A team of Oregon Health & Science University researchers has discovered a compound that offers the benefits of estrogen but lacks the popular hormone replacement therapy's suspected side effects and risks.

Scientists in the OHSU School of Medicine's Department of Physiology and Pharmacology, in collaboration with an organic chemist at the University of California, San Francisco, developed a new selective estrogen receptor modulator (SERM) called STX that shows promise as an alternative to estrogen treatment used by postmenopausal women to relieve symptoms of menopause, such as hot flashes and sleeplessness.

Martin J. Kelly, Ph.D., and Oline K. Rønnekleiv, Ph.D., professors of physiology and pharmacology at OHSU, led the team of investigators that discovered a novel estrogen signaling pathway in nerve cells in the brain. Their findings were published in The Journal of Neuroscience.

"The function of STX was really identified from our electrophysiological assay based on testing different (SERM) compounds that acted like estrogen in the central nervous tissue, but not in other tissues susceptible to the cancer-causing effects of estrogens," Kelly said. Other compounds tested included the well-known SERMs tamoxifen and raloxifene, used for the prevention and treatment of breast cancer and osteoporosis, respectively.

STX mimics the effects of estrogen by activating a novel rapid signaling pathway, discovered by Kelly and Rønnekleiv, in nerve cells of the hypothalamus. The hypothalamus is a thumb-sized, central area on the underside of the brain that controls endocrine and autonomic functions, such as ovulation, lactation, stress responses, body temperature and energy balance.

STX appears to act by stimulating a novel estrogen receptor, located in the cell membrane, that activates proteins involved in rapid cell signaling. In this way, it avoids the uterus and breasts, whose growth is stimulated by estrogen through a different pathway, leading to increased cancer risk.

Despite the discovery of STX, Rønnekleiv stopped short of rejecting estrogen as an effective therapy, saying its many benefits far outweigh the risks that studies have yet to unequivocally demonstrate.

"Estrogen definitely has neuroprotective effects in the brain," Rønnekleiv said. "At least in animal models, it's been shown that estrogen can reduce neuronal cell death from stroke. One of the other important actions of estrogen is to prevent osteoporosis."

Peter Kohler, M.D., an endocrinologist and president of OHSU, said the discovery of STX could lead to improvements in the quality of life for tens of thousands of women suffering from the uncomfortable symptoms of menopause.

"This drug has the potential to change the way we treat postmenopausal women," Kohler said. "It appears to be superior to other SERMS in efficacy and potency while avoiding the growth in the target tissues in which cancer risks are greatest."

But Kohler agreed that estrogen's many benefits can't be discounted. The new signaling pathway unveiled by the OHSU team demonstrates the hormone's importance to the brain in protecting itself from cell death caused by disease and the aging process. "Research is continuing, but this important discovery gives us a much better understanding of how the body responds to estrogen at the molecular level," he said.

SOURCES:
The Journal of Neuroscience, October 22, 2003
Oregon Health & Science University (http://www.ohsu.edu)