Living With Endometriosis

Neuroendocrine cells in eutopic endometrium of women with endometriosis
(Research from Qilu Hospital of Shandong University in the area of endometriosis described.(Report)
Article from: Women’s Health Weekly Article date: January 28, 2010 )

Data detailed in ‘Neuroendocrine cells in eutopic endometrium of women with endometriosis’ have been presented. “Endometriosis is a common gynaecological disease, but the pathogenesis of endometriosis and pathophysiological basis for endometriosis-associated painful symptoms are still uncertain. Little is known about neuroendocrine (NE) cells in the uterus,” scientists in Jinan, People’s Republic of China report (see also Endometriosis).

“For this study, 38 premenopausal women with histologically diagnosed ovarian endometrioma or peritoneal endometriosis and 24 women without endometriosis were selected. Biopsy samples from eutopic endometrium were used for immunohistochemical staining to detect synaptophysin (SYN) and neuron-specific enolase (NSE) expression in women with and without endometriosis. There were substantially more NE cells of eutopic endometrium stained with SYN and NSE in women with endometriosis than in those without endometriosis (3.8 [+ or -]1.8 versus 0.5 [+ or -]0.7/mm2, p<0.001, and 2.8 [+ or -]2.1 versus 0.4 [+ or -]0.6/mm2, respectively, p<0.001). These cells were scattered in the epithelium of endometrial glands. At all stages of the menstrual cycle, the densities of NE cells stained with SYN and NSE were greater in women with endometriosis than in those without endometriosis (p <0.05)," wrote G. Wang and colleagues, Qilu Hospital of Shandong University.

The researchers concluded: “These results suggest that NE cells in eutopic endometrium probably play some role in the pathogenesis or symptoms of endometriosis.”

Wang and colleagues published their study in Human Reproduction (Neuroendocrine cells in eutopic endometrium of women with endometriosis. Human Reproduction, 2010;25(2):387-91).

For additional information, contact G. Wang, Qilu Hospital of Shandong University, Dept. of Obstetrics and Gynecology, Jinan 250012, China.

A year ago, I found and posted some old research articles about aromatase and endometriosis. In the first article, dated May 2004, it reads, “Aromatase P450 (P450arom) is the key enzyme for biosynthesis of estrogen, which is an essential hormone for the establishment and growth of endometriosis. There is no detectable aromatase enzyme activity in normal endometrium; therefore, estrogen is not locally produced in endometrium. Endometriosis tissue, however, contains very high levels of aromatase enzyme, which leads to production of significant quantities of estrogen. Moreover, one of the best-known mediators of inflammation and pain, prostaglandin E2, strikingly induces aromatase enzyme activity and formation of local estrogen in this tissue. Additionally, estrogen itself stimulates cyclo-oxygenase-2 and therefore increases the formation of prostaglandin E2 in endometriosis. We were able to target this positive feedback cycle in endometriosis using aromatase inhibitors. In fact, pilot trials showed that aromatase inhibitors could decrease pelvic pain associated with endometriosis“.

In the second article, dated August 2007, researchers confirmed that “molecular alterations such as the presence of aromatase in endometriotic tissues could be involved in the development or maintenance of endometriosis.”

In the third article, dated January 2009, Dr. Serdar Bulun, George H. Gardner Professor of Clinical Gynecology at Northwestern University’s Feinberg School of Medicine said, ““We came up with a new treatment of choice for post-menopausal women with endometriosis,” Bulun said. Moreover, treatment with an aromatase inhibitor is a very good option for premenopausal women with endometriosis not responding to existing treatments, he said“.

Now, it seems people are rethinking that avenue…

Aromatase Inhibitors: Potential Reproductive Implications
Mohamed A. Bedaiwy, MD, PhD, Noha A. Mousa, MD, Robert F. Casper, MD
Received 10 March 2009; accepted 12 May 2009. published online 16 July 2009.

Abstract
MEDLINE, EMBASE, Scopus, and Web of Science databases literature search from inception to March 2009 was performed to identify published clinical trials and cohort, observational, and in vitro studies that evaluated the use of aromatase inhibitors in reproductive medicine for indications other than ovulation induction. Aromatase inhibitors are currently being investigated for breast cancer prevention in women at high risk. Aromatase inhibitors may be used for treatment of symptomatic myomas and endometriosis as an alternative to surgical intervention. Current evidence does not support the routine use of aromatase inhibitors for these conditions without prospective controlled trials. Aromatase inhibitor cotreatment can be used to prevent the initial estrogen flare effect of gonadotropin-releasing hormone agonist treatment to offer flexibility in initiating this therapy.

Endometriosis not predicted by hormone effect
Internal Medicine News, Feb 1, 2008 by Miriam E. Tucker

WASHINGTON — Response to hormonal therapy does not accurately predict whether a patient has endometriosis, Dr. Todd R. Jenkins reported at the annual meeting of the AAGL.

Laparoscopy has long been considered the standard for diagnosing endometriosis. However, a 1999 paper by Dr. Frank W. Ling called into question the necessity for doing laparoscopy in women with chronic pelvic pain (Obstet. Gynecol. 1999;93:51-8). The findings of that study, which was sponsored in part by depot leuprolide manufacturer TAP Holdings Inc., suggested instead that a diagnostic algorithm plus a reduction in symptoms with a 3-month trial of depot leuprolide could non-invasively identify those women for whom endometriosis was the cause of pain.

“Our clinical impression has been that many women who failed to respond to hormonal treatment did, in fact, have endometriosis. Unfortunately, many women have been told that they did not have endometriosis since they did not respond to hormonal treatment,” said Dr. Jenkins, director of the division of women’s reproductive health care in the department of obstetrics and gynecology at the University of Alabama at Birmingham.

In a retrospective study conducted by Dr. Jenkins and his then-associates at the Chattanooga (Tenn.) Women’s Laser Center, chart reviews identified 486 patients at the private endometriosis referral center who had undergone laparoscopy for chronic pelvic pain and who had received at least 3 months of preoperative hormonal therapy. Of those, a total of 105 met the study criteria, which included complete information regarding response to treatment and less than 3 months between completion of hormonal therapy and the laparoscopy.

The hormonal treatments were oral contraceptive pills in 80% of the patients and gonadotropin-releasing hormone (GnRH) agonists in 20%. Response to the hormones, defined as either partial or complete symptom relief, was achieved in 46% (48), while 54% (57) had no relief of symptoms. Endometriosis was identified subjectively during laparoscopy in 84% (88) of the women, and a pathological diagnosis was made in 67% (70). These findings confirm those of Dr. Ling and others that endometriosis is present in approximately 80%-85% of women with well-defined chronic pelvic pain, Dr. Jenkins noted.

There was no significant difference in the rate of endometriosis between all hormonal therapy responders and nonresponders, either by subjective impression or pathological diagnosis. Subjective diagnoses of endometriosis were made for 85% of responders (41/48) and 81% of nonresponders (46/57), and pathological diagnoses in 65% (31/48) and 68% (39/57), respectively. Endometriosis rates also did not differ between the 35 responders and 48 nonresponders to oral contraceptives specifically.

Differences were significant for those who took GnRH agonists: Subjective diagnoses of endometriosis were made in 100% (9/9) of responders, compared with just 50% (4/8) of nonresponders, and pathological diagnoses in 89% (8/9) of responders vs. 25% (2/8) of nonresponders. However, the number of cases was too small to be conclusive, he said.

Response to hormonal therapy also did not predict the diagnosis of endometriosis at any specific location except for the anterior bladder wall peritoneum (70% of responders vs. 30% of nonresponders), but only 10 patients had endometriosis at that site. The same was found for pathologically confirmed diagnoses: Only endometriosis of the anterior peritoneum was statistically more likely among responders than nonresponders (85% vs. 15%), and again, the data were limited because the numbers were very small, Dr. Jenkins added.

He noted that these findings should not be interpreted to mean that a trial of GnRH agonists isn’t a good idea, since they were found to be the most effective hormonal treatment for the relief of symptoms. “We do not disagree with a trial of empiric therapy in patients with chronic pelvic pain. But no judgment should be made regarding the diagnosis of endometriosis based on the response to hormonal therapy without a laparoscopic evaluation. A laparoscopic diagnosis is still the gold standard.”

BY MIRIAM E. TUCKER

Senior Writer
COPYRIGHT 2008 International Medical News Group
COPYRIGHT 2008 Gale, Cengage Learning

Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada
Published on: 2010-01-19

Objectives: Endometriosis has been believed to increase the risk of developing ovarian cancer, but recent data supporting this hypothesis are lacking. The aim of this study was to verify whether the incidence of endometriosis, ovarian cancer and the both increased during the last 10 years among women living in the Estrie region of Quebec.

Methods: We collected data of women diagnosed with endometriosis, ovarian cancer or both, between 1997 and 2006, from a population living in the Estrie region of Quebec.

We performed this retrospective cross-sectional study from the CIRESSS (Centre Informatise de Recherche Evaluative en Services et Soins de Sante) system, the database of the CHUS (Centre Hospitalier Universitaire of Sherbrooke), Sherbrooke, Canada.

Results: Among the 2854 identified patients, 2521 had endometriosis, 292 patients had ovarian cancer and 41 patients had both ovarian cancer and endometriosis. We showed a constant increase in the number of ovarian cancer (OC) between 1997 and 2006 (r2 = 0.557, P = 0.013), which is not the case for endometriosis (ENDO) or endometriosis-associated ovarian cancer (EAOC).

The mean age +/- SD was 40.0 +/- 9.9 and 53.9 +/- 11.4 for patients having ENDO and OC, respectively. Mean age of women with EAOC was 48.3 +/- 10.8, suggesting an early onset of ovarian cancer in women having endometriosis of about 5.5 years average, P = 0.003.

Women with ENDO were at increased risk for developing OC (Rate Ratio [RR] = 1.6; 95% Confidence Interval [CI] = 1.12-2.09). Pathological analyses showed the predominance of endometrioid type (24.4%) and clear-cell type (21.9%) types in EAOC compared to OC, P = 0.0070 and 0.0029, respectively.

However, the serous type is the most widespread in OC (44.5%) in comparison to EAOC (19.51%), P = 0.0023.

Conclusion: Our findings highlight that the number of cases of ovarian cancer is constantly increasing in the last ten years and that endometriosis represents a serious risk factor which accelerates its apparition by about 5.5 years.

Author: Aziz Aris
Credits/Source: Journal of Ovarian Research 2010, 3:2

Expression of interleukin-1 (IL-1) ligands system in the most common endometriosis-associated ovarian cancer subtypes
Published on: 2010-01-28

Objectives: Endometrioid carcinoma of the ovary is one of the most types of epithelial ovarian cancer associated to endometrioisis. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of both, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors.

Pro-inflammatory cytokines, including interleukin-1 (IL-1) have been reported to be involved in both endometriosis and ovarian carcinogenesis. The major objective of this study was to determine the level expression of IL-1 ligands system (IL-1alpha, IL-1beta and IL-1RA) in the most common subtypes of ovarian cancer cells compared to endometrial cells.

Methods: We used primary endometrial cells, endometrial cell line RL-952 and different subtypes of epithelial ovarian cancer cell lines including TOV-112D (endometrioid), TOV-21G (clear cell) and OV-90 (serous).

Immunofluorescence and real-time PCR analysis were used respectively for detecting IL-1 ligands at the levels of cell-associated protein and mRNA. Soluble IL-1 ligands were analyzed by ELISA.

Results: We demonstrated that IL-1 ligands were expressed by all endometriosis-associated ovarian cancer subtypes and endometrial cells.

In contrast to other cancer ovarian cells, endometrioid cells exhibit a specific decrease of cell-associated IL-1RA expression and its soluble secretion.

Conclusion: Endometrioid ovarian cancer exhibits an alteration in the expression of IL-1RA, a key protector against tumorogenic effects of IL-1. This alteration evokes the same alteration observed in endometriotic cells in previous studies.

This suggests a possible link between the endometrium, the tissue ectopic endometriosis and endometrioid ovarian cancer.

Author: Mamadou KeitaPaul BessetteManuella PelmusYoussef AinmelkAziz Aris
Credits/Source: Journal of Ovarian Research 2010, 3:3

In a study published January 19, 2010, researchers let us know that previous studies show for a fact that angiogenesis is largely found in rectosigmoid endometriosis (found near the sigmoid colon and the upper part of the rectum), and it embeds deeply.

They concluded that rogue cell growth of endo does of course proliferate in the peritoneum, and would like to use this study to open the door to develop antiangiogenic drugs to prevent such rogue cell growth - to help prevent the spread of endometriosis.

Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases

Endometriosis is a common disease characterized by the presence of a functional endometrium outside the uterine cavity, causing pelvic pain, dysmenorrheal, and infertility. This disease has been associated to development of different types of malignancies; therefore new blood vessels are essential for the survival of the endometrial implant.

Our previous observations on humans showed that angiogenesis is predominantly found in rectosigmoid endometriosis, a deeply infiltrating disease. In this study, we have established the experimental model of rat peritoneal endometriosis to evaluate the process of angiogenesis and to compare with eutopic endometrium.

Methods: We have investigated the morphological characteristics of these lesions and the vascular density, VEGF and its receptor Flk-1 and MMP-9 expression, and activated macrophage distribution, using immunohistochemistry and RT-PCR.

Results: As expected, the auto-transplantation of endometrium pieces into the peritoneal cavity is a well-established method for endometriosis induction in rats.

The lesions were cystic and vascularized, and demonstrated histological hallmarks of human pathology, such as endometrial glands and stroma. The vascular density and the presence of VEGF and Flk-1 and MMP-9 were significantly higher in endometriotic lesions than in eutopic endometrium, and confirmed the angiogenic potential of these lesions.

We also observed an increase in the number of activated macrophages (ED-1 positive cells) in the endometriotic lesions, showing a positive correlation with VEGF.

Conclusion: The present endometriosis model would be useful for investigation of the mechanisms of angiogenesis process involved in the peritoneal attachment of endometrial cells, as well as of the effects of therapeutic drugs, particularly with antiangiogenic activity.

Author: Daniel MachadoPlinio BerardoCelia PalmeroLuiz Nasciutti
Credits/Source: Journal of Experimental &Clinical Cancer Research 2010, 29:4
Published on: 2010-01-19

Curcumin arrests endometriosis by downregulation of matrix metalloproteinase-9 activity.
Indian J Biochem Biophys. 2009 Feb;46(1):59-65.
Swarnakar S, Paul S.
(for the entire text of the study, click here. Many thanks to Nathan Mitchell for finding this article).

Department of Physiology, Drug Development Diagnostics and Biotechnology Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India. snehasiktas@hotmail.com

Curcumin, a polyphenol derived from turmeric (Curcuma longa) possesses diverse pharmacological properties including antioxidant, anti-inflammatory and antiproliferative activities. Endometriosis is a gyneocological disorder characterized by growth of endometrial tissues outside uterus that involves aberrant matrix remodeling. In this study the effect of curcumin was studied on surgically developed endometriosis in mice. Endometriosis with varying severity was developed in mice by peritoneal implantation of uterine fragments. The changes in matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloprotease (TIMP)-1 were investigated in endometriotic tissues following curcumin pre- and posttreatment. Results showed that MMP-9 activity increased gradually in endometriotic tissues with severity and curcumin treatment reversed the MMP-9 activity near to control value. Curcumin administered either post- or pre-endometriosis arrested endometriosis in a dose-dependent manner. It inhibited both MMP-9 activity and its expression at the level of secretion, during regression of endometriotic lesion. In addition, the attenuated activity of MMP-9 was associated with decreased expression of tumor necrosis factor-alpha (TNF-alpha) during healing, suggesting the anti-inflammatory property of curcumin. Moreover, curcumin pretreatment prevented lipid peroxidation and protein oxidation in endometriotic tissues. We reported here for the first time the anti-endometriotic property of curcumin via MMP-9 dependent pathway that may lead to new therapeutic intervention.

PMID: 19374255 [PubMed - indexed for MEDLINE]

This is one of those studies that makes me shake my head and ask WHY the study had to be conducted in the first place. To me, it is common sense that a person with chronic pain has in fact a disability, and is similar in this regard to a person who is two to three decades older who does not suffer with pain. Of COURSE our bodies act older under the stress of chronic pain!

Chronic Pain May Cause Similar Disability Linked With Aging at Earlier Ages
Laurie Barclay, MD

September 29, 2009 — Younger people with pain have disability similar to that of people who are 2 to 3 decades older without pain, according to the results of a cross-sectional study published in the September issue of the Journal of the American Geriatrics Society.

“We found that the abilities of those aged 50 to 59 with pain were far more comparable to subjects aged 80 to 89 without pain, of whom 4% were able to jog 1 mile and 55% were able to walk several blocks, making pain sufferers appear 20 to 30 years older than non-pain sufferers,” lead author Kenneth E. Covinsky, MD, MPH, from the University of California, San Francisco, said in a news release.

“After adjustment for demographic characteristics, socioeconomic status, comorbid conditions, depression, obesity, and health habits, across all four measures, participants with significant pain were at much higher risk for having functional limitations….Patients may be better served if pain and disability are evaluated and treated jointly rather than treated as separate issues.”

The goal of this study was to evaluate the relationship between functional limitations and pain across a spectrum of age, ranging from mid life to advanced old age, among 18,531 participants in the 2004 Health and Retirement Study, a nationally representative study of community-dwelling persons 50 years and older. Significant pain was defined as pain that was moderate or severe most of the time and that often troubled the person reporting the pain.

Participants were classified based on their degree of functional limitation in each of 4 functional domains: mobility, stair climbing, upper extremity tasks, and activities of daily living function. Significant pain was reported by 24% of participants aged 50 to 59 years. In all 4 domains, rates of functional limitations were much higher in participants with pain vs those without pain.

In functional limitation, participants with pain were similar to participants 2 to 3 decades older. In the mobility domain, 37% of participants aged 50 to 59 years without pain could jog 1 mile, 91% could walk several blocks, and 96% could walk 1 block without difficulty. However, of participants aged 50 to 59 years with pain, only 9% could jog 1 mile, 50% could walk several blocks, and 69% could walk 1 block without difficulty. Mobility limitations in this group were similar to those in participants aged 80 to 89 years without pain, of whom 4% could jog 1 mile, 55% could walk several blocks, and 72% could walk 1 block without difficulty.

Participants with significant pain were at much higher risk of having functional limitations across all 4 measures, after adjustment for demographic and socioeconomic factors, comorbid conditions, depression, obesity, and health habits. Adjusted odds ratio was 2.85 for mobility (95% confidence interval [CI], 2.20 - 3.69), 2.84 for stair climbing (95% CI, 2.48 - 3.26), 3.96 for upper extremity tasks (95% CI, 3.43 - 4.58), and 4.33 for activities of daily living function (95% CI, 3.71 - 5.06).

The investigators concluded that younger subjects with pain experience functional limitations classically associated with aging.

“Our study cannot determine whether pain causes disability or whether disability causes pain,” Dr. Covinsky said. “We think it is likely that both are true and that pain and disability probably can act together in ways that make both problems worsen in a downward spiral. One implication of our study is that pain and disability may not be fully separate processes, but may often be part of the same underlying process.”

Limitations of this study include cross-sectional design and difficulties inherent in pain measurement.

“The drastic effect that pain can have on sufferers’ abilities to carry out everyday tasks in their lives highlights the importance of managing pain and treating it effectively,” said Thomas Yoshikawa, MD, editor of the Journal of the American Geriatrics Society, “Last month, we published our annual guidelines on the pharmacological management of persistent pain in older persons, and this study really brings home how essential it is for healthcare providers to be able to improve quality of life through awareness of the best treatments.”

The National Institute of Arthritis and Musculoskeletal and Skin Diseases funded the Health and Retirement Study. Dr. Covinsky is supported in part by a midcareer investigator award from the National Institute on Aging. The other study authors have disclosed no relevant financial relationships.

J Am Geriatr Soc. 2009;57:1556-1561. Abstract

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.

###

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

At last — a quick and accurate way of diagnosing endometriosis
August 18, 2009

A quick and accurate test for endometriosis that does not require surgery has been developed by researchers from Australia, Jordan and Belgium, according to new research published online today (Wednesday 19 August) in Europe’s leading reproductive medicine journal Human Reproduction [1].

Until now there has been no way of accurately diagnosing endometriosis apart from laparoscopy — an invasive surgical procedure — and this often leads to women waiting for years in pain and discomfort before their condition is identified correctly and treated.

Now researchers at the University of Sydney and Mu’tah University in Karak, Jordan, have discovered that if they take a small sample of the endometrium (the lining of the uterus), which can be done by inserting the device for taking the biopsy via the vagina, and then test for the presence of nerve fibres in the sample, they can diagnose whether or not endometriosis is present with nearly 100% accuracy.

Endometriosis, which has been estimated to affect 10-15% of women of reproductive age, is a chronic gynaecological disease in which cells from the endometrium establish themselves outside the uterus, within a woman’s pelvic area. Symptoms associated with it include infertility, painful periods, pelvic pain and pain during sexual intercourse. Once laparoscopy has identified endometriosis as the cause of these symptoms, treatment involves surgical removal (usually via laparoscopy) of the abnormally sited endometrial cells. However, laparoscopy itself can be associated with complications and can adversely affect fertility in women who do not have endometriosis.

In a separate study also published online today in Human Reproduction, another research group from Belgium and Hungary has found that the density of nerve fibres in the endometrium was about 14 times higher in women with endometriosis than in healthy women, and that using specific markers to identify the presence of nerve fibres could predict with nearly 100% accuracy the presence of minimal to mild endometriosis [2].

In the first study, led by Professor Ian S. Fraser, head of the Queen Elizabeth II Research Institute for Mothers and Infants at the University of Sydney and Dr Moamar Al-Jefout, assistant professor in reproductive medicine at Mu’tah University, researchers took endometrial biopsies from 99 women who had consulted doctors about pelvic pain, infertility or both and who were undergoing laparoscopy for the condition.

The results from the endometrial biopsies were compared with the results of the laparoscopies, and the researchers found that in 64 women who had endometriosis confirmed by laparoscopy, all but one tested positive for the presence of nerve fibres in the endometrial biopsy. In the 35 women who were found not to have endometriosis by laparoscopy, no nerve fibres were found in 29 of the endometrial biopsies. In the other six cases, the biopsy found there were nerve fibres present; three of these women had severely painful periods and painful sex, and also a history of infertility, and of the other three, one had adhesions that were considered too slight to be endometriosis, while the other had a previous history of endometriosis.

Women with endometriosis and painful symptoms had significantly higher nerve fibre density in comparison with women with infertility but no pain (2.3 nerve fibres per mm2 compared to 0.8 per mm2 respectively). The mean average of nerve fibre density in the women with a laparoscopic diagnosis of endometriosis was 2.7 per mm2.

The study showed that testing endometrial biopsies for the presence of nerve fibres was able to diagnose endometriosis with 83% specificity (the proportion of negative cases of endometriosis correctly identified) and 98% sensitivity (proportion of positive cases correctly identified). This double blind study confirmed the results of a pilot study published in 2007 by the same group [3].

Dr Al-Jefout said: “This study has shown that testing for nerve fibres in endometrial biopsies is a valid and highly accurate diagnostic test for endometriosis. This test is probably as accurate as assessment via laparoscopy, the current gold standard, especially as it is unclear how often endometriosis is overlooked, even by experienced gynaecologists. Endometrial biopsy is clearly less invasive than laparoscopy, and this test could help to reduce the current lengthy delay in diagnosis of the condition, as well as allowing more effective planning for formal surgical or long-term medical management. It may be particularly helpful in cases of infertility.”

Currently, diagnosing endometriosis via laparoscopy involves the woman being booked into hospital for the surgical procedure, an anaesthetic, and the presence of doctors, nurses and expensive equipment. In some countries there are long waiting lists for operations. In contrast, taking an endometrial biopsy is relatively quick and easy to organise and perform, and results are available within about three days. However, Dr Al-Jefout said: “It needs to be emphasised that this test requires a carefully collected endometrial biopsy and an experienced immunohistochemical pathology laboratory to confirm or exclude the presence of nerve fibres.”

He continued: “Our results indicate that a negative endometrial biopsy result would miss endometriosis in only one percent of women. Performing a planned laparoscopy only on a woman with a positive endometrial biopsy result would result in endometriosis being confirmed in eighty to ninety percent of these women. Thus, using this diagnostic test in an infertility workup would significantly reduce the number of laparoscopies performed without reducing the number of women whose endometriosis is diagnosed and surgically treated.”

In addition, he said it could be particularly useful in teenagers with spasmodic symptoms but a family history of endometriosis. “The usual diagnostic delay in this special group is greater than in older women. An endometrial biopsy to confirm or exclude the diagnosis of endometriosis will help initiating earlier treatment and possibly preventing the progress of endometriosis, thus improving life style and protecting their future fertility.”

The researchers plan to continue using the test in patients and to search for other markers to help refine the test further. “Ideally, we would like to develop a blood test as an even simpler means of providing early information on the presence or absence of endometriosis in order to assist doctors in early diagnosis. However, this endometrial biopsy test has proven so effective that it is currently the only test which appears to have equivalent efficacy to a diagnostic laparoscopy carried out by an experienced gynaecologist,” he concluded.

In the second study, led by Professor Thomas D’Hooghe, coordinator of the University of Leuven Fertility Centre (Belgium), researchers looked at 40 endometrial samples, half taken from women with minimal to mild endometriosis diagnosed by laparoscopy and histology (microscopic examination of tissue), and half from women without the condition. They analysed the tissues for several markers indicating the presence of four types of nerve fibres (sensory C, A∂, adrenergic and cholinergic nerve fibres).

Dr Attila Bokor, a doctoral fellow at the University of Leuven, who did the study as part of his PhD project said: “We observed nerve fibres in the endometrial samples of ninety percent (18 out of 20) of the women with endometriosis. The density varied throughout the samples, with few specimens showing counts above 30 per mm2, and with most between 0 and 10 per mm2. None, or very few, nerve fibres, were detected in any of the samples from women without endometriosis. The density of the small nerve fibres was about 14 times higher in endometrium from patients with minimal to mild endometriosis when compared with women with a normal pelvis.”

Prof D’Hooghe said: “Our data show that the combination of three different neural markers increases the sensitivity, specificity and diagnostic accuracy of this method of testing for endometriosis. The test diagnosed endometriosis with 95% sensitivity and 100% specificity.”

Dr Bokor and the team of Prof D’Hooghe will do a blinded validation study in September 2009 to confirm the results of their research. “If this confirms our findings, we believe our research can be a solid base for a simple, reliable and relatively cheap method for non-invasive diagnosis of minimal and mild endometriosis, since trans-cervical endometrium sampling and immunohistochemical analysis are routine gynaecological and pathological procedures. Our research programme is also aimed at discovering new biomarkers that can enable a blood test for endometriosis to be developed,” said Prof D’Hooghe.

[1] Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Human Reproduction journal. doi:10.1093/humrep/dep275

[2] Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis. Human Reproduction journal. doi:10.1093/humrep/dep283

[3] A pilot study to evaluate the relative efficacy of endometrial biopsy and full curettage in making a diagnosis of endometriosis by the detection of endometrial nerve fibers. Al-Jefout M, Andreadis N, Tokushige N, Markham R, Fraser I. Am J Obstet Gynecol 2007 Dec 197(6):578.e1-4