February 6, 2014
Illuminating The Complexities Of Endometriosis
April Flowers for redOrbit.com - Your Universe Online
Affecting at least 10 percent of women, endometriosis is a disease characterized by endometrial-like tissue found in places other than the lining of the womb, resulting in chronic pelvic pain, infertility and organ dysfunction. Endometriosis is often misdiagnosed, and little is known about how it arises, even though it can cause severe pain and even infertility.
In 2009, the Center for Gynepathology Research was launched at MIT by biological engineer Linda Griffith, with the goal of learning more about the molecular and cellular basis for endometriosis. This would give scientists better drug targets and help doctors decide how to best treat individual patients.
Griffith collaborated with Keith Isaacson, director of the Newton-Wellesley Hospital Center for Minimally Invasive Gynecologic Surgery, and Michael Beste, a postdoc in MIT's Department of Biological Engineering, to identify pattern of immune system signaling molecules that correlates with certain symptoms of endometriosis. The team also identified the underlying cellular activity that produces this signature, which was described in a recent issue of Science Translational Medicine.
The identification of this signature could help researchers develop a patient stratification system similar to that used for breast cancer patients, which tailors treatments to the specific molecular profile of the tumor.
"Endometriosis patients report symptoms of infertility and pain, and beyond that, it's just kind of a guessing game. There are few molecular mechanisms known," Griffith told Anne Trafton of the MIT News Office.
Due to widespread lack of awareness, endometriosis is often undiagnosed or misdiagnosed for many years. The symptoms and severity of the disease can vary, making it difficult to study.
"The delay to a conclusive diagnosis can range anywhere from three to 15 years," Beste said. "There's a real need in the field to improve our understanding of both the basic biology and the clinical manifestations of the disease to better treat and improve the quality of life of affected women."
Endometriosis is often called a "disease of theories" because so little is known about how it works. The theories range from genetics, to environmental toxicants, to a "broken" immune system to reflux menstruation — but so far, no definitive answer has been found for why so many women are afflicted with this disease.
"We know there is a genetic component, we know there is an environmental component, and we know there is an inflammatory component. But it's very difficult to say for individual patients what particular sequence of events led to particular symptoms," Beste said.
Because the disease itself is so little understood, the treatments are not reliable as cures. It is often treated with hormones to produce a menopausal state — which is impractical for women wanting to become pregnant. Select medications are currently used in endometriosis treatment, but these merely minimize symptoms and do not actually treat the disease. Laparoscopic Excision surgery has the highest success rate, but is also not a universal cure. Some women may undergo surgery several times over the course of their life, particularly if endometriosis is superficially treated and not excised.
The new study analyzed peritoneal fluid from 77 patients who reported a wide range of symptom severity. Fifty proteins, including inflammatory compounds known as cytokines, were measured for each sample. Cytokines are used by the body to regulate infectious agents, but can also cause inflammation in the absence of any pathogen, as they do during endometriosis.
A distinctive profile of cytokine activity was found by the researchers to be associated with certain symptoms, specifically ovarian and rectovaginal lesions. Thirteen cytokines were included in the pattern, which also negatively correlated with patient infertility.
Many of the inflammatory compounds that are included in the signature have been previously implicated in endometriosis. The researchers identified c-Jun, a protein that drives inflammation, as one of the key regulators of the newly discovered signature. c-Jun has been linked to endometriosis by prior research, and clinical trials are proceeding on a drug to inhibit the protein.
The team also discovered that many of the molecules that make up the signature are secreted by macrophages, which are a type of immune cell that acts as a guardian. Macrophages patrol tissues, digest foreign materials and present them to other immune cells.
The researchers are continuing their research by investigating the triggers for this immune response, which are likely not the same in every patient. The new study will analyze tissue from subsets of endometriosis patients, including those who experience infertility and those with deeply infiltrating lesions affecting the colon and other pelvic organs. Additionally, they hope to conduct a long-term study of patients who will be tracked from the first report of symptoms. Studies such as these could lead to targeted drugs, as well as a better understanding of a highly complex disease.
"This paper isn't to say we discovered the answer. We're trying to start a conversation with a broad translational science community about this because it is such a terrible disease," Griffith said. "We found something really interesting, but it's only the tip of the iceberg, and if other clinicians are interesting in setting up a similar study with their patients, we're happy to talk about collaborating with them."
Heather C. Guidone, Surgical Program Director at the Center for Endometriosis Care, commented on the new research: "Having been with Dr. Griffith and her team at their Center's launch in 2009, I am always encouraged to see their research progression. It is without question that endometriosis continues to negatively impact the social, physical, emotional and sexual quality of life for 176 million women and adolescents globally; not to mention the profound economic consequences of the disease on society as a whole. There remains an urgent need for continued clarity on pathogenesis, pain mechanisms and potential links to other morbidities; while preliminary, the collaborative conversation started by Dr. Griffith and the MIT team gives us hope that the isolation, lack of public understanding and barriers to quality care faced by so many struggling with this insidious disease may one day - hopefully soon - become things of the past."