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.

The hypothalamus "controls all autonomic functions and maintains homeostasis eating, drinking, sex behavior, maternal and even paternal behavior," Kelly said. In particular, hypothalamic POMC neurons, which are especially sensitive to STX, "are what activate the natural reward pathways. This is the brain's endogenous opiate system."

Having a selective estrogen trigger for rapid signaling is critical for estrogen replacement therapy, Kelly said. STX is structurally distinct from tamoxifen and raloxifene, and it's about 10 times more potent than estrogen and has the potential to be more effective at maintaining cognitive performance of postmenopausal women.

"Women that don't have hormone replacement therapy have been known to have more cognitive impairment in terms of loss of memory, and a higher incidence of Alzheimer's disease," Kelly said. "At least at the basic level, existing SERMs do not seem to help. So the search was on for other compounds one can use to replace tamoxifen. The collaboration with Dr. Scanlan at UCSF made it possible to synthesize and test a series of related compounds before we came up with STX."

Despite the discovery of STX, Rnnekleiv 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," Rnnekleiv 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."

Kelly's and Rnnekle
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Contact: Jonathan Modie
modiej@ohsu.edu
503-494-8231
Oregon Health & Science University
30-Dec-2003