How the Hormone DHEA Affects Cells

A major stumbling block to understanding how dehydroepiandrosterone (DHEA) affects the body has been the lack of a clearly identifiable mechanism of how the hormone, often touted as the "fountain of youth," acts on cells.

However, a University of Iowa Health Care study is the first to show evidence of a cellular receptor through which DHEA stimulates production of nitric oxide, a chemical that helps regulate blood pressure, inhibits blood clotting and prevents narrowing of the arteries. The findings, which appear in the June 14 issue of the Journal of Biological Chemistry, may help investigators design clinical trials of DHEA, which have been few.

"The significance of our study is that it provides a scientific basis for further study of the DHEA action in humans," said the study's lead investigator Joseph Dillon, M.D., University of Iowa assistant professor of internal medicine and a researcher and staff physician with the Veterans Affairs Medical Center in Iowa City. "Our findings show that there is a receptor for DHEA on the inner lining cells of blood vessels. The receptor responds to levels of DHEA that circulate normally within the blood stream and links DHEA to the production of nitric oxide. Unlike research with all the other major hormones and steroids, no one had previously been able to identify a receptor for DHEA in cells."

DHEA and a closely related molecule called DHEAS are made mainly in the adrenal gland and circulate in the blood stream in higher concentrations than any other steroid hormone, including estrogen or testosterone. DHEA production increases around age 6 and peaks in the mid-20s. A 75-year old person has about 20 percent of the amount of DHEA in circulation that he or she had at age 25. Some older people take DHEA supplements, which are available without a physician's prescription.

Dillon, whose co-investigator was Dongmin Liu, Ph.D., a University of Iowa research investigator, said their strategy was to look in an unusual place for the receptor.

"All steroid hormones have receptors within cells. The hormone enters the cell and then turns on the receptor," Dillon explained. "We found the DHEA receptor on the outside, not inside, of cells. We also looked at cells which have not previously been examined. Other investigators have focused their research on immune blood cells or the liver, but we looked at the endothelium, or cells lining the blood vessels."

It appears Dillon's findings have made a substantial contribution to begin to figure out the DHEA biological puzzle, said Frank Bellino, Ph.D., administrator of the Endocrinology Program within the Biology of Aging Program at the National Institute on Aging (NIA), which provided funding for the study.

"I think this is the first paper with apparently reasonably firm evidence that DHEA interacts with G-protein coupled receptors, a class that people have not previously investigated," Bellino said. "Knowing the biological pathway through which DHEA may act will help in designing better clinical studies."

Bellino emphasized that Dillon's findings do not reveal whether there are benefits to taking DHEA but provide a firm starting point for conducting studies to sort out risks and benefits. The NIA currently does not recommend that people take DHEA because of the lack of evidence of any benefits.

"There is the issue of exaggerated claims -- that the DHEA stops cancer and prevents diabetes and obesity -- and these claims are based on rodent research. However, the biology of DHEA is very different in rodents than it is in humans," Bellino said. "Rodents are not a good model for humans when it comes to DHEA. They make it differently and at much lower levels."

The Food and Drug Administration does not currently regulate DHEA because of its status as a dietary supplement.

Dillon said the next steps in his research will be to define all the cellular steps involved in how DHEA and closely related steroids produce their effects.

"We can now start to tease apart the effects of DHEA that definitely can be attributed to a specific mechanism," he said. "Once we have fully isolated the receptor, we will be able to determine if there are DHEA steroid products that are even more powerful than DHEA itself.

"Completing the isolation of the receptor will help us to rapidly test novel compounds and other natural hormonal products of DHEA in order to eventually develop medications that have beneficial effects in a wide range of diseases, including cancer, heart disease, obesity and diabetes," Dillon added.

In addition to receiving National Institute on Aging funding, the investigation also was facilitated by the Office of Research at the Veterans Affairs Medical Center in Iowa City.