Elevated testosterone kills nerve cells

New Haven, Conn.--A Yale School of Medicine study shows for the first time that a high level of testosterone, such as that caused by the use of steroids to increase muscle mass or for replacement therapy, can lead to a catastrophic loss of brain cells.

Taking large doses of androgens, or steroids, is known to cause hyperexcitability, a highly aggressive nature, and suicidal tendencies. These behavioral changes could be evidence of alterations in neuronal function caused by the steroids, said the senior author, Barbara Ehrlich, professor of pharmacology and physiology.

"Next time a muscle-bound guy in a sports car cuts you off on the highway, don't get mad, just take a deep breath and realize that it might not be his fault," said Ehrlich.

Testosterone is the main male hormone and it plays fundamental roles in development, differentiation, and cellular growth. In neurons, testosterone acts as a neurosteroid and can induce changes at the cellular level, which in turn lead to changes in behavior, mood and memory. Both neuroprotective and neurodegenerative effects of androgens have been reported.

The researchers showed that high levels of testosterone triggered programmed cell death in nerve cells in culture. Cell death, or apoptosis, is critical in many life processes, including development and disease. It is characterized by membrane instability, activation of caspases, which are the executioner proteins in apoptosis, change in membrane potential, and DNA fragmentation.

"In the present study we have demonstrated for the first time that the treatment of neuroblastoma cells with elevated concentrations of testosterone for relatively short periods, six to 12 hours, induces a decrease in cell viability by activation of a cell death program," Ehrlich said. "Low concentrations of testosterone had no effects on cell viability, whereas at high concentrations the cell viability decreased with incremental increases in hormone concentration."

The testosterone-induced apoptosis described in this study occurs through overactivation of intracellular Ca2+ signaling pathways. Overstimulation of the apoptotic program in neurons has been associated with several neurological illnesses, such as Alzheimer disease and Huntington disease.

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Co-authors include Manuel Estrada, now continuing his work at the University of Chile in Santiago, and Anurag Varshney, now working at Ranbaxy, a drug discovery company in New Delhi, India.

Journal of Biological Chemistry 281: 25492-25501 (September 2006)


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