By Jill Elish
July 2004

FSU STUDY MAY HELP EXPLAIN PAIN OF ENDOMETRIOSIS
Cysts in Rats Develop Two-Way Communication with Brain

TALLAHASSEE, Fla.-Researchers know what causes endometriosis, but how the cysts that are characteristic of the disease maintain themselves and produce severe pain in some women has remained a mystery.

New research led by Florida State University Professor of Neuroscience Karen Berkley indicates that endometrial cysts develop their own nerve supply that could contribute both to the pain symptoms and the body's ability to maintain the disease.

"The new nerves likely sprout from those that supply the blood vessels that grow along with and nourish the cysts," Berkley said. "It has been well known that the cysts need a blood supply to survive. It also has been well known that blood vessels have their own nerve supply. Surprisingly, no one before us had put the two ideas together - that the cysts would be supplied by nerves that grow and extend from those that supply the cyst's blood vessels."

Berkley and colleagues Natalia Dmitrieva and Kathleen Curtis, both of FSU, and Raymond Papka, of Northeastern Ohio Universities College of Medicine, drew the conclusion after studying rats with surgically induced endometriosis. Their findings will be published in the Proceedings of the National Academy of Sciences journal.

The researchers transplanted small pieces of the rats' uteruses into their abdomens to produce cysts similar to those found in women with endometriosis. When the full-grown cysts were later removed, Berkley and her colleagues found that the cysts had become supplied by two main types of nerves, sensory and sympathetic. The sensory nerves are a type that transmits information about inflammation and injury from the cysts to the central nervous system. These nerves could therefore influence the brain's systems that give rise to bodily perceptions such as pain.

The sympathetic nerves send information from the central nervous system to the cysts. These nerves normally control functions such as blood vessel constriction and thus could influence the cysts' blood supply and growth.

"If what we have seen in rats also occurs in women, what may be the case in women with endometriosis is that some of their abnormal growths develop a direct way to communicate with the brain and for the brain to communicate with the growths," she said. "It's a two-way system of communication with the brain."

The variability of the nerve supply of the growths in different individuals may help explain why symptoms and severity of pain vary so greatly in women who have endometriosis, a disease that may affect up to 50 percent of women in their reproductive years, according to Berkley.

"The symptoms and the severity of the disease are not necessarily correlated, so you can have someone with severe disease and no symptoms, or someone with a lot of symptoms but minimal disease," she said. "That's been a puzzle for years. Knowing that some growths may have a sensory and/or sympathetic nerve supply gives us a new way of thinking about how this variability occurs."

Endometriosis occurs when cells from the lining of the uterus escape into the pelvic cavity, perhaps during menstruation, and attach themselves to the outside of the uterus, ovaries or other organs in the abdomen. The cells can develop into growths or cysts that impact fertility and may cause severe menstrual cramps and other pelvic pains.


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16 July 2004

Endo Risk Linked To Diet?

Women may be able to lower their risk of endometriosis by eating more fresh fruit and green vegetables. But, eating red meat and ham appears to increase their risk, according to a study published in the journal Human Reproduction. The researchers in Milan have now called for a study to further investigate the possible links between diet and endometriosis.

Lead researcher Dr Fabio Parazzini from the University of Milan, explained the study: "We asked women about their diet in the year leading up to the interview. In particular, we asked how many times a week they ate portions of selected dietary items, including the major sources of retinoids and carotenoids in the Italian diet. We also asked about their alcohol and coffee consumption. We divided their intake into portions approximating to low, intermediate and high intake of the various dietary factors. What we found was that there was a 40% relative reduction in risk of endometriosis in women with higher consumption of green vegetables and fresh fruit. But, for those with a high intake of beef, other red meat and ham, there was an increase of about 80-100 percent in relative risk."

There was no significant link between endometriosis and consumption of milk, liver, carrots, cheese, fish, whole-grain foods, coffee or alcohol and no association with butter, margarine or oil.

"With a prevalence of 5% in endometriosis in Italy, this means that if our findings are confirmed in prospective studies, we have the potential to cut the prevalence of endometriosis to around 3-4%, which would mean about 200,000 prevalent cases (and about 10,000 new cases a year) fewer in Italy and probably 800,000 fewer prevalent cases in Europe.

The association between vegetables, fruit and meat was unlikely to be due to chance because the researchers analysed several dietary items. However, it was possible there was a 'healthy woman' effect as a high intake of green vegetables, fruit and fish may be generally indicators of more health-conscious attitudes. Also, women who paid closer attention to their health may be more likely to have endometriosis diagnosed.

"However, despite these limitations, our study does suggest that there is some link between diet and risk of endometriosis and indicates that we now need a proper prospective interventional investigation to study these factors. Endometriosis is a distressing condition that affects the quality of life for many women and if there are adjustments that can be made in the diet to lower the risk it is vital that we gain really firm evidence about which foods protect and which foods increase risk," said Parazzini.

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Breast Cancer Drug May Ease Endometriosis

Femara May Offer Alternative in Endometriosis Treatment

By Jennifer Warner
WebMD Medical News Reviewed By Brunilda Nazario, MD
Friday, February 13, 2004

Feb. 13, 2004 -- A drug used to help prevent breast cancer from coming back may also ease the pain and suffering of endometriosis in women who can't get relief from other treatments.

A new study shows the drug Femara, in combination with progestin, significantly slowed the progression of endometriosis as well as reduced the pain associated with the disease.

Endometriosis affects about 10%-15% of women of reproductive age. It occurs when tissue similar to the lining of the uterus grows in other places in the body. Depending on its severity, the disease may cause little or no symptoms or lead to severe pelvic pain and infertility.

There is no cure for endometriosis. Treatment options include surgery to remove the excess tissue or hysterectomy and/or drugs that can drastically decrease the production of estrogen to postmenopausal levels. Occasionally, oral contraceptives or progestins are given to help alleviate the pain of endometriosis.

Researchers say the problem with surgical treatments is that endometriosis often comes back after surgery. Drugs used to treat endometriosis also have unpleasant side effects such as bone loss and may only be used for limited periods of time.

New Option for Endometriosis Treatment?

In this study, published in the February issue of Fertility and Sterility, researchers looked at the possibility of using Femara as an alternative treatment in premenopausal women with endometriosis.

Femara is a type of drug known as an aromatase inhibitor. Aromatase inhibitors work to prevent breast cancer recurrence by reducing the production of estrogen in the body.

Researchers say aromatase, which helps produce estrogen, is also found in the endometrial tissue of women with endometriosis.

"Endometriosis is an estrogen-dependent disease, so estrogen for endometriosis is like fuel for fire. We need to attack the root problem -- the aromatase -- in order to eliminate this cycle, halt the local production of estrogen, and treat women with this disease," says researcher Serdar Bulun, MD, chief of the division of reproductive biology research at Northwestern Memorial Hospital in Chicago, in a news release.

To test that theory, researchers looked at the effects of six months of treatment with Femara, along with progestin to reduce potential hormone-related side effects, in 10 women who had previously been treated for endometriosis with surgery or drugs with unsatisfactory results. The women also took calcium citrate and vitamin D to help prevent bone loss.

Researchers evaluated the women's pelvic pain and performed laparoscopy, a minimally-invasive surgical procedure to visualize the pelvic area, before and after the treatment.

The study showed that none of the women had evidence of endometriosis by the end of the study, as indicated by the second laparoscopy. Pelvic pain was also significantly reduced in nine out of 10 women who had not responded previously to other treatments.

The most commonly reported side effects were irregular bleeding and mild hot flashes. No significant change in bone density (strength) was detected.

"This study demonstrates the potential of aromatase inhibitors to significantly and rapidly reduce disease severity and pain, offering women a new and more effective way of suppressing endometriosis with fewer side effects," says Bulun. "These results appear extremely promising and constitute the rationale for further investigation of this regimen as a first-line treatment for endometriosis."

SOURCES: Ailawadi, R. Fertility and Sterility, February 2004; vol 81: pp 290-296. News release, Northwestern Memorial Hospital.


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by Nancy Humphrey

July 11, 2003

Some women who have infertility due to endometriosis lack molecules in the uterus that allow the embryo to attach to the uterine wall, according to a study published in the July 2003 issue of Endocrinology.

Kevin Osteen, Ph.D., professor of Obstetrics and Gynecology at Vanderbilt University Medical Center, is one of the authors of the study that provides a better understanding of the disease, a painful condition in women of reproductive age.

By continuing the studies with larger numbers of women, the research may eventually lead to a non-invasive way to diagnose endometriosis and the ability to develop drugs that correct the dysregulation of genes associated with this disease.

The study is a collaboration of several members of the Specialized Cooperative Center Program in Reproduction Research (SCCPRR). The SCCPRR, part of the National Institute of Child Health and Human Development, supports 14 centers, including one at Vanderbilt. It is a research-based centers program designed to bring together investigators from multiple institutions to focus on reproductive disorders such as endometriosis.

About 10 to 15 percent of all women have endometriosis. Among women with endometriosis, more than half are infertile.

Endometriosis occurs when bits of the endometrium — the tissue that lines the uterus — are expelled from the uterus during menstruation and travel back up into the fallopian tubes and then into the pelvic cavity, and then become implanted on other pelvic organs. Most often the implants develop on the outside of the ovaries, the fallopian tubes, or the uterus. The mislocated cells imitate the menstrual cycle, first thickening and then bleeding as menstruation begins. Because the implants are imbedded within other tissue, there is nowhere for the blood to go. They form blood blisters that irritate the surrounding tissues, and often a cyst forms to encapsulate the blister. The cyst may become a scar or an adhesion. The end result may be infertility.

The study builds on an earlier NICHD-funded study that reported that a molecule called L-selectin needs to be present on the uterine wall before an embryo can attach to the uterus and a pregnancy can begin.

In the current study, the researchers found that at the time the uterus is most receptive to the embryo, women with infertility due to endometriosis have very low levels of an enzyme that is involved in synthesizing the ligand for L-selectin. The ligand is a rubber band-like molecule that helps L-selectin attach to the uterine wall. Because these women lack the enzyme that makes the L-selectin ligand, the embryo may not be able to attach, which would inhibit pregnancy.

The researchers from Stanford, the University of California in San Francisco, Vanderbilt and the University of North Carolina at Chapel Hill collected endometrium samples from 15 volunteers, eight with endometriosis, during the “window of implantation,” which are the days of a woman’s menstrual cycle when the uterus is receptive to an embryo. With the help of a new technology called microarray analysis, where thousands of genes can be screened at once instead of one at a time, the group analyzed more than 12,000 genes and identified large numbers that are not regulated.

Recent Vanderbilt studies have shown that women with endometriosis fail to respond to progesterone during preparation for pregnancy in terms of down-regulating key enzymes that are associated with menstruation. Past studies have shown that the endometrium makes enzymes called matrix metalloproteinases (MMPs) that are linked not only to endometrial breakdown and regulation, but also to invasive processes, such as cancer or endometriosis. In the normal endometrium MMPs are highly regulated and are suppressed during the time that pregnancy is established. This allows the endometrium to avoid menstruation-like breakdown during early pregnancy.

The Endocrinology study found that 91 genes had more than a two-fold increase in gene expression in women with endometriosis, compared to those without the disease, and 115 genes had more than a two-fold decrease in women with endometriosis compared to those without. These genes are believed to be crucial in the development of endometriosis and in loss of fertility associated with the disease. Osteen said the research shows that genes present in the incorrect amount may contribute to the ectopic development of endometriosis and that it may also create an environment where it is difficult for the embryo to attach to the uterus. It also shows that the endometrium of a woman with endometriosis is abnormal.

Vanderbilt will continue its studies as to why the endometrium of women with endometriosis is different.

“There could be environmental influences that account for endometriosis showing up in more women, and in younger women,” Osteen said. “The epidemiology suggests that this disease is showing up in a younger population, in women in their teens. This could be explained by more awareness, mothers being more attuned to their daughter’s health than in the past, but there’s probably more to it than that.”

Osteen said Vanderbilt researchers are exploring the theory that there is a fetal origin with endometriosis, and that environmental endocrine disruptors, such as dioxin, may be involved. Dioxin is a by-product of combustion and a known human carcinogen, perhaps best known for being in Agent Orange during the Vietnam War. Vanderbilt has received funding from the Environmental Protection Agency (EPA) to study the effect of dioxin on endometriosis. Osteen’s group has also received more recent funding from the National Institute of Environmental Health Services to develop a fetal utero exposure model in mice to investigate whether the failure of steroids to regulate the MMPs could have originated from an environmental exposure.

“We’re all exposed to dioxin,” Osteen said. “We can’t avoid it. It’s in our food and our water. What we want to know is, ‘is it a risk factor?’ What we’re finding is that dioxin has been traditionally viewed as a compound that interferes with estrogen action. But we’re finding it interferes with progesterone-mediated endometrial preparation for pregnancy. This is intriguing because we now know that many genes that are important for normal fertility aren’t regulated normally in women with endometriosis. We can induce a similar effect in the lab by exposing the endometrium to dioxin.”

Funding from the Endometriosis Association helped bring Grant Yeaman, Ph.D., a reproductive immunologist, to Vanderbilt from Dartmouth Medical School. Working with Yeaman the Vanderbilt group is also looking into the possibility that a systemic inflammation and an autoimmune response may be components of the disease process. Osteen said that Vanderbilt is also working with a new biotechnology company to explore the development of a non-invasive, diagnostic test for endometriosis.

“This is both an endocrine disease and a steroid-induced immune disease, involving some disruption of the immune system,” he said. “We have shown that women with endometriosis have a hypersensitivity to pro-inflammatory agents that are normally produced in the endometrium.”