Medical studies in mice at Vanderbilt University Medical Center may soon prompt a major shift in the traditional clinical approach to endometriosis, after their results suggest that prevention of this common disease may be the most viable option.
The studies found that the risk for endometriosis may manifest as early as fetal development, leading some to believe the condition may be averted, said Kevin Osteen, Ph.D., Pierre Soupart Chair of Obstetrics and Gynecology at Vanderbilt.
“Nobody is looking at prevention; that’s a new frontier for endometriosis.”
“Nobody is looking at prevention; that’s a new frontier for endometriosis,” Osteen said.
Until recently, reactivity to the condition has been the focus for most physicians, Osteen says.
“At conferences, it’s all about which treatments and which surgeries and how to find a good doctor,” added Osteen’s long-time research partner, Kaylon Bruner-Tran, Ph.D., a professor of obstetrics and gynecology at Vanderbilt. “Instead, we’re trying to prevent the disease.”
Risks Start at Home
Osteen and Bruner-Tran have published seminal papers on root causes of endometriosis, with a particular focus on environmental toxicant exposure. Young women born to parents – or even grandparents – with a history of exposure to certain manmade toxic agents are at heightened risk of developing endometriosis later in life.
“Toxicant exposure, particularly dioxin exposure, induces epigenetic changes that go across generations,” Bruner-Tran said. “We’ve gone out five generations in females and three generations in males and the changes are still there.”
Environmental exposure of humans to dioxin and similarly acting compounds is common, the researchers said. Those most at risk include military servicemembers, people working in chemical industries, and residents of low-income areas.
The researchers’ most recent review article outlines how exposure to environmental contaminants also fuels disparities in reproductive health.
The disproportionate exposure of women of color exposed to endocrine-disrupting chemicals, persistent organic pollutants, and heavy metals may be reflected in racial disparity of women’s health conditions, according to the authors’ manuscript.
Prevention With Fish Oil
While environmental risk mitigation is one approach to endometriosis prevention, Bruner-Tran has also focused on nutritional interventions, while Osteen uses organ-on-a-chip technology to zero in on underlying mechanisms that might be targeted pharmaceutically.
A major finding is that a father’s toxicant exposure can be transmitted to his daughter at conception. Fortunately, that is among the type of cases that may be preventable. In mice, the team has shown that treating dioxin-exposed fathers with fish oil prior to mating can improve his partner’s pregnancy outcome as well as reduce the risk of neonatal inflammatory disease in offspring.
“We believe this same approach will also greatly reduce the risk of developing endometriosis in adulthood,” Bruner-Tran said.
“If we offer that intervention to humans – women who have endometriosis and therefore have daughters at higher risk – would their daughters be less likely to develop endometriosis? That’s the next step,” she said.
Immune Cell Training
Additional studies by the research team suggest that immune cells may be contributing to the biologic memory of toxicant exposure through a mechanism mediated by interleukin-1 (IL-1).
“If we could target this immunological defect with immunotherapy, then we reduce the likelihood that the endometriosis phenotype would emerge,” Osteen said. “In mice, for example, before sexual maturity, you can treat some immunological aspects that we think drive infertility, endometriosis and preterm birth.”
Osteen draws parallels from the natural process of immune cell training that the body undergoes in response to infection.
“To understand the mechanism, we’re trying to see if the immunological defect that’s caused by the toxicant exposure is impacting the way the immune system starts to deal with infections,” he said. “Immune cell training hasn’t been looked at in terms of toxicant exposure or in the reproductive field at all as a targetable aspect to preventing endometriosis.”
Prevention On All Fronts
While their research is ongoing, Osteen and Bruner-Tran have drawn clear conclusions.
“We have to be aware of what risks might have been prior to conception,” Osteen said. “In the clinic, there has to be crosstalk between fertility specialists and maternal-fetal medicine.
“We have to be aware of what risks might have been prior to conception.”
“When a pregnancy gets labeled high-risk, the consideration is rarely what the risks were prior to conception, it’s always about looking forward and focusing on carrying the baby to term, et cetera. Fish oil in the third trimester isn’t going to do anything. The maternal-placental relationship is already established.”
“A healthy pregnancy sets the stage for your adult health. And a pregnancy isn’t just nine months, it’s 12, because at a minimum those three months prior to conception – in both males and females – are critical.”
The researchers also emphasize the need for a multifaceted approach to preventing endometriosis and other reproductive health issues. With additional studies, this might include pre-pregnancy fish oil, IL-1 antagonists or other agents to help overcome toxicant exposure, plus mitigation strategies during gestation.
“A healthy pregnancy sets the stage for your adult health,” Bruner-Tran said, adding: “And a pregnancy isn’t just nine months, it’s 12, because at a minimum those three months prior to conception – in both males and females – are critical.”
