Research opens the door to prevention, risk reduction

Research opens the door to prevention, risk reduction


Endometriosis research is multilayered, increasingly multispecialty, and full of loops, intersections, and offshoots. It’s driven by medicine’s immediate goals of understanding disease pathogenesis and defining its heterogeneity, and of developing noninvasive diagnostic tests and better treatments.

At the same time, some researchers are investigating even larger, longer-term questions. With ongoing epidemiological research and fast-advancing genetics research, they wonder whether endometriosis might someday be preventable, or whether a young woman might be able, at minimum, to fully understand her own risks and work to reduce them.


Perspectives on Endometriosis Management

“We still don’t really know who is at risk, which makes discovering how and where we can intervene very difficult,” said Stacey Missmer, ScD, the scientific director of the Boston Center for Endometriosis and director for epidemiologic research in the division of reproductive medicine at Brigham & Women’s Hospital.

Even so, she said, “it’s not unreasonable to think about preventing endometriosis in the same way we think about preventing other chronic diseases, particularly other chronic diseases of adulthood.”

The possibility of risk reduction or prevention is framed largely by two forces. One is growing knowledge of the genetics and epigenetics of endometriosis. The other is the “exposome” – the compilation of exposures a person experiences over time, including diet, lifestyle, and toxins.

Researchers involved in genetics and epidemiology are increasingly thinking about synergies.

“It may be that a woman has a certain genetic profile and that exposure to a particular toxin, and a particular diet in childhood, for instance, act in synergy to increase her risk,” said Dr. Missmer, adding that “the critical window for prevention and intervention and mitigation may actually be in childhood.”

Family history

Familial tendencies have long been described for endometriosis. In studies published more than 35 years ago, investigators reported endometriosis in 6% of female siblings and 8% of mothers of patients with histologically verified disease.

Some research published in the 1990s showed even stronger heritability with more than 9% of endometriosis patients having affected first-degree relatives. And in at least several studies, familial cases were reportedly more likely to show severe endometriosis than nonfamilial cases.

Genome-wide association studies (GWAS) aimed at localizing the genes important to endometriosis have turned up numerous candidates. But as has been the case with some other complex diseases, these genes appear to explain only a fraction of the condition’s heritability.

Investigators using even newer DNA sequencing and population-based gene mapping techniques say they’ve been able to look efficiently beyond the types of mutations that are passed down through long ancestral lines and toward genetic modifications or variations that are less frequent (arising more recently) and more likely to impact disease risk in a complex polygenic fashion.

Kenneth Ward, MD, an ob.gyn., left academic medicine 10 years ago to start a medical genetics company in Salt Lake City, Utah. Researchers at Juneau Biosciences now have a list of several hundred gene mutations and variations that appear to be correlated with endometriosis based on DNA analyses of more than 27,000 women with surgically confirmed disease and 2,000 unaffected women matched for ancestry.

Statistical analyses of DNA data from these women, as well as sequencing data from more than 100,000 published population controls, are showing that some genetic variants hold more weight than others. “Some appear to be a major nudge toward endometriosis, and others are a tiny nudge,” said Dr. Ward, who serves as CEO of Juneau.

Photo credits: Allen J. Ward

In the general population it’s unusual to see one or at most two of these variants, whereas patients with endometriosis usually carry at least several,”
he said, noting that the “most valuable” genetic markers they’ve found appear to be “low frequency exome variants predicted to damage the protein being coded for.”

The company has been working on developing a diagnostic DNA test, aimed initially for use in infertility clinics. Dr. Ward will present his findings at the World Congress on Endometriosis in May.

Chemical exposures

Louis DePaolo, PhD, chief of the Fertility and Infertility Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is watching genetics research with interest. Appreciation is growing, he said, for the likely involvement of the epigenome – the collection of chemical modifications to DNA and DNA-associated proteins that alter gene expression – in endometriosis and its inheritability.

Certain environmental toxins have been shown to affect the epigenome in animal studies, in ways that correlate with the attributes of endometriosis, he noted, and ongoing research measuring micro-RNAs in women suggest that the toxins and other components of the exposome may have similar effects in humans.

“It’s not just the DNA that’s important [to inheritability], but epigenetic regulation, changes in how DNA is regulated… how it’s replicated and transcribed, for instance,” Dr. DePaolo said. While some of the epigenome is reset when parents pass on their genomes, “part of this can be inheritable.”

Dioxin and dioxin-like compounds such as polychlorinated biphenyls (PCBs) were among the earliest chemicals to be studied and positively associated with endometriosis in both animal research and human epidemiologic studies.

More recently, attention has shifted to endocrine-disrupting chemicals (EDC) and their role in the disease.

Notably, in a recent assessment of the health care and economic costs attributable to specific EDC exposures in the European Union, an expert panel concluded that between 20% and 39% of uterine fibroids and endometriosis cases are linked to chemical exposures – phthalates in the case of endometriosis.

The panel estimated an annual cost of about 1.4 billion Euros a year and said that prevention of the chemical exposures would substantially reduce disease among European women (J Clin Endocrinol Metab. 2016 Apr;101[4]:1562-70).

In the United States, the ENDO Study, being conducted by the National Institutes of Health, has been among the studies assessing the relationship between various environmental chemicals and endometriosis.

In a recent analysis, it found positive associations for select phthalate metabolites (using banked urine samples) and a twofold increase in the odds of endometriosis, but only in a population cohort where endometriosis was diagnosed from pelvic MRIs and not in an operative cohort (Fertil Steril. 2013 Jul;100[1]:162-9.e1-2).

Such inconsistencies have not been uncommon in correlative epidemiologic and cohort studies, many of which face methodological challenges. Thus far, in research on environmental toxins, there “seem to be differential responses to toxins,” Dr. Missmer said.

This may not be surprising, said the NIH’s Dr. DePaolo. While environmental exposures appear “quite important” for endometriosis, “it’s probably never the environment acting alone or the genome acting alone” in driving the disease, he said. “Women may be susceptible [genetically] and may [need] the right condition to express the endometriosis phenotype.”

Impact of diet

Diet has also been of interest, largely because of its known influence on some of the physiological and pathological processes associated with endometriosis, such as inflammation and estrogen activity.

In a literature review on diet and endometriosis risk published several years ago, investigators concluded that women with endometriosis seem to consume fewer vegetables and omega-3 polyunsaturated fatty acids, and more red meat, coffee, and trans fats. They also reported, however, that the 11 identified studies offered conflicting and variable results, and noted that it may be important to separately analyze the role of diet in the development of endometriosis and in its clinical consequences (Reprod Biomed Online. 2013 Apr;26[4]:323-36)

Dr. Missmer similarly teases things apart.

“There are two ways of thinking about diet,” she said. “There’s risk of the disease: Can diets in childhood, adolescence, and early adulthood impact whether a women will ever be diagnosed with endometriosis? And separately, in girls and women who are experiencing endometriosis already, are there dietary interventions that can decrease their pain symptoms?”

Overall, research that Dr. Missmer has conducted, including some to be presented at the upcoming World Congress on Endometriosis, suggest that a Western diet with less healthy fats and fewer fruits and vegetables is associated with increased risk, compared with a more Mediterranean-like diet, she said.

Body Mass Index may also matter. There is “robust evidence” across various studies, Dr. Missmer said, that endometriosis is more prevalent among girls, adolescents, and young adult women who are lean with a low BMI, compared with others with a high BMI. The inverse relationship remains puzzling and thus far doesn’t lend itself to any preventive measures.

“It may be something genetic, metabolic, something involving nutrient processing,” she said. “We have to figure [this] out.”

Dr. Ward stepped into genetics research after having diagnosed and treated endometriosis as a physician. His vision for the future is framed by both experiences.

“I think there’s a future coming where we’ll probably screen for endometriosis risk using genetic methods during the teen years,” he said.

Certainly, said Dr. Missmer, there are a growing number of “areas of investigation [aimed at determining] if there’s something prior to a girl’s first period that we might be able to influence.”

In the future, she said, “it may well be the pediatricians and the adolescent clinicians who will be at the front lines of care.”

Dr. Missmer serves on the board of the World Endometriosis Research Fund, is the chair-elect of the Endometriosis Special Interest Group for the American Society for Reproductive Medicine, and serves on an endometriosis advisory board for Abbvie. Dr. Ward is employed by and holds equity in Juneau Biosciences. Dr. DePaolo reported having no relevant financial disclosures.

Christine Kilgore is a contributing writer for Ob.Gyn. News.