Excerpt from Endometriosis Sourcebook

by Mary Lou Ballweg

Editor's note: The dramatic news that endometriosis in monkeys could be caused by exposure to dioxin was first published in the association newsletter in the summer of 1992.

At the workshop "Basic Pathophysiology of Endometriosis" held in Washington in September 1991, a research paper was handed around that marked a surprising finding. It described a very high rate of endometriosis in rhesus monkeys that have been studied by the U.S. Air Force and National Aeronautics and Space Administration over many years to learn about the effects of radiation.

The endometriosis developed spontaneously in 53 percent of the monkeys in the study group that received no radiation, the incidence of spontaneous endometriosis (endometriosis that developed on its own, not due to endometrium transplanted for research purposes) was 26 percent.

The authors note: "Endometriosis in our monkey colony was conclusively linked to whole-body, or in particular, abdominal, exposure to penetrating doses of protons or x-rays should be considered to be at a higher risk of developing endometriosis than unexposed women."

The radiation study brought to mind another study our medical advisor Dr. Paul Dmowski had mentioned in the past on PCBs causing endometriosis in monkeys. I began a fascinating detective effort to track down information about these monkeys once and for all. I learned that this very interesting study involving PCB-induced endometriosis in rhesus and cynomolgus monkeys was reported by now-retired Ottawa physician James Campbell to the Ontario Association of Pathologists in October 1985. The report - entitled "Is Simian Endometriosis an Effect of Immunotoxicity?" - had received little attention. "Simian" refers to monkeys or apes. The study was carried out by the Canadian federal government to determine the effects of PCBs in food. The endometriosis finding was a surprise to the researchers.

In the abstract for his presentation Dr. Campbell wrote: "The endometriosis in these rhesus monkeys was much more productive of inflammatory reaction than the otherwise similar process in humans..." The abstract notes that spontaneous endometriosis is regarded as rare in monkeys and apes. In another presentation on the findings in 1988, Dr. Campbell also noted that the animals experienced marked impairment of reproduction.

PCBs are pollutants that were discharged as waste water by industrial plants until they were banned. They were long lasting, accumulated in water and soil and in animal and human fat, and are secreted in breast milk. The Great Lakes basin is the most PCB-contaminated area of North America; Great Lakes fish are particularly contaminated.

Is it possible, based on the PCB study, to speculate that the disease of endometriosis might have been a mild, mostly tolerable disease in the past (except for presumably for a few unlucky souls) that has become severe and distinctly intolerable with the additional effects of modern pollutants in our bodies? Perhaps these studies will help explain why there seems to be an epidemic of endometriosis in this country.

From Dr. Campbell I learned that there was another colony of rhesus monkeys in which two animals had died of endometriosis. This colony had been part of a toxicology study to evaluate long-term effects of TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin), another environmental pollutant. Groups of eight animals received either 25 parts per trillion of (ppt; high dose) or 5 ppt dioxin (low dose); control monkeys received no dioxin.

TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin) is the most toxic of a group of chemicals widely prevalent in the environment from herbicides, industrial wastes, and other sources. Dioxin is known to cause immune suppression (based on animal research), cancer and birth defects. In addition, it has the ability to act like a hormone in the body.

Dioxin acts with the same mechanism of toxicity as PCBs do according to Dr. Bob Bowman, a researcher involved in the TCDD study. Although the study was originally begun to study the impact of TCDD on reproduction, it was difficult, according to the researcher, because the animals exposed to the chemical had a lot of problems producing viable offspring.

In both the Ottawa study and the TCDD study, reproduction by the animals was markedly impaired. Sixty of the PCB-treated monkeys achieved only 26 pregnancies, with nine stillbirths, for deaths within 1 to 11 days after delivery, and three miscarriages. Sixteen control monkeys achieved nine live births, with two still births.

Removal of the ovaries was carried out in some of the animals to control the disease but was not always successful, lending further support to the EA study showing that the removal of the ovaries does not always cure the disease. (For more on this, see "Does Hysterectomy and Removal of the Ovaries Offer a Cure for Endometriosis?" in Chapter 2.)

Obviously these studies are of extreme importance, providing clues about endometriosis that might not have been found for decades since no one thus far has suspected a link to environmental pollutants and radiation. Also in the TCDD study, endometriosis did not show up until many years after the exposure, making it easy to overlook the link.

At the time I learned of these animals, the original research team had disbanded except for Dr. Bowman, who had been studying the behavioral effects of dioxin in the offspring. And the EPA funding for the colony had run out. Our efforts to secure further funding failed. The university where the monkey are housed began selling them but had not yet shipped them. I called an emergency board meeting of the Endometriosis Association, and we decided to fund the colony for two months and carry out laparoscopies on the colony to determine if endometriosis was present in those still alive.

We asked our medical advisor Dr. Dan Martin, a leading endometriosis surgeon, to carry out the laparoscopies on the monkeys. He was assisted by our vice president of research Sherry Rier and advisor Paul Dmoski, M.D., Ph. D At the end of a long day of laparoscopies - when their researchers broke the code to determine which animals were dioxin-exposed and which were not - there were astounded by the highly statistical results.

Seventy-nine percent of the animals exposed to dioxin had developed endometriosis. More over, the disease increased in severity in direct proportion to the amount of dioxin exposure (the more dioxin the animal had received, the more severe the disease). Control monkey tended to have no disease or minimal disease; exposed monkeys moderate or severe, depending on the amount of dioxin exposure. The dose-dependent relationship was high statistically significant (p less than 0.001) using the American Fertility Society and revised American Fertility Society classifications.

The Endometriosis Association decided to raise the money to maintain the colony for at least three years (beginning in 1992), when the monkeys would probably be in menopause. Our members, primarily women with endometriosis, have generously contributed more than $230,000 thus far for this research. Our goal was to learn as much as possible from this colony. We alerted the research community and requested proposals for further research.

This is a tremendous breakthrough for a disease in which decades of research had not led to any clear understanding of causes of the disease and in which researchers have never been able to cause spontaneous development of the disease. (All the animals studied previously have required researchers to transplant endometrium, the lining of the uterus, in to the animal's abdomen. However, there is no guarantee that transplanting endometrium results in a situation in which the immunological factor that perhaps lead to the disease are recreated in the animal model, meaning that the conclusions drawn from model with transplanted endometrium could be misleading.) So, besides pointing the direction to a possible cause of the disease, this dioxin work also provides a much -needed animal model for studying the disease. (In Brussels, at the Third World Congress on Endometriosis, it was pointed out that endometriosis develops in cycling, menstruating women and should be studied in a cycling menstruating animal.)

Obviously, this work also raises numerous questions and takes us into the completely new area of toxicology. While dioxin is know to cause changes in the immune system, what those changes may be related to endometriosis is still being studied. Sherry Rier, PhD, has continued her immune studies related to endometriosis and the dioxin colony, now as the Tracy H. Dickninson Research Chair of the Endometriosis Association. The program was established at Dartmouth Medical School in fall 1994. (See the next article.)

Work with the dioxin colony will continue as long as funding is available and as long as scientifically valid work can be done with the aging rhesus colony. The original dioxin findings were published in Fundamental and Applied Toxicology in November 1993. Adding to the probable significance of our work, a German study has been published finding that women with endometriosis and antithyroidal antibodies had higher levels of PCBs in their blood. (Interested researchers may contact association headquarters - see "Additional Resources" - for a translation of the study.)

Our work has also been presented at the Society for Gynecologic Investigation (1993), the American Association of Immunology (1993), the Estrogens in the Environment conference (1994), the EPA (1994), and at the National Institutes for Health Endometriosis 2000 conference (1995). (The last conference came about because of the testimony I gave at a U.S. Senate hearing on hysterectomies called by Senator Bargara Mikulski. After the hearing, Senator Mikulski's staff asked what needed to happen next for women with endometriosis. When I said we needed a forum for bringing together toxicologists and endocrinologists so we could make sense out of the new dioxin work, a process that might take 10 to 15 years without a special push, Mikulski's office wrote legislation appropriating funds for the conference!)

Fortunately, the research community has responded with significant interest to the dioxin work (in part because research funds were available). As of this writing, more than 15 studies have been initiated because of the association's dioxin work. Here's a sampling:

The National Institute of Environmental Health Sciences is carrying out a study to determine blood levels in women with endometriosis of dioxin, furans (another pollutant closely related to dioxin), and PCBs.

The Environmental Protection Agency ( EPA) is carrying out a study to determine if a dioxin causes endometriosis like changes in rats with transplanted endometrium.

A study of natural killer cell activity is being expanded by scientists Christopher Coe and Sherry Rier. (Natural killer cells are immune cells that attack tumor cells and virally infected cells.)

A study of antiphospholipid antibodies is being carried out on serum from the animals by Paul Wooley, an expert on the role of these antibodies in autoimmune diseases such as lupus.

The dioxin breakthrough was also covered by leading scientific publication. Science Magazine, in an article entitled "Dioxin Tied to Endometriosis" by Ann Gibbons that appeared in the November 26, 1993, issue, introduce the subject in this way:

More than 5 million women in the U.S. have endometriosis, and nobody knows why. The disease, in which tissue from the uterus mysteriously migrates to the abdomen, ovaries, bowels or bladder, often causes internal bleeding, severe pelvic pain, infertility, and other problems. Researchers have speculated that the disease might be caused by menstrual blood that flows backward or by a developmental disorder that causes tissue to form where it should not, but proof hasn't been forthcoming. Now a study has fingered a new suspect, one with a decidedly unsavory reputation: dioxin.

In human beings, this environmental toxin causes cancer and birth defects, among a host of other ills, and in a colony of female rhesus monkeys researchers have found that it can also play a key role in endometriosis. . ... "This is the first big piece of evidence than environmental toxins may be involved in the pathogenesis of endometriosis," says David Olive, chief of reproductive endocrinology and infertility at the Yale University School of Medicine. "It opens up a whole new area of research."

Scientific American; Science News; Chemical Engineering News; Environmental Health Perspectives: Journal of the National Institute of Environmental Health Sciences, and other also carried stories. The fact that these respected scientific publications mad space for the story indicates the importance of this research. Association members can be proud of these accomplishments - they would not have happened without us.

Notes

1. J.W. Fanton and J. G. Golden, "Radiation-Induced Endometriosis in Macaca Mulatta," Radiation Research 126 (1991): 141-46.
2. J.S. Campbell, J. Wong, L. Tryphonas, D.L. Arnold, E. Nera, B. Cross, and E. La Bossiere, "Is Simian Endometriosis an Effect of Immunotoxicity?" Presented at the Ontario Association of Pathologists Forty-Eighth Annual Meeting (London, Ontario, October 1985).