Living With Endometriosis

Omega fatty acid balance can alter immunity and gene expression
By Nick Zagorski
American Society for Biochemistry and Molecular Biology
Appearing in the June 5, 2009 issue of the Journal of Biological Chemistry (JBC)

For the past century, changes in the Western diet have altered the consumption of omega-6 fatty acids (w6, found in meat and vegetable oils) compared with omega-3 fatty acids (w3, found in flax and fish oil). Many studies seem to indicate this shift has brought about an increased risk of inflammation (associated with autoimmunity and allergy), and now using a controlled diet study with human volunteers, researchers may have teased out a biological basis for these reported changes.

Anthropological evidence suggests that human ancestors maintained a 2:1 w6/w3 ratio for much of history, but in Western countries today the ratio has spiked to as high as 10:1. Since these omega fatty acids can be converted into inflammatory molecules, this dietary change is believed to also disrupt the proper balance of pro- and anti- inflammatory agents, resulting in increased systemic inflammation and a higher incidence of problems including asthma, allergies, diabetes, and arthritis.

Floyd Chilton and colleagues wanted to examine whether theses fatty acids might have other effects, and developed a dietary intervention strategy in which 27 healthy humans were fed a controlled diet mimicking the w6/w3 ratios of early humans over 5 weeks. They then looked at the gene levels of immune signals and cytokines (protein immune messengers), that impact autoimmunity and allergy in blood cells and found that many key signaling genes that promote inflammation were markedly reduced compared to a normal diet, including a signaling gene for a protein called PI3K, a critical early step in autoimmune and allergic inflammation responses.

This study demonstrates, for the first time in humans, that large changes in gene expression are likely an important mechanism by which these omega fatty acids exert their potent clinical effects.

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From the article: Effect of dietary fatty acids on inflammatory gene expression in healthy humans, by Kelly L. Weaver, Priscilla Ivester, MIchael C. Seeds, L. Douglas Case, Jonathan Arm and Floyd H. Chilton
Article Link: http://www.jbc.org/cgi/content/abstract/M109.004861

Corresponding Author: (Ski) Floyd H. Chilton, III, Ph.D., Director, Wake Forest and Brigham and Women’s Center for Botanical Lipids, Winston-Salem, NC; Tel: 336.713.7105, email: schilton@wfubmc.edu

Discovery May Lead To New Endometriosis Treatments
By Jennifer Warner
WebMD Health News
Reviewed by Brunilda Nazario, MD

June 18, 2003 — Genetic abnormalities may explain why some women with endometriosis suffer from infertility. New research shows that women with endometriosis-related infertility lack a certain enzyme in their uterus that allows the embryo to attach the uterine wall, which establishes a normal pregnancy.

Researchers say the finding could lead to new screening tests for the condition as well as treatments for endometriosis and the infertility often caused by it.

“The causes of endometriosis and of the infertility that’s associated with it have eluded scientists for many years,” says Duane Alexander, MD, director of the National Institute of Child Health and Human Development (NICHD, which partially funded the research), in a news release. “This study provides a better understanding of this disease, and may lead to new therapies to treat women who have the disorder.”

Endometriosis affects 10%-15% of women of reproductive age and occurs when endometrial tissue that normally lines the inside of the uterus spreads to other organs, such as the fallopian tubes, intestines, and ovaries. The severity of the condition varies greatly among women and may cause no symptoms at all, but it can also lead to severe pelvic pain and infertility.

Discovery Adds Evidence to Endometriosis-Infertility Link

Researchers say the discovery builds on previous research that found a molecule known as L-selectin needs to be present on the uterine wall for an embryo to attach itself and allow a pregnancy to begin.

In this study, researchers found that at the moment in a woman’s menstrual cycle when the uterus is most receptive to embryo implantation (days 20-24 of a 28-day cycle), women with endometriosis-related infertility lack an enzyme that holds L-selectin in place on the wall of the uterus, making it impossible for the embryo to attach itself.

Researcher Linda Giudice, MD, PhD, of Stanford University, and colleagues also found that certain genes also appear to be malfunctioning in the endometrial tissue of women with endometriosis, based on samples they collected from 15 non-pregnant women, eight with endometriosis and seven without.

The findings, published in the July issue of Endocrinology, may also lead to new, noninvasive ways to screen women for endometriosis. Currently, diagnosis of the condition is usually confirmed through a surgical procedure called a laparoscopy or laparotomy, to remove tissue samples from the abdomen.

But if further studies confirm these results, researchers say new treatments and a screening test that detects the abnormal genetic activity associated with endometriosis may one day be developed.

“This now offers an opportunity to create drugs to correct this error in gene expression, and therefore a treatment for endometriosis-related infertility,” says Giudice in a news release.

Caffeine Linked To Sex Hormones
SOURCE: American Journal of Epidemiology (October 1996;144(7):642-644)

NEW YORK (Reuters) — Older women who drink two or more cups of coffee a day, or four cans of caffeinated cola daily may be lowering their risk for breast cancer, while at the same time upping their chances of developing osteoporosis, a new study on caffeine and sex hormones suggests.

Reporting in the October issue of the American Journal of Epidemiology, researchers say these changes in disease risk may be associated with decreased levels in some types of estrogen, and a decrease in the male sex hormone testosterone in postmenopausal women who consume a lot of caffeine.

According to Drs. Rebecca Ferrini and Elizabeth Barrett-Conner of the University of California-San Diego, in La Jolla, their three-year study of 728 Caucasian women, aged 42 to 90 years, showed that the blood of high-caffeine consumers had increased amounts of a substance — sex hormone-binding globulin — produced by the liver that sweeps up and metabolizes steroid hormones, such as testosterone and estradiol, a form of estrogen.

“The higher level of binding globulin probably explains the observed reduction in bioavailable testosterone levels,” they write.

However, the researchers did not find a similar drop in estradiol, which they say is probably because levels of this estrogen hormone are already very low in women who have gone through menopause.

Estradiol is the most important of the female sex hormones, and is essential for breast development and the health of the reproductive system.

“These intriguing caffeine-hormone associations may explain some of the previously reported associations between hormone-related conditions and the intake of caffeinated beverages,” they write.

“If caffeine increases sex hormone-binding globulin levels, this may result in decreased levels of bioavailable estradiol and testosterone, providing one possible mechanism for both a diminished breast cancer risk, and increased risk of osteoporosis among caffeine users,” the authors conclude.

But, they also note that their finding of high levels of estrone — another estrogen hormone — among high-caffeine users “may partially account for the association between caffeine consumption and endometriosis” (inflammation of the uterus lining) found in studies of younger, premenopausal women.

Role of endometriosis in cancer and tumor development
2002 Mar; 955:281-92; discussion 293-5, 396-406.

Department of Gynecology and Obstetrics, Stanford University, California 94305, USA. lswiersz@leland.stanford.edu

Endometriosis, like cancer, is characterized by cell invasion and unrestrained growth. Furthermore, endometriosis and cancer are similar in other aspects, such as the development of new blood vessels and a decrease in the number of cells undergoing apoptosis. In spite of these similarities, endometriosis is not considered a malignant disorder. The possibility that endometriosis could, however, transform and become cancer has been debated in the literature since 1925. Mutations in the genes that encode for metabolic and detoxification enzymes, such as GALT and GSTM, have been implicated in the pathogenesis of endometriosis and in the progression to carcinoma of the ovary. PTEN, a tumor suppressor commonly mutated (50%) in endometrial carcinoma, is found mutated in endometrioid carcinoma of the ovary, but not in other forms of ovarian cancer. A recent study has shown that somatic mutations in the PTEN gene were identified in 20% of endometrioid carcinomas and 20.6% of solitary endometrial cysts, suggesting that inactivation of the PTEN tumor suppressor gene is an early event in the development of ovarian endometrioid carcinoma. In addition to cancerous transformation at the site of endometriosis, there is recent evidence to indicate that having endometriosis itself may increase a woman’s risk of developing non-Hodgkin’s lymphoma, malignant melanoma, and breast cancer.

Scientists Discover Trigger for Autoimmune Diseases
Monday, December 22, 2008; 12:00 AM

MONDAY, Dec. 22 (HealthDay News) — Healthy adults have potential autoimmune disease-causing cells, but these cells stay in an “off” state, a U.S. study shows.

Immune cells that attack the body cause autoimmune diseases such as lupus and rheumatoid arthritis (RA). Whether the switched-off cells in healthy adults are true precursors of the self-attacking immune cells and, if so, what prevents them from causing disease in certain people, isn’t known, the researchers said.

J. Andrew Duty, of the Oklahoma Medical Research Foundation, and colleagues found that anergic (dormant) autoimmune disease-causing cells account for 2.5 percent of immune B-cells circulating in the blood of healthy adults.

These anergic cells don’t appear to cause problems in healthy adults, but did produce self-reactive antibodies when exposed to a strong stimulus in lab experiments. This means these anergic cells may contain the precursors for the self-attacking B-cells in patients with autoimmune disease, the researchers said.

In previously healthy people, anergy may somehow break down and allow self-attacking B-cells to cause autoimmune disease.

The study was published in the Dec. 22 online issue of The Journal of Experimental Medicine:

Learning To Tolerate Ourselves
Amy Maxmen
Published online December 22, 2008

Duty et al. find self-reactive B cells in healthy adults that might harm their own body if given the chance.

Checkpoints during B cell development ensure that immune cells won’t confuse the self for an intruder. At birth, many B cells express self-reactive receptors. Most of these potentially harmful cells are either set straight by rearranging new receptors or are eliminated before leaving the bone marrow. Yet a minority manages to escape, slipping into the periphery as mature B cells with a propensity for self-attack.

In healthy mice, autoimmunity is avoided because most self-reactive escapees, which classically express high levels of IgD and reduced IgM, are arrested in an anergic state. But until now, a similar population of anergic, autoreactive B cells hadn’t been found in humans.

Duty et al. have now spotted these cells in the blood of healthy adults, where they accounted for 2.5% of peripheral B cells. These cells turned out to be mature and autoreactive, bearing no signs of antigen encounter in vivo. The cells were also anergic, as they had faulty signaling in response to BCR ligation. These defects were overcome, however, when the authors gave cells a strong enough signal.

Autoreactive B cells are common in patients with autoimmune diseases, such as lupus or rheumatoid arthritis (RA). And the authors suspect that the new population may contain the precursors of these troublemaking cells. Lapses in early steps of self-tolerance have been shown to contribute to disease in patients with lupus or RA. Alternatively, suggests author Patrick Wilson, anergy may fail in these patients, allowing self-sabotaging cells to run free.

Why the body silences these potentially mutinous cells after they escape rather than putting them to death is unclear. Perhaps, suggests Wilson, a limited amount of autoimmunity isn’t such a bad thing, as long as it’s not chronic. For example, anergic cells might help attack pathogens disguised as self-antigens.

There are ongoing studies to make public the FACT that Endometriosis is an autoimmune disease.

September 26, 2002
A research team from the Endometriosis Association in Milwaukee; the National Institute of Child Health and Human Development, Bethesda Maryland; and the School of Public Health and Health Services at George Washington University in Washington D.C. carried out and analyzed a survey of 3,680 members of the Endometriosis Association who had endometriosis…“These findings suggest a strong association between endometriosis and autoimmune disorders,” said lead investigator Ninet Sinaii from the National Institute of Child Health and Human Development. “Health care professionals may need to consider these disorders when evaluating their patients for endometriosis.” - Read the entire article at the Endometriosis Association website, and the full text of the research at the Oxford Journal’s Human Reproduction website.

And then this year, Confirmation:

Autoimmune Endometriosis: Autoimmune Nature Confirmed
Elaine Moore
Sep 18, 2008

In 1984, researchers at the Upstate Medical Center in Syracuse, New York first suspected the autoimmune nature of endometriosis. Confirmation came in 2008.

Aniko Hever, R. Roth, P. Hervezi, M. Marin, “Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator,” PNAS July 24, 2007 vol. 104 no. 30 12451-12456.

As you can see, the second article I posted contains a lot of tech speak. The next step is getting more researchers and media PR on this to get it in to the news in a more understandable manner.

Serial analysis of gene expression reveals differential expression between endometriosis and normal endometrium. Possible roles for AXL and SHC1 in the pathogenesis of endometriosis

Endometriosis is a clinical condition that affects up to 10% of the women of reproductive age. Endometriosis is characterized by the presence of endometrial tissues outside the uterine cavity and can lead to chronic pelvic pain, infertility and, in some cases, to ovarian cancer.

Methods: In order to better understand the pathogenesis of endometriosis, we have used Serial Analysis of Gene Expression (SAGE) to identify genes differentially in this disease by studying three endometriotic tissues and a normal endometrium sample. Promising candidates (AXL, SHC1, ACTN4, PI3KCA , p-AKT, p-mTOR, and p-ERK) were independently validated by immunohistochemistry in additional normal and endometriotic tissues.

Results: We identified several genes differentially expressed between endometriosis and normal endometrium.

IGF2, ACTN4, AXL, and SHC1 were among the most upregulated genes. Comparison of the endometriosis gene expression profiles with the gene expression patterns observed in normal human tissues allowed the identification of endometriosis-specific genes, which included several members of the MMP family (MMP1,2,3,10,11,14).

Immunohistochemical analysis of several candidates confirmed the SAGE findings, and suggested the involvement of the PI3K-Akt and MAPK signaling pathways in endometriosis.

Conclusion: In human endometriosis, the PI3K-Akt and MAPK signaling pathways may be activated via overexpression of AXL and SHC1, respectively. These genes, as well as others identified as differentially expressed in this study, may be useful for the development of novel strategies for the detection and/or therapy of endometriosis.

Author: Hiroshi Honda, Fermin F Barrueto, Jean Gogusev, Dwight D Im and Patrice J Morin
Credits/Source: Reproductive Biology and Endocrinology 2008, 6:59

Circulating IGF-binding protein 7 (IGFBP7) levels are elevated in patients with endometriosis or undergoing diabetic hemodialysis
Published on: 2008-11-19

Insulin-like growth factor-binding protein-7 (IGFBP7) is a secretory protein with a molecular mass of approximately 30 kDa. It is abundantly expressed in the uterine endometrium during the secretory phase of the menstrual cycle.

Decreased IGFBP7 expression has been observed in some cancers and leiomyomata.

Methods: To determine whether serum IGFBP7 levels reflect changes in uterine IGFBP7 expression in humans during the menstrual cycle, and to examine whether serum IGFBP7 levels are altered in patients with various disorders, we developed a novel, dual-antibody sandwich enzyme-linked immunosorbent assay (ELISA).

Firstly, concentrations of IGFBP7 released into the medium were determined in cultured endometrial stromal and glandular cells. Blood samples were collected from women who had normal menstrual cycles and who had been diagnosed with endometriosis.

Serum from hemodialysis patients and gastrointestinal cancers was also used to determine the IGFBP7 levels.

Results: Using this new ELISA, we demonstrated that cultured uterine cells secrete IGFBP7 into the medium. Patients with endometriosis and those with type II diabetes mellitus undergoing hemodialysis had significantly higher serum concentrations of IGFBP7 than the relevant control subjects.

There were no differences in serum IGFBP7 levels in women at different stages of the menstrual cycle. Furthermore, serum IGFBP7 levels in patients with colorectal, esophageal, or endometrial cancer were not different than normal healthy subjects.

Conclusion: Our observations suggest that IGFBP7 is associated with the pathophysiology of endometriosis and diabetes mellitus, and that serum IGFBP7 levels do not reflect enhanced uterine expression of IGFBP7 mRNA during the menstrual cycle.

Author: Masahiko Kutsukake, Ryosuke Ishihara, Katsutoshi Momose, Keiichi Isaka, Osamu Itokazu, Chinatsu Higuma, Takeshi Matsutani, Akihisa Matsuda, Koji Sasajima, Takahiko Hara and Kazuhiro Tamura
Credits/Source: Reproductive Biology and Endocrinology

Breakthrough for endometriosis sufferers as discovery offers hope for treatment and cure
By Jenny Hope
Last updated at 2:54 AM on 06th August 2008

A painful womb condition that affects around two million British women may be triggered by an out-of-control enzyme, scientists claim.

They say the information could be used to diagnose and treat endometriosis, which causes infertility and pain and currently has no cure.

The condition has a number of high-profile sufferers including singer Louise Redknapp and TV presenter Anthea Turner.

The problem arises when cells normally found in the womb lining attach themselves to other parts of the pelvic area, causing scar tissue, pain and inflammation.

Researchers at Liverpool University have now identified that the enzyme - or biological catalyst - telomerase could be responsible.

Telomerase is normally released by cells in the inner lining of the womb during the early stages of the menstrual cycle.

But in those affected by endometriosis, the enzyme is also released during the later stages when it can wreck a woman’s chances of becoming pregnant.

The enzyme helps the replication of DNA sequences and is found in cells that divide frequently, including cancer cells.

It also maintains the length of the telomeres, which are tiny ‘caps’ on the ends of chromosomes that help protect DNA strands from inflammation and other ageing processes.

The research shows women with endometriosis had abnormally long telomeres.

The telomerase-generating cells lining their womb behaved like cancer cells, dividing uncontrollably and acquiring the ability to spread and survive in other parts of the body.

Dr Dharani Hapangama, who led the research, said: ‘Women who have endometriosis express this enzyme in both the early and late stages of the menstrual cycle which means that the cells will continue to divide and lose their “focus” in supporting the establishment of a pregnancy.

‘As a result, the lining of the womb may be more hostile to an early pregnancy, and the cells that are shed at this late stage in the menstrual cycle may be more ‘aggressive’ and more able to survive and implant outside the uterus, causing pain in the pelvic or abdomen area.’

The research, which was published in the journal Human Reproduction, is now expected to help scientists develop new techniques for diagnosing and treating the condition.

In most cases, endometriosis is diagnosed between the ages of 25 and 40.

The disorder can occur in several places in the body, most commonly the fallopian tubes, ovaries, bladder, the bowel, the intestines, the vagina and the rectum.