CAVHS / UAMS Scientists Show How Synthetic Hormone Stops Bone Loss without Risking Cancer

By todd

LITTLE ROCK – Arkansas scientists who first reported a possible safe alternative to traditional hormone replacement therapy now have unraveled the mystery of how the synthetic hormone works.

A group of researchers at the University of Arkansas for Medical Sciences (UAMS) and Central Arkansas Veterans Healthcare System (CAVHS) reports in the June 1 issue of the Journal of Clinical Investigation that the synthetic hormone, estren, operates through a chain of events involving enzymes known as kinases – working not only to stop bone loss but to promote improved bone strength.

Scientists and health care leaders interested in aging have waited expectantly for more developments from the group, led by Stavros Manolagas, M.D., Ph.D., who is a professor in the UAMS College of Medicine and endocrinology chief at CAVHS. Manolagas attracted worldwide attention in October 2002 with the revelation that a synthetic hormone he calls estren appeared to be a safer method of curbing bone loss.

Manolagas and his colleagues at UAMS describe the chemical process by which estren prevents bone deterioration, like traditional hormone replacement, without the risk of uterine or breast cancer of traditional therapy. The synthetic hormone appears to be effective in men as well as women. The researchers also propose that estren illustrates the potential of an entire class of synthetic chemical compounds that could be therapeutic for a variety of diseases and conditions without the negative side effects of their natural counterparts.


Hormones like estrogen operate in two ways in the body, launching separate cascades of signals, Manolagas and his colleagues have found in previous studies. The so-called “genotropic” signaling pathway regulates the expression of genes in the cell nucleus. This pathway has been linked to cancer development in reproductive tissues. The “non-genotropic” pathway promotes bone growth by extending the lives of bone-building cells, called osteoblasts, and shortening the lives of bone-destroying cells called osteoclasts.

Manolagas’s research group reported last year in the journal Science that they had found the possible alternative to hormone replacement therapy. Their findings were especially timely because of federal concern about the risks of hormone replacement therapy (HRT). That therapy, which has involved a combination of the hormones estrogen and progestin, provides some protection from bone fractures in women but increases women’s risk for breast cancer, uterine cancer, heart attack, stroke, and blood clots.

Manolagas is director of the Division of Endocrinology in the Department of Internal Medicine of the UAMS College of Medicine. He directs the -Center for Osteoporosis and Metabolic Bone Diseases at the Arkansas Cancer Research Center at UAMS.

His colleagues in the study are Stavroula Kousteni, Li Han, Jin-Ran Chen, Maria Almeida, Lilian I. Plotkin, and Teresita Bellido.

Manolagas received his doctorate of medicine from the University of Athens Medical School in Athens, Greece. He served his residency at Stepping Hill Hospital in Stockport, England, and was a fellow in endocrinology at Manchester Royal Infirmary, University of Manchester, England. Prior to his present position, he was on the faculty of the University of California at San Diego for nine years, and Indiana University for six years.

Author of more than 200 articles and book chapters, and more than 300 abstracts, Manolagas has conducted research on the pathophysiology of osteoporosis and other disorders of bone and mineral metabolism, and the interactions of the endocrine and the immune system.

He is a member of the highly prestigious Association of American Physicians, the recipient of the Founder’s Award of the American Society for Bone and Mineral research for his fundamental contributions to the field, the winner (among 52 contestants across the nation) of the highly prestigious AlliedSignal award for research on aging for studies on the new drugs in 1999, and the UAMS Distinguished Faculty Scholar in 2000.