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NIH research grant goes to VMRCVM's Ahmed

By Jeffrey Douglas

Spectrum Volume 18 Issue 34 - June 27, 1996

Estrogens and estrogen-like compounds have recently been implicated in the development of a host of immune-mediated disorders like lupus, rheumatoid arthritis, thyroid disorders, diabetes, and others which seem to affect women more frequently than men.

"Estrogens have been shown to be powerful modulators of the immune system," said Ansar Ahmed, an immunologist in the Virginia-Maryland Regional College of Veterinary Medicine who specializes in the new field of immunoendocrinology. "What remains unknown is the immunological consequences of long-term exposure to estrogen."

Researchers began focusing on a connection between estrogen and autoimmune disorders when they observed that male hormones seemed to do a much better job of suppressing the development of autoimmune disorders than female hormones, which tend to increase their incidence.

Recently funded with a $562,506 grant from the National Institutes of Health, Ahmed and his colleagues hope to learn more about the long-term consequences of estrogen overexposure. Specifically, the researchers will determine whether or not laboratory animals exposed prenatally to hyperestrogenous environments have an abnormal immune system. Ahmed believes this altered immune system makes these animals more susceptible to immune-mediated disorders and less resistant to infections later in life.

There are several ways people are exposed to estrogen, a hormone that helps regulate the female reproductive system, besides those quantities that are naturally manufactured by the endocrine system. For example, estrogen-supplementation therapy is frequently used in post-menopausal women, estrogen-like compounds are created in the environment through the metabolism of industrial and agricultural chemicals like DDT and PCB's, and phytoestrogens occur in plants and vegetables often eaten by people.

The researchers will study diethylstilbestrol (DES), a potent synthetic estrogen once used in people and animals as a therapeutic agent in the treatment of preeclampsia, premature labor, prostatic and breast cancer, pregnancy complications, and as a common estrogen-replacement therapy.

Scientists estimate that anywhere from two- to five-million human offspring were exposed to DES from approximately the 1940s through 1971. In addition, DES was used in about 80 percent of the lambs and cattle produced in the United States between 1955 and 1979, according to Ahmed.

DES was banned in 1979 when medical researchers determined that it was linked to the development of cancer. More recently, it was observed that women prenatally exposed to DES also developed a range of autoimmune disorders. While DES is banned, Ahmed says, the studies are useful since a number of environmental estrogens may have similar properties to DES.

"We hypothesize that an imbalance of the prenatal sex hormone microenvironment could critically influence the highly sensitive fetal immune system and pre-program the individual for eventual autoimmune and/or lymphoproliferative disorders," Ahmed said. He calls this immunological imprinting.

Ahmed believes that pre-natal exposure can cause long-term effects which manifest themselves much later in life when affected individuals experience autoimmune disorders related to problems with T-cell and lymphocyte function.

Just because a woman undertook DES therapy before it was banned does not mean her offspring will necessarily develop autoimmune disorders, said Ahmed, who stresses that the research is preliminary and that some women metabolize these compounds better than others.

Researchers have also learned in recent years that the immune system does not function in "splendid isolation," as was once believed, Ahmed said. Instead, the immune system interacts with the central nervous system and the endocrine system in "bi-directional" ways that promote and diminish immune function in unpredictable ways.

"We are just beginning to understand many of these issues," said Ahmed. "Once we know more about how these estrogenic immunomodulaters influence the immune system, we can use this information to maximize the health and effectiveness of the immune system in people and animals." One long-term goal of the research is to learn how to employ estrogen antagonists (or anti-estrogen or modified hormones) as immunotherapeutic agents, he said.