But the verdict is still out on synthetic DHEA, which was banned by the Food and Drug Administration in the 1980s and can now be sold only as a food supplement.
Now, researchers at Lehigh University believe they have established a possible cause-and-effect relationship between DHEA and the workings of the body's central nervous system.
Neal Simon, chair of the biological sciences department at Lehigh, says he and his colleagues have discovered the "genomic effect" of DHEA, or its influence at a cell's genetic level. By contrast, says Simon, most of the other research into neurosteroids has focused on their activity at the cell surface.
"We are one of only a few groups - to the best of my knowledge - that has demonstrated a genomic effect of DHEA in the central nervous system. This finding opens up a wide range of possibilities regarding how DHEA produces its effect as a neurosteroid. You have to consider a host of other effects it might produce." Two of those effects could be improved survival of neurons, or nerve cells, or increased neurite outgrowth, which could contribute to improved cognition and memory.
Simon and his group are particularly interested in the interaction between DHEA and androgen, the hormone that stimulates the development of sex characteristics in males. "We have looked at DHEA's structure, and at metabolic pathways in cells, to determine what effects androgen might have at the genetic level," says Simon. "We are the first lab to demonstrate that DHEA can act to regulate gene function by interacting with androgen receptors, either by itself or after its conversion to other androgens. This is a very new view of how DHEA works. After you establish its genomic effects, you have to consider a host of other effects it might also have."
One of those effects could be improved survival of neurons, or nerve cells, says Simon. DHEA might contribute to this by promoting the growth of dendrites, the short branches protruding from neuronal surface that conduct impulses back to the neuron. Dendrites form as a person learns, enriching and enhancing brain function. Dendrites tend to grow less readily on the neurons of older or depressed people, says Simon, but this can be reversed when people take on new learning challenges.
"We think the potential contribution of androgens to psychological well-being has not been well-examined," says Simon. "The focus of most research in this field has been on estrogen. Both men and women have androgen and estrogen, but in different ratios. While estrogen has been considered in a positive light, androgen, possibly because the rates of heart attacks are higher in men, has historically been regarded more negatively."
The applications of this research, says Simon, are exciting. "Can hormone replacement therapy be valuable for men, too?," he asks. "Women are often prescribed estrogen during and after menopause, and that has a lot of benefits, although it is not without risks. How should we approach replacement therapy with men? That's an open question. DHEA is one possible replacement."
Simon is now trying to determine how DHEA affects brain function - both through its influence on certain genes and also through its effect on cell-surface receptors, particularly the GABAA receptor, which is associated with inhibition and anxiety.
"By affecting the GABA system through multiple paths and gene function through the androgen receptor, you can at least tie DHEA to the modulation of anxiety," he says. "Impulsive behavior, sexual function, and cognition also have to be considered as potential targets for DHEA. We expect that modulation of neuronal growth factors is part of the picture."
The human body produces its own DHEA in the brain and in the adrenal glands, says Simon, and, when needed, it converts DHEA into other hormones such as testosterone and estrogen. The body's supply of DHEA peaks in the twenties and drops as much as 90 percent by the seventies.
Simon stresses that he and his team are only beginning the search to determine the impact of DHEA. They will look for changes in gene expression, changes in growth factors, and for structural changes in the brain such as neurite outgrowth. If they find such phenomena, "then we could say there is some basis for potentially positive effects of DHEA. But we haven't looked that far yet."
Simon will use models from animals treated with DHEA and study material from their brains "to get a picture of what gene activity has gone up or down in response to DHEA. We would like to know if DHEA potentially has value as a therapeutic intervention strategy, what it is doing, and how it is doing it."
Simon has received major awards to conduct his research including grants from the National Institutes of Health and the Guggenheim Foundation. He has worked with the eminent French scientist Marc Haug, in Strasbourg, France, and collaborates with Dr. Shi-fang Lu, a research scientist in Lehigh's biological sciences department, and Shan Hu, a Ph.D. candidate at Lehigh.
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