Testosterone needs estrogen's help to inhibit depression

Specifically, the testosterone must first be converted into estrogen. That's the latest discovery from the lab of biomedical sciences Professor Mohamed Kabbaj. With a six-year grant from the National Institute of Mental Health, he is investigating the ways in which anxiety affects the sexes differently.

Women are 70 percent more likely than men to experience depression during their lifetime, according to the NIMH. It also reports that "major depressive disorder" affects more than 20 million U.S. adults each year.

So far, the link between testosterone conversion and anxiety/depression has been detected only in laboratory animals. But Kabbaj says the results are potentially promising for humans as well.

"Maybe in the future, when we are trying to develop an antidepressant that works in low-testosterone males, we can target some of the mechanisms by which testosterone acts, since it has numerous side effects," he said.

Testosterone acts on many receptors and pathways in the brain, so the challenge is to come up with a drug that provides only the effect you want.

"A number of treatments are available for depression, but the drugs are not effective in all patients and the side effects can be serious, especially on the heart," said biomedical sciences Professor Pradeep Bhide, director of the College of Medicine's Center for Brain Repair. "Therefore, there is an urgent need for safer and more efficacious drugs to treat depression. Dr. Kabbaj's research is offering new insights into the causes of depression and the role of hormones in this disorder. Such insights are critical for the development of new drugs and diagnostic tests."

Kabbaj's latest paper was published in Biological Psychiatry.

He already knew that testosterone had a protective effect on males, just as estrogen and progesterone do on females. He also knew that most testosterone was converted into estrogen in the brain. What he didn't know was that those anxiety- and depression-inhibiting effects couldn't be produced unless the testosterone was first converted to estrogen.

"There is an enzyme in the brain that 'mediates' the conversion of testosterone into estrogen," Kabbaj said. "We inhibited that enzyme in a specific brain area implicated in the regulation of mood. And when you do that, you lose the antidepressant effect of testosterone. So the conversion is very important."

His lab targeted the hippocampus area of the brain, where testosterone acts through what's known as the MAPK pathway to induce its antidepressant and anti-anxiety effects.

"But we have to be careful about that pathway," Kabbaj said, "because it's also implicated in cellular growth and cancer. Therefore, we're looking for other pathways that don't have these effects. It's complicated. Nothing is ever simple, but we'll get there."