(continued from previous page)

Osteen and Bruner-Tran’s work is attracting international interest.

“Until Kevin and Kaylon’s work came along, no one had really taken the trouble to look closely at the endometrial tissue inside the uterus of patients with the disease; people had instead fixed their attention on implanted tissue outside the uterus,” Eisenberg said.

Because endometriosis is primarily a disease of the reproductive years, thinking about the disease traditionally focused on the role of estrogen, the primary female sex hormone. There was less attention to progesterone, the hormone which, among other things, appears to moderate the immune response in the uterus, such as to allow pregnancy to occur.

“In our lab, we some time ago found reduced sensitivity to ovarian progesterone in the endometrium of women with endometriosis. It sent us on a chase to understand how the disruption of progesterone action might lead to the disease,” Osteen said.

Osteen has more recently linked failure of progesterone to an increased sensitivity to pro-inflammatory signaling compounds, called cytokines; this increased sensitivity may promote earlier than normal degradation of endometrial tissue in menstruation, and may have a role in the development of the disease.

Osteen has also shown an association between endometriosis, progesterone failure, and reduced expression of an anti-inflammatory protein regulated by progesterone, called CD55.

Osteen and Bruner-Tran said half of their current effort in the lab is concerned with understanding what role the environmental toxicant dioxin may have in endometriosis. In particular, they wonder if exposure to dioxin serves to disrupt the equilibrium between the protective capacity of progesterone and the inflammatory action of cytokines.

“Disrupted equilibrium of progesterone and cytokines seems to be a cardinal aspect of the disease,” Osteen said.

In mice, developmental dioxin exposure creates a disequilibrium similar to that of endometriosis. Bruner-Tran has shown that exposure in pregnant mice sets up disequilibrium in adult offspring, and that the echo of this so-called epigenetic effect lasts up to four generations. Bruner-Tran’s refinement of mice as a disease model for endometriosis will be increasingly helpful in the next chapter of research.

“A number of studies have suggested a relationship between dioxin exposure and the development of endometriosis; our studies are really beginning to sort out the tissue-specific mechanisms of dioxin action,” Bruner-Tran said.

“The next step will be to determine what we can do about it,” Osteen said. “Dioxin is a ubiquitous contaminant that we all carry in our bodies. Are there dietary modifications that we can make to better protect ourselves and our children? Our research suggests that the answer is ‘yes.’”

Osteen and Bruner-Tran still face a welter of interesting questions. Is the immunological dimension of endometriosis a cause or a result of the disease? How might inflammation promote endometriosis, and what is the association with other inflammatory processes in the pelvic theater, such as that leading to irritable bowel? How does progesterone inhibit inflammation? What’s the significance of the apparent association, in both humans and lab mice, between endometriosis and increased exposure to certain environmental toxins? What underlies the association of ovarian cancer and endometriosis in the ovary? In what sense is endometriosis an inherited condition? By way of strengthening anti-inflammatory mechanisms, how effective could nutrition be in inhibiting endometriosis? Could more powerful, synthetic versions of progesterone stop endometriosis?

“The broad scope of these questions explains why people once typically gave up on finding a cure,” Osteen said.

“This is a disease that probably has multiple triggers. We can’t limit our thinking to one system. I consider our lab a functional biology lab.

“The core mechanisms of the disease and the potential therapeutic targets are beginning to be revealed. Our lab has taken a lead in helping pharmaceutical companies identify potential therapies. I foresee new treatments becoming available in the next five to 10 years that will make this chronic condition more manageable for patients.”

Meanwhile, Eisenberg has adopted a new treatment in her clinical practice that’s not yet well known. For patients with intractable pelvic pain, especially those who’ve already had a hysterectomy or hormone therapy, she’ll often use a combination of fish oil and progesterone or progestin. She explains that fish oil is an antioxidant that may affect the immune response.

“It seems to work for our patients. They feel better. I’ve had patients who come in on high levels of narcotics whom we’re able to help,” she said.

Back in the lab, Osteen and Bruner-Tran have taken note of Eisenberg’s success with fish oil and have begun studying the mechanisms of its action. In particular, they are interested in the ability of fish oil to dampen the impact of dioxin exposure.

“We’ve worked together on this disease for more than 10 years,” Osteen said. “We make a good team.” VM

<<back