4% more cases of colon cancer than the state Age (yr) registry. The number of colon cancer cases expected on the Յ44 8.5 8.5 basis of race/sex/age-specific rates from the Surveillance, Ep- 45–54 30.8 30.8 idemiology, and End Results registries is similar to the number 55–64 35.0 35.0 of observed cases in the cohort that donated blood for the serum 65ϩ 25.6 25.6 bank, suggesting that reporting is essentially complete for this Cigarette smoking population. Never 44.4 53.0 Cases of rectal cancer were not included in the study. Of Past 35.9 33.3 Current 19.7 13.7 121 incident cases of colon cancer that were diagnosed during Period diagnosed with cancer this period and had no prior history of cancer (other than 1975–1978 21.4 NAa nonmelanoma skin cancer or cervical carcinoma in situ) that 1979–1982 18.8 were used for a study of serum micronutrients (9), sufficient 1983–1986 33.3 serum for the DHEA and DHEAS assays was available for 117 1987–1991 26.5 cases. One cancer-free control was matched to each case by Age diagnosed with cancer age, sex, and race (all were white). The controls were age- 35–44 3.4 NA matched to within 1 year of the case, except for three matched 45–54 9.4 55–64 28.2 sets where the control was within 2 years of the case and one 65–74 26.5 matched set where the control was 4 years older than the case. 75ϩ 32.5 Measurement of Serum DHEA and DHEAS. Aliquots of the Cancer site stored serum specimens were prepared and were then immedi- Cecum and ascending 36.8 NA ately refrozen at Ϫ70°C until the assays were performed. Transverse colon 11.1 DHEA and DHEAS were assayed using commercial RIA kits Descending colon 10.3 (Wien Laboratories, Succasunna, NJ) according to the manu- Sigmoid colon 36.8 Other, multiple sites 5.1 facturer’s instructions, except that hexane:methylene chloride (1:1) was used to extract the DHEA. These kits were selected a NA, applies only to the case group. based on a favorable comparison to reference methods used to measure DHEA and DHEAS (10). Matched case-control sets were assayed together in the same RIA run. The laboratory for men and women because colon cancer mortality is higher in personnel were masked to the case-control status of the serum men than women and because men have higher circulating specimens. DHEAS has been observed to be stable at Ϫ20° for concentrations of DHEAS. The etiology of colon cancer may a storage period of similar duration (11). differ by anatomical site (13). Using a convention common to Statistical Analysis. All data analyses accounted for the many epidemiological studies, colon cancer sites were grouped matched study design. The distributions of DHEA and DHEAS as right-sided (cecum, ascending colon, and transverse colon, were skewed toward high values. Hence, the data were trans- which included the hepatic and splenic flexures) and left-sided formed by the natural logarithm for computing paired t tests to (descending colon and sigmoid; Ref.