Dehydroepiandrosterone: A chemoprotective steroid

Abstract

Dehydroepiandrosterone (DHEA) and its sulfate conjugate, DHEAS, are steroids found in high concentration in human plasma. Levels peak in young adulthood and decrease steadily with age as the incidence of cancer increases. Several studies have found that low serum levels of DHEA or DHEAS or their urinary metabolites were associated with the presence or development of breast cancer. Dietary administration of DHEA significantly reduces the incidence of spontaneously and chemically induced mammary tumors in animals. DHEA also has potent chemoprotective actions in several other target organs against a variety of carcinogens. DHEA's mechanism of action is not known but may be due to its uncompetitive inhibition of glucose-6-phosphate dehydrogenase. Animal studies and tissue culture models support this hypothesis. DHEA and synthetic analogues of DHEA have been proposed as possible chemoprotective agents in selected groups. A nested case-control study was conducted using serum samples from a population-based serum bank to examine the association between serum DHEA and DHEAS levels and the risk of developing breast cancer. Blood samples were collected from 20,305 Washington County, MD residents. Incident breast cancer cases were identified through the Washington County Register. Fifteen premenopausal and 30 postmenopausal breast cancer cases were identified and matched to two controls by age and time since last menstrual period. Controls were alive and free of other cancers except for nonmelanoma skin cancer at the time the case was diagnosed. Serum steroid levels were determined by radioimmunoassays (RIAs). The associations between DHEA and DHEAS levels and the risk of developing prostate, bladder, and gastric cancers have also been examined. Prediagnostic serum levels of DHEA were lower in women who developed premenopausal cancer compared to the controls, while postmenopausal cases had significantly higher prediagnostic levels of DHEA than the controls. DHEAS levels were not significantly different between cases and controls in either group. These associations between DHEA and the risk of developing breast cancer did not vary by time to diagnosis. This discrepancy between the results for premenopausal and postmenopausal women may result from the contribution of these steroids to the synthesis of estrogens in postmenopausal women. In similar nested case-control studies, we have shown low levels of DHEA to be a risk factor for subsequent bladder and gastric cancer, but not for prostate or ovarian cancer. These associations between serum levels of DHEA and DHEAS and the risk of developing specific cancers should be considered in the decision to employ DHEA or a synthetic analogue in selected highrisk populations.