OHSU Team Discovers Compound That Lacks Estrogen's 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 are published in the Oct. 22 edition of 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.

Key to the development of STX was the work of organic chemist Thomas Scanlan, Ph.D., a UCSF professor whose laboratory synthesized the estrogen-like compounds tested in the electrophysiological assays used by Kelly and Rønnekleiv.

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, 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."

Kelly's and Rønnekleiv's laboratories will continue to study the new signaling pathway, as well as the membrane estrogen receptor and its role in estrogen's many positive functions.

"We'd like to clone the receptor in order to effectively study its function, but we're not there yet," Kelly said. "That would be some time down the road, but with this new compound we now have a clear strategy for cloning this novel receptor."

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.

Other study collaborators were: Jian Qiu, Ph.D., postdoctoral research fellow, Martha Bosch, research associate, and David Grandy, Ph.D., associate professor, OHSU; and Sandra Tobias, Ph.D., postdoctoral research fellow, UCSF Department of Pharmaceutical Chemistry. The study was supported by grants from the United States Public Health Service.