Endometriosis NEWS.Direct! by iLogy iLogy

Volume 01, Issue 01

June - July 2010

ENDOMETRIOSIS NEWS.Direct!

Endometriosis and Infertility FOREWORD

Lone Hummelshoj

Focus on Endometriosis is Welcome! INTERVIEW

MINI-REVIEWS and NEWS Increased Leptin Levels Implicated in Endometriosis Surgical Resection Improves Fertility Follicular Fluid Proteins Expressed Differently in Endometriosis Anti-endometrial Antibodies May Help Predict Implantation Failure

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Dr. Pratap Kumar

Clinical Perspectives FEATURED MINI-REVIEW Does Endometriosis Really Affect IVF Outcome?

ENDOMETRIOSIS NEWS.Direct!

CONTENTS Editorial Advisory Board

Foreword Focus on Endometriosis is Welcome! Lone Hummelshoj

Dr. Nicolas Bourdel CHU Clermont Ferrand, Department of ObGyn, La Polyclinique, Clermond Ferrand, France

Dr. Santhamma Mathew Chief Consultant, Department of ObGyn and Reproductive Medicine, Credence Hospital, Trivandrum, India Associate Professor (Retd), Department of ObGyn, Trivandrum Medical College, India

7 12

Dr. Paul P. G. Chief Consultant and Laparoscopic Surgeon, Paulâ&#x20AC;&#x2122;s Hospital, Kochi, India

Dr. Pratap Kumar Head, Division of Reproductive Medicine Kasturba Medical College and Kasturba Hospital Manipal, India

For contributions, guidelines, and comments: editor@endometriosis.in For advertisements and reprints: sales@endometriosis.in For complete Terms of use: www.endometriosis.in/?page_id=62 Editorial Process: www.endometriosis.in/?page_id=60

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Endometriosis and Infertility Dr. Shylaja B. Rajiv

Interview Clinical Perspectives on Endometriosis Dr. Pratap Kumar

Featured Mini Review

New Study Questions Effect of Endometriosis on IVF Treatment Outcome

Mini Reviews

Follicular Fluid Proteins Differently Expressed in Endometriosis Patients undergoing IVF

LH Beta-subunit Gene Variant linked to Endometriosis-associated Infertility

Serum Anti-endometrial Antibodies May be Potential Risk Factor for Implantation Failure

INFORMATION

Review Article

Editorial Team

News

Elevated Expression of Macrophage Migration Inhibitory Factor Noted in Endometriosis Patients

Dysregulated Activin-A Concentrations Play Crucial Role in Endometriosisassociated Infertility

Research Analysts Dhanya Mohan Shruthi V. B. Dr. Raghavendra Rao

Study Validates Safety and Improved Outcomes with Laparoscopic Colorectal Resection

Design Balamurugan M.

Link between Increased Leptin Levels and Endometriosis Identified

Study Reports Link between Impaired E-Cadherin and β-Catenin Expression and Endometriosis-associated Infertility

Study Demonstrates Therapeutic Application of Pyrrolidine Dithiocarbamate against Endometriosis

Managing Editor Dr. B. M. John Assistant Content Editor Dr. Shylaja B. Rajiv Assistant Copy Editor Amoolya Moses

Designed and Published On behalf of Endometriosis NEWS.Direct! by iLogy Healthcare Solutions www.ilogy.com Disclaimer Views and opinions expressed in this publication are not necessarily those of iLogy. iLogy reserves the right to use the information published herein in any manner whatsoever. While every effort has been made to ensure accuracy of the information published in this edition, neither iLogy and its employees nor its information vendors and advertisers accept responsibility for any errors or omissions. Further, iLogy, its information vendors and advertisers do not take any responsibility for loss or damage incurred or suffered by any reader of this magazine as a result of accepting any invitation/offer published in this edition. Please read the complete “Terms of Use” for more information. No part of this publication may be reproduced in any form without the written permission of the publisher.

June - July 2010

FOREWORD Focus on Endometriosis is Welcome! The arrival of another publication dedicated to endometriosis is testimony that this disease - affecting an estimated 176 million women across the world (32 million in India alone)1,2 - is finally beginning to get the attention that it deserves. And rightly so! This disease affects women during the prime years of their lives: a time when they should be finishing an education, starting and maintaining a career, building relationships and, perhaps, starting a family. For many women with endometriosis, however, this – taken for granted by many – is not possible due to the, potentially devastating, symptoms associated with the disease. I would therefore like to congratulate Dr. Bimal John and the editorial team on this initiative and wish Endometriosis NEWS.Direct! the best of success in uniting efforts in India to improve care of women with endometriosis and to share and build upon clinical research efforts and results.

Lone Hummelshoj Publisher/Editor-in-chief, Endometriosis.org Secretary General, World Endometriosis Society Chief Executive, World Endometriosis Research Foundation

Endometriosis is defined as the presence of endometrial tissue outside the uterus that induces a chronic, inflammatory reaction. The associated pain, infertility and pelvic masses can impact on general physical, mental and social well-being, and symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease.3 From a woman’s perspective, however, this definition may also encompass a disease that is surrounded by taboos, myths, delayed diagnosis, hit-and-miss treatments, and a lack of awareness, overlaid on a wide variety of symptoms that embody a stubborn, frustrating and, for some, chronic condition.4,5 Furthermore, from a societal perspective, endometriosis compounds into a much wider issue, where the health care and lost productivity costs associated with the disease were estimated to be more than USD 22 billion in 2002 in the United States alone.6 These costs are considerably higher than those associated with Crohn’s disease or migraine. In short, endometriosis is an unresolved disease in which the natural history and precise mechanisms by which it causes pain and sub-fertility are not well understood. There is no known cure and most current medical treatments are not suitable for long-term use due to their efficacy and/or side effect profile.3, 5 Despite this, we see relatively little investment in finding long-term treatments for endometriosis, and consequently treatment failures are common.1,3 Furthermore, many clinical questions remain unanswered because of a lack of large-scale, multicentre, clinical trials with sufficient patient numbers to provide results with statistical significance. This primarily occurs because researchers tend to perform small, isolated projects, often with limited local funding, resulting in even well-designed studies producing no definitive results and/or answers. In fact, a common conclusion seen in papers relating to

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FOREWORD

June - July 2010

endometriosis is: ‘while these results are encouraging, a larger prospective trial that is adequately powered is required to test this hypothesis properly’.1

• surgical outcome dependent on the individual surgeon’s skills; • little or no knowledge of concomitant conditions.

This issue is something which the World Endometriosis Research Foundation (WERF) has been created to address. WERF provides a global platform where resources and intelligence are pooled to enable international collaboration in order to find answers so that treatments for endometriosis can be improved and prevention can become a reality in future generations of women.1 Needless to say, WERF is enthusiastic in terms of collaborating with Indian centres, which specialise in the treatment of endometriosis and basic research into disease mechanisms.

These and other unanswered questions are the challenges we collectively face to address the complexity of endometriosis and improve treatments for the 176 million women across the globe who struggle with this disease during the prime years of their lives. Involvement in solving these questions is surely welcomed!

REFERENCES 01. Adamson GD, Kennedy SH, Hummelshoj L. Creating solutions in endometriosis: global collaboration through the World Endometriosis Research Foundation.

The main topic covered in this first issue is that surrounding the diagnostic methods for endometriosis and this is a tremendous start. But as the Indian collaboration grows, it is wise to not lose sight of the challenges we face when it comes to unlocking the mystery that is currently endometriosis, and which must be addressed. In endometriosis there is: • no known aetiology or pathogenesis, including the exact relationship with pain and subfertility, which are not necessarily proportional to the physical manifestation and/or extent of the disease; • a lack of awareness, with a consequent delay in early diagnosis and treatment of symptoms; • no accurate non-invasive diagnostic tool, contributing to the diagnostic and treatment delay; • hit and miss medical treatments, often with significant side effects and indicated only for short-term use;

www.endometriosis.in

J Endometriosis.

2010;2(1):3–6. 02. World Bank Population projection tables by country and group. Available at: http://go.worldbank.org/KZHE1CQFA0. Accessed 22 June 2010. 03. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20(10):2698–2704. 04. Hummelshoj L. Endometriosis — how big is the problem? In: García-Velasco JA, Rizk BRMB, eds. Endometriosis — current management and future trends. India: Jaypee Brothers Medical Publishers, 2010:3–9. 05. Hummelshoj L. Medical needs in endometriosis. Gynaecology Forum. 2010;15(2):5-7. 06. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update. 2007;13:395–404.

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June - July 2010

REVIEW ARTICLE Endometriosis-associated Infertility: Review of Literature on Aetiopathogenesis and Diagnostic Strategies Endometriosis, a common gynaecological condition and a leading cause of infertility, affects around 2-10% of reproductive-aged women in the US, with a global prevalence of 0.5-5% and 25-40% in fertile and infertile women, respectively.1 Since endometriosis is commonly associated with infertility and chronic pelvic pain, it may lead to a reduction in quality of life, work absenteeism, and psychological morbidity. Despite this, making a diagnosis is a great stumbling block to the conditionâ&#x20AC;&#x2122;s clinical management.2 Although several studies have reported the association of endometriosis with infertility, there is a lack of sufficient evidence to establish a direct cause-andeffect link, especially in the early disease stage when the pelvic anatomy is not disrupted. Even with vast technological advancements in the field of assisted reproduction, endometriosis still remains an enigmatic disease.1

Dr. Shylaja B. Rajiv Assistant Content Editor, Endometriosis NEWS.Direct!

Plausible Underlying Mechanisms for Infertility in Endometriosis Although various biological mechanisms have been indicated for the association of endometriosis and infertility, none have been substantially established.3 Some of them have been listed below.4

Possible factors causing infertility in endometriosis patients Pelvic anatomy distortion Endocrine and ovulatory abnormalities Immune system abnormalities Abnormal endometrial and tubal function Abnormalities in fertilisation and implantation Adverse factors in peritoneal fluid A 2006 report of the Practice Committee of the American Society for Reproductive Medicine (ASRM) also emphasised that these mechanisms have not been proven to reduce the fecundity in patients.3

Diagnosis of Endometriosis-associated Infertility Laparoscopy is considered as the only definitive diagnostic tool.5 It has been identified as the standard of reference in endometriosis diagnosis, and can be used to stage and treat the disease.6 A recent 2009 study reaffirmed that diagnostic laparoscopy has several advantages, such as detection of the causative factor of infertility, and also helps in determining a plan for the future management of the condition. Based on the findings, the scientists recommended that laparoscopy, with its diagnostic and therapeutic advantages, should be performed in endometriosis patients.7 A 2006 report of the Practice Committee of ASRM also stated that surgical

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techniques like laparoscopy are mandatory to form a definitive diagnosis of endometriosis.3 However, the regulatory body recommended the use of laparoscopy only in patients with confirmed/suspected conditions, such as endometriosis, pelvic/adnexal adhesions, and significant tubal disease (positive HSG findings).8

• Ultrasound: It is commonly used to confirm the diagnosis of endometriosis in suspected cases. Colour Doppler flow imaging has the potential to enhance the diagnostic ability of ultrasound. Kinkel et al, in a 2006 review, noted that pelvic ultrasound is considered as the primary imaging strategy, both for identifying and distinguishing lesions in the ovary and bladder wall.11 Diffuse low-level internal echoes, hyperechoic foci in the wall, and multilocularity are some sonographic features of endometriomas. In order to differentiate endometriomas from functional corpus luteum, the researchers recommended the use of repeat ultrasound in patients with unilocular cysts having low-level internal echoes.

It is still a matter of debate as to the appropriate time of performing laparoscopy to confirm the presence of the disease. The report mentions that although ultrasound may help in arriving at a presumptive diagnosis of endometriosis affecting ovaries, laparoscopy is needed to confirm it. Yet, despite being identified as the gold standard for diagnosis of endometriosis, laparoscopy has its disadvantages, such as invasiveness and risk for damage to internal organs during surgery.

A recent trial published in the journal, Ultrasound in Obstetrics and Gynecology, highlighted the effectiveness of transvaginal ultrasound (TVS) in evaluating the severity of pelvic endometriosis.12 The imaging test was found to be very accurate for diagnosing severe endometriosis, thus facilitating triage of patients for surgical treatment. In an earlier study, Savelli et al noted that the diagnostic accuracy of TVS for bladder endometriosis varied as per the size of the endometriotic nodules; a high detection rate was observed for bigger lesions. Furthermore, the likelihood ratio of detecting the disease using ultrasound increased in patients with a previous history of surgery for endometriosis.13

Apart from laparoscopy, there are several other methods available for diagnosing the condition. • History and physical examination: On examination, the findings may vary based on the location and severity of the disease. Many women with endometriosis are asymptomatic, but some may complain of pain during intercourse and chronic pelvic pain, or present with dysmenorrhoea and fertility-related problems.9 The clinical presentation thus cannot be used for reliable detection of the disease, owing to the lack of specific and sensitive signs or symptoms.

A 2009 review by Hudelist and Keckstein recommended the use of TVS and/or MRI as an additional tool for detecting ovarian endometriomas or adenomyosis. They summarised that recent evidences emphasise the role of TVS in diagnosing DIE of pelvis, not only affecting the ovaries, but also other structures like rectovaginal space, uterosacral ligaments, vagina and bladder, or the rectal wall.14

Although various other significant observations based on history and pelvic examination, such as affected first degree relatives, menstrual cycle regularity, ever use of oral contraceptives, retroverted uterus, adnexal masses, uterosacral ligament thickening and tenderness, and cul de sac nodularity, may be noted, none can accurately confirm the disease.3 A retrospective analysis has shown that routine clinical examination is not sufficient to identify high locations of deep-infiltrating endometriosis (DIE) like those at the bottom of the pouch of Douglas, level of uterosacral ligaments, and upper one-third of the posterior vaginal wall.10

Similarly, in 2008, Griffiths et al demonstrated the ability of transrectal ultrasound in predicting rectovaginal endometriosis and assessing the need for subsequent extensive laparoscopic dissection and bowel resection.15 Usually, a follow-up ultrasound or MRI may be required to confirm the diagnosis owing to the large variability in the ultrasonic features of endometriomas, which lead to difficulty in diagnosis.6

• Imaging tests: Wide array of imaging tests are performed to detect endometriosis owing to the difference in symptoms experienced by patients.6 The radiological evaluation, including techniques like ultrasound, CT scan, and magnetic resonance imaging (MRI), may aid in identifying and distinguishing cysts from endometrioma, characterizing the fluid within ovarian cysts, and evaluating patients with chronic pelvic pain or infertility.9

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• Sonorectovaginography: This relatively new technique, which involves instilling fluids like saline solution into the posterior compartment of the pelvis, produces acoustic interfaces between the vagina, rectum, cervix, and pouch of Douglas. This helps in simultaneously visualising all the areas and detecting

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deep endometriosis. However, the researchers suggested further studies to verify its reproducibility, accuracy, and tolerability.16

spite of significant advancements in technology, as they are comparable to normal endometrium.6

Comparative studies

• CT imaging: A 2010 retrospective study reiterated the potential of CT imaging as a complementary imaging technique to laparoscopy for evaluating DIE. The researchers evaluated patients with histologically confirmed ovarian endometriomas with CT scans for the presence of tethered rectal appearance in the direction of the uterus, uterosacral ligament thickening, periuterine pelvic fat stranding, and retroflexed uterus. With exception of the retroflexed uterus, the CT imaging showed 61.7% accuracy, 56.9% mean sensitivity, 70.0% specificity, 78.1% positive predictive value, and 60.4% negative predictive value.17

There are equivocal results on the effectiveness of the different diagnostic modalities. The selective use of the tests like TVS and MRI aids in diagnosing large endometriomas and endometriotic implants, while others such as CT scanning may give non-specific findings. Comparing the diagnostic accuracies of various modalities like physical examination, rectal endoscopic sonography (RES), TVS, and MRI in detecting DIE, Bazot et al concluded that the efficiency of MRI is similar to TVS and RES in diagnosing intestinal endometriosis. However, its sensitivity and likelihood ratio was higher for vaginal and uterosacral ligament endometriosis.20

• Magnetic resonance imaging: The adjunctive noninvasive tool, which is especially useful for identifying endometriomas, is valuable for pre-selected high-risk population. Several previous studies have indicated that MRI has better specificity than other non-invasive diagnostic methods in identifying endometriosis.6 Also, since it enables a larger view and better analyses the impact of adhesions on the surrounding anatomic features when compared to ultrasound, it could serve as a useful adjunct in assessing adnexal masses. Jarlot and co-workers noted the diagnostic ability of MRI for deep pelvic endometriosis of the bladder, rectosigmoid, and Douglas pouch, but found its sensitivity lower for lesions affecting the rectovaginal septum, posterior vaginal cul-de-sac, and uterosacral ligaments.18 As per an earlier study by Del Frate et al, MRI was considered as an important adjunctive tool to physical examination, TVS, or transrectal imaging in detecting DIE.19

In contrast, an earlier longitudinal study demonstrated the accuracy of MRI to be greater than RES for diagnosing uterosacral and vaginal endometriosis, but similar for the presence of the disorder in the colorectum.21 Another trial, comparing clinical examination, TVS, and MRI, found TVS to have better accuracy, sensitivity, specificity, positive and negative predictive values for detecting deep retrocervical and rectosigmoid endometriosis.22

Non-invasive diagnosis Owing to the non-specific characteristics of the endometriosis-associated symptoms and the need for confirming the disease surgically, there is frequently a delay in arriving at the diagnosis. These necessitate the need for identifying a non-invasive diagnostic tool that has the potential to avoid unnecessary diagnostic methods and finding treatment failure at early stages.23

Limitations Some of the shortcomings noted with the various techniques are listed below. • Although ultrasound can detect cysts of >1 cm in general, it is difficult to locate small cysts or endometrial implants on the ovarian surface or peritoneum • Ultrasound cannot be relied on to make decisions in all patients owing to its lower sensitivity in posterior lesions 11 • Sensitivity is low with respect to TVS, and MRI in locating peritoneal and ovarian implants, and adhesions • Exploratory laparoscopy is not very accurate in locating deep endometriotic lesion that are concealed in the subperitoneal space or by adhesions 11 • Diagnosis of small endometriotic cysts is difficult in

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• Endometriosis index: A software-derived score has been developed by Fasciani et al in a 2010 prospective observational study for diagnosing the disease and predicting its severity. The correlation of macroscopic/ microscopic endometriosis presence or absence with clinical parameters was used to calculate the index. The sensitivity and specificity of an EI score of >28 for indicating DIE were 72.4% and 90.1%, respectively.24 • Biomarkers: A 2010 systemic review by May et al recognised >100 putative biomarkers that met the selection criteria. However, none of them were found to be clinically useful to be recommended in routine practice.23 A recent prospective study also

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identified around 64 proteins having differential expression patterns following the assessment of protein expression profiles of subjects with and without endometriosis. It was purported that these proteins may aid in detecting potential biomarkers for diagnosis and treatment of infertility caused due to the gynaecological condition.25

curate tool for diagnosing the disease and laparoscopy is necessary to either confirm or exclude the disease. These reiterate the need for further studies to elucidate the functional role of these markers in order to better understand the debilitating gynaecological disorder and associated infertility, as well as for developing novel diagnostic and screening strategies.

A case control study by Mihalyi et al reported that the evaluation of a panel of 6 plasma biomarkers taken during menstruation or in the secretory phase facilitated the diagnosis of minimal-mild and moderate-severe endometriosis with clinically acceptable specificity and high sensitivity. The markers included interleukin (IL)-6, IL-8, tumour necrosis factor-alpha, high-sensitivity C-reactive protein (hsCRP), and cancer antigens, CA-125 and CA-19-9.26

ESHRE Guidelines on Diagnosis

Similarly in an earlier study, IL-6 was found to be a promising serum marker for non-surgically predicting endometriosis.27 Kurdoglu and co-workers, in 2009, demonstrated that CA-19-9 in conjunction with CA125 could serve as a valuable predictor of severe endometriosis, and when used alone, may aid in identifying endometriosis.28 A recent case-control study has demonstrated a predisposition for infertility and minimal/ mild endometriosis-associated infertility in subjects with luteinising hormone beta-subunit gene (LHbeta) G1502A polymorphism.29 Several other recent trials have also identified the role of other factors, such as macrophage migration inhibitory factor (MIF), in the pathogenesis of endometriosis-associated infertility.30 Cytokines, the primary mediators of intercellular communications, are potentially involved in endometriosis development and progression. In a 2009 study, Hou et al found that among the cytokines, beta-nerve growth factor, activin A, and Smad7 were associated in the pathogenesis of endometriosis. The knowledge of those cytokines which are differentially expressed could help in better understanding the endometriosis pathophysiology, which could thereby serve as probable diagnostic and therapeutic targets.31 A recent double blinded study has suggested the efficacy of micro-anatomical endometrial markers in endometriosis diagnosis, as it has the potential to overcome some of the limitations of laparoscopy. The study suggested that reliable and quicker diagnosis of endometriosis could be made by nerve fibre detection in endometrial biopsy; the accuracy of which is probably similar to laparoscopic assessment.32 Currently, there lacks a single, non-invasive, and ac-

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In order to impart up-to-date information pertaining to the diagnosis and treatment strategies of endometriosis to the clinicians, the European Society of Human Reproduction and Embryology (ESHRE) has issued guidelines based on available evidence.33 The working groups, comprising of practising gynaecologists, evidence-based medicine experts from Europe, and representatives of the endometriosis self-help group, drafted recommendations after analyzing systemic reviews and evidence-based guidelines. The diagnostic aspects are mentioned in table 1.34

Delay in Diagnosis In 2006, a quantitative study by Ballard et al substantiated the findings of several other studies by concluding that there is a delay of around 8.5 years in endometriosis diagnosis. The plausible reasons provided are as follows: • Assumption by women that the symptoms are normal • Wrong diagnosis by physicians, assuring the patients that the symptoms were normal, and were asked to take analgesics as and when required • Temporary relief due to the prescription of hormonal drugs • Application of inadequate diagnostic techniques The study results reiterated the need for increasing the awareness level about the symptoms of endometriosis, in the general population, especially in adolescent girls, to differentiate those of normal menstruation from those requiring medical help. Also, the physicians need to update themselves on the latest guidelines and better understand the symptoms to advocate the right diagnostic test. With diagnostic laparoscopy being considered as the secondary test following the failure of treatment in patients with chronic pelvic pain, this study underscores that early diagnosis is paramount to relieve the women from social, economic, and physical burden.35,36 In light of the available evidence, several researchers have stressed on the importance of conducting well-designed randomised clinical research on the immunological, endocrinological, and genetic aspects of the disease. Understanding these characteristics of endometriosis will help in arriving at a consensus on its aetiopathogenesis, prompt diagnosis, and recognizing optimal treatment strategies.

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Table 1: ESHRE Guidelines on Diagnostic Aspects of Endometriosis Diagnostic Tools/ Assessments

Recommendations

Laparoscopy

• Vital to observe and record the findings, especially location, type, and extent of lesions, ideally on the video or DVD • Lack of sufficient evidence to recommend any particular timing for laparoscopy during the menstrual cycle. However, it is preferable not to perform it within or during the 3 months of hormonal treatment in order to avert underdiagnosis • Subjective nature of all endometriosis classification systems, apart from poor correlation with pain symptoms. However, they may be useful for infertility management and prognosis • Probable under estimation of the disease severity owing to the laparoscopic appearance of DIE as minimal disease

Ultrasound

• Although TVS does not have any value in the diagnosis of peritoneal endometriosis when compared to laparoscopy, it could help to confirm or exclude the diagnosis of ovarian endometrioma • Potential to identify endometriosis affecting the bladder or rectum

MRI

Lack of sufficient evidence to support the usefulness of MRI over laparoscopy in the diagnosis or exclusion of endometriosis

Blood tests

Elevation of serum CA-125 levels is found in endometriosis. However, measurement of serum CA-125 concentrations does not serve as a valuable diagnostic tool as opposed to laparoscopy

Evaluation of disease extent

Involvement of ureter, bladder, and bowel should be assessed in case of clinical evidence of DIE. In such cases, multifocal evaluation is needed; transrectal and/or transvaginal and/or renal ultrasound or MRI may need to be performed, with or without intravenous pyelogram and barium enema studies, based on individual situations

Ovarian cyst assessment

Patients with endometrioma should be managed using the local guidelines for suspected ovarian malignancy. Rare cases of ovarian cancer may be detected using ultrasound ±serum CA-125 testing

References

06. Woodward PJ, Sohaey R, Mezzetti TP Jr. Endometriosis:

01. Ozkan S, Murk W, Arici A. Endometriosis and infertility:

radiologic-pathologic correlation. Radiographics. 2001 Jan-

epidemiology and evidence-based treatments. Ann N Y Acad Sci.

Feb;21(1):193-216; questionnaire 288-94. 07. Tsuji I, Ami K, Miyazaki A, Hujinami N, Hoshiai H. Benefit of

2008 Apr;1127:92-100. 02. Olive DL, Lindheim SR, Pritts EA. Endometriosis and infertility:

diagnostic laparoscopy for patients with unexplained infertility

what do we do for each stage? Curr Womens Health Rep. 2003

and normal hysterosalpingography findings. Tohoku J Exp Med.

Oct;3(5):389-94.

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03. Practice Committee of the American Society for Reproductive

08. Practice Committee of the American Society for Reproductive

Medicine. Endometriosis and infertility. Fertil Steril. 2006

Medicine. Optimal evaluation of the infertile female. Fertil Steril.

Nov;86(5 Suppl 1):S156-60.

2006 Nov;86(5 Suppl 1):S264-7.

04. Schenken R. Infertility Aspects of Endometriosis. Glob libr women’s

09. ENDOMETRIOSIS. A Guide for Patients. ASRM. Last accessed June

med, (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10330.

24, 2010.

05. Al-Jefout M, Dezarnaulds G, Cooper M, et al. Diagnosis of

10. Chapron C, Dubuisson JB, Pansini V, et al. Routine clinical

endometriosis by detection of nerve fibres in an endometrial

examination is not sufficient for diagnosing and locating deeply

biopsy: a double blind study. Hum Reprod. 2009 Aug 18. [Epub

infiltrating endometriosis. J Am Assoc Gynecol Laparosc. 2002

ahead of print]

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More References Available Online

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June - July 2010

INTERVIEW Clinical Perspectives of Endometriosis Dr. Shylaja B. Rajiv, Assistant Editor, Endometriosis NEWS.Direct! interviews Dr. Pratap Kumar about a clinician’s perspectives on endometriosis in India and explores the challenges a doctor faces while dealing with a patient with this intriguing condition. Q: Endometriosis, although a common disease, is often not clearly understood by patients. How would you describe endometriosis to a patient suffering from the condition? A: I would explain that there is abnormal menstruation occurring in different places, more commonly in the ovary. The blood would collect in that area, causing a cyst, especially in the ovary. With the collection increasing every month, there would be leakage of the material leading to adhesions, which would distort the anatomy, cause severe pain and infertility too.

Dr. Pratap Kumar Head, Division of Reproductive Medicine, Kasturba Medical College and Kasturba Hospital Manipal, India

Q: How many women with endometriosis have infertility and what is the general awareness level? A: The incidence in India is about 10% to 15% of all infertile women. Although there is a general lack of awareness, it is better among women today as compared to the 80s and 90s. Q: What common symptoms do the patients normally experience or complain of? What are the symptoms that prompt the patients to visit the specialist? Do you think it is different in India compared to the western countries? A: It is not different in India. The usual symptoms can be put as the five Ds: Dysmenorrhoea (painful menses), Dyspareunia (painful intercourse), Disorders of menses, Defecation pain, and Dull ache in the abdomen, usually intermittent. I would also tell them that it is not necessary that all these symptoms should be present for the condition to be diagnosed, since it varies among different individuals. There may not be any symptoms, yet there can be endometriosis, or the only symptom may be infertility. Pain during menses is usually ’triple dysmenorrhoea’ which means before, during and after menses. The dysmenorrhoea is progressive in nature. Q: Are there any new insights into the probable mechanisms and causative factors of endometriosis? Is endometriosis related to other diseases or is it genetic? Does it cause other conditions like chronic inflammation, rheumatoid arthritis, etc? A: Yes, there is a link to genetics since it is seen in families. Inflammatory response may be a cause of the symptoms. However, more work on this is needed to better understand the problem.

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Q: With endometriosis causing considerable morbidity, what are the risk factors for the condition? Is it true that oral contraceptive use reduces the risk of endometriosis? A: Risk factors are not yet clearly identified but it is known that the oestrogen hormone in a woman is responsible for the growth of the endometriosis. Yes, it has been suggested that oral contraceptive pills lower the symptoms or suppress the gynaecological disorder as they cause chronic suppression of the endometriotic implants. It often works as long as the woman takes the pills. Once it is stopped, symptoms of endometriosis may return. Q: What are the current diagnostic tools followed in India? What are the benefits and limitations of imaging tools in the diagnosis? Are there any non-invasive diagnostic tools currently available? A: Laparoscopy is the gold standard for its diagnosis, and also for operation and removal of the same. Ultrasound is able to diagnose ovarian cysts (chocolate cysts) and also adhesion by looking at the ovarian anatomy in relation to the uterus. Blood tests, like CA125, are not good tests as the results just suggest that the levels have raised and this can be due to many other conditions too. Q: What are the difficulties faced by infertility experts while diagnosing and managing endometriosis? A: It is a frustrating experience for the patient and the treating doctor as the recurrences are present in about 30% of women who have undergone surgery. The success rate after any kind of management, whether it is ovulation induction, or assisted reproductive technology, is lower than the non-endometriotic group of infertile women. Q: What is the latest research on endometriosisassociated infertility, especially in terms of diagnosis? A: The future would be to study the immune system (both, cell-mediated and humoral immunity) in relation to endometriosis. There is a thought that migrating endometriotic tissues affect women who have ‘deficient cell mediated immunity.’

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Q: Since use of alternative medicine is very common in India, do you think it has any adverse effect, either on quick diagnosis or treatment outcome? A: I do not think so. www.ilogy.com

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FEATURED MINI REVIEW New Study Questions Effect of Endometriosis on IVF Treatment Outcome There is still no clear consensus whether medical or surgical treatment of endometriosis prior to IVF should be carried out to improve the infertility treatment outcome. Now, a breakthrough study by a group of infertility specialists reports that there is no significant influence of endometriosis on the implantation and delivery rates in ART patients. However, the study findings published in the online issue of the Journal of Endometriosis caution about diminished oocyte reserve, oocyte quality, and embryo grading in such patients. The study conducted by Ioannis Matalliotakis, from the Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, and colleagues, compared the following parameters between endometriosis patients (n=135) and controls with tubal factor infertility (n=3) undergoing IVF or ICSI: • Number and grade of oocyte-corona-cumulus complex • Most viable embryos available for transfer During the study, the subjects and controls were monitored from 262 and 203 consecutive ART cycles, respectively. All patients had undergone laparoscopy prior to IVF. During the follow-up, the response of patients to factors such as gonadotrophin, oocyte and embryo grade, cleavage, fertilization, implantation, pregnancy, miscarriage, and delivery rates, were determined. The key study findings noted in endometriosis patients in contrast to controls were as follows:

• Reduction in - oocyte-corona-cumulus complex (OCCC) - mature follicles and oocytes collected - two-pronuclear (2PN) oocytes - grade 1 and 2 embryos obtained on days 2 and 3 - peak E2

two groups with regard to cleavage, implantation, fertilization, conception, miscarriage, and delivery rates. In stark contrast to these study findings, an earlier metaanalysis by Barnhart et al concluded (Fertility and Sterility, 2002) that the chances of pregnancy in patients with endometriosis-associated infertility undergoing IVF is around one-half of that of patients opting for IVF due to other indications. The researchers also reported that the presence of endometriosis would adversely affect uterine receptivity, as well as oocyte/embryo development. Certain studies defend the surgical excision of endometriomas prior to IVF by presenting the following arguments: • Surgical resection of endometriomas is linked to increased chances of destroying adjacent normal ovarian tissue or reducing ovarian arterial blood flow, which may in turn contribute to diminished ovarian reserve • Although the surgery is considered as minimally invasive, it is associated with certain life-threatening complications • There is an increased risk for infection owing to the endometrioma aspiration, regardless of prophylactic antibiotic use The recommendations of the Royal College of Obstetricians and Gynaecologists (RCOG) are in agreement with the European Society of Human Reproduction and Embryology (ESHRE) suggesting excision of endometriomas ≥4 cm diameter before IVF treatment. However, ASRM has not put forth any such recommendations, considering that the benefits of such a surgery are doubtful. This reiterates the need for clear consensus to aid physicians in appropriate patient selection and also in decision-making regarding the optimal therapeutic intervention prior to IVF.

References

• Increase in - total gonadotrophin - cycle cancellation rate

01. Matalliotakis I, Cakmak H, Sakkas D, Matalliotaki C, Arici A. Assessment of oocyte and embryo quality in women with endometriosis. Journal of Endometriosis. 2010;2:87-94.

However, no substantial variation was noted between the

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June - July 2010

MINI REVIEWS Follicular Fluid Proteins Expressed Differently in Endometriosis Patients A recent prospective case control study, published in the journal Human Reproduction, has identified around 64 proteins having varied expression patterns after comparing the protein expression profiles of subjects with and without endometriosis. Researchers suggest that these proteins may aid in recognising potential biomarkers for the diagnosis and treatment of infertility caused due to endometriosis. Edson Guimaraes Lo Turco, from the Sao Paulo Federal University, Brazil, and co-workers, conducted the study to quantify proteins and also investigate their expression pattern in follicular fluid (FF) of women with and without endometriosis. The subjects (maximum age=35 years) were categorised into 2 subsets: individuals having stage III or IV endometriosis (Group I), and pregnant women without the disorder (Group II). Ultrasound-assisted ovarian aspiration was used to collect FF after subjecting the IVF patients to controlled ovarian stimulation. Multidimensional protein identification technology (MudPIT), and subsequently, label-free quantification with ProteinLynxGlobalServer 2.4v, IdentityE and ExpressionE software were used to separate and analyse protein samples after pooling the FF from both the ovaries. The study results are mentioned below: • Identification of random sequence of 416 proteins • Differential expression of 62 proteins between the groups • Groups I and II exclusively expressed 58.1% (n=36) and 27.4% (n=17) of proteins, respectively • Expressions of 1.6% (n=1) and 12.9% (n=8) proteins were at greater levels in groups I and II, respectively • The 62 proteins differentially expressed were correlated with various functions as below: o 24.2% to binding (n=15) o 1.6% to immune response (n=1) o 12.9% to cell division (n=8) o 4.8% to cellular metabolism (n=3) o 25.8% to general function (n=16)

However the function of nearly 31% (n=19) proteins is yet to be identified. Based on the findings, the investigators proposed that the differentially expressed proteins may be associated with the endometriosis pathophysiology. In an earlier study, Pellicer et al (Journal of Reproduction and Fertility, 2000) suggested the probable association of infertility in endometriosis with the altered follicular environment, resulting in the development of low quality oocytes and embryos in IVF cycles. Evaluating the autocrine, endocrine, and paracrine conditions stimulated during the process of folliculogenesis in subjects with and without endometriosis, the study results demonstrated the following: • Progesterone level in the FF was directly proportional to the disease severity • Interleukin-6 (IL-6) concentrations were higher in patients with endometriosis compared to those without, due to their excess production by granulosa luteal cells • Vascular endothelial growth factor (VEGF) was collected from FF in lesser levels in patients with endometriosis Endometriosis, a leading aetiological factor of infertility, has a global prevalence of around 0.5-5% and 25-40% in fertile and infertile women, respectively. However, the exact cause-and-effect link between infertility and endometriosis is not clearly understood. The current study, identifying the variedly expressed proteins in FF of patients with endometriosis, could serve in better understanding the aetiopathogenic mechanisms, and developing novel diagnostic and therapeutic strategies for the enigmatic disease.

References 01. Lo Turco EG, Souza GH, Garcia JS, Ferreira CR, Eberlin MN, Bertolla RP. Effect of endometriosis on the protein expression pattern of follicular fluid from patients submitted to controlled ovarian hyperstimulation for in vitro fertilization. Hum Reprod. 2010 Apr 28. [Epub ahead of print]

More References Available Online

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June - July 2010

LH Beta-subunit Gene Variant linked to Endometriosis-associated Infertility Several genetic and hormonal factors have been reported to play a substantial role in the development and clinical progression of endometriosis. Now, a recent case-control study published in the European Journal of Obstetrics & Gynecology and Reproductive Biology has reported a predisposition for infertility and minimal/ mild endometriosis-associated infertility in women with luteinising hormone beta-subunit gene (LHbeta) G1502A polymorphism. Fernanda A Mafra and co-workers, from the Department of Gynecology and Obstetrics, ABC School of Medicine, Sao Paulo, Brazil, assessed the frequency of LHbeta G1502A variant among infertile subjects with endometriosis (110), infertile women without the disease (84) and a control group comprising of healthy fertile women (209). The occurrence of polymorphism was assessed using restriction fragment length polymorphism-polymerase chain reaction (RPLP-PCR). The frequency of occurrence of GG, GA and AA genotypes of the LHbeta polymorphism are listed in Table 1.

Table 1: LH Beta polymorphism distribution Groups assessed

GG (%) GA (%) AA (%) 68.9

21.5

9.6

Infertile women without endometriosis

52.4

38.1

9.5

0.0123

Women with endometriosis

54.6

31.8

13.6

0.0398

Women with minimal/mild endometriosis

47.3

36.4

16.3

0.0118

Women with moderate/ severe endometriosis

61.8

27.3

10.9

0.5975

Groups assessed

Allele G

Allele A

Control group

79.7

20.3

Infertile women without endometriosis

71.4

28.6

Women with endometriosis

70.5

29.5

Women with minimal/mild endometriosis

65.5

34.5

Women with moderate/severe endometriosis

75.5

24.5

Although endometriosis-related findings could be coincidental with infertility, the researchers suggested that the presence of the LHbeta variant may increase a woman’s risk for infertility and minimal/mild endometriosis-associated infertility. An earlier study conducted by Gazvani et al (Human Reproduction, 2002) explored the possible association between LHß-subunit variant and endometriosis in 230 subjects undergoing laparoscopy for diagnosing infertility. However, the study did not yield positive results to substantiate the hypothesis that LH variant is linked to altered endometriosis risk.

P value

Control group

Table 2: Allele frequency in the different groups

More recently, a meta-analysis by Guo et al (Gynecologic and Obstetric Investigation, 2006) reported the lack of substantial evidence to validate the putative relation between such genetic polymorphisms and endometriosis. The study reiterated the need for proper study design, execution, and data evaluation for the independent replication of these positive findings. Further validation of the genetic link with endometriosisassociated infertility could be promising for developing newer diagnostic and treatment strategies.

The allele frequencies noted in the different groups are listed in Table 2.

References 01. Guo SW. Association of endometriosis risk and genetic polymorphisms involving sex steroid biosynthesis and their receptors: a metaanalysis. Gynecol Obstet Invest. 2006;61(2):90-105.

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June - July 2010

Serum Anti-endometrial Antibodies May be Potential Risk Factor for Implantation Failure Autoimmunity is known to play a key role in the onset and progression of endometriosis. Now, a recent study has reported that the presence of anti-endometrial antibodies (AEA) in the serum of infertile women could raise the risk of implantation failure. The findings of the study are published in the recent issue of the American Journal of Reproductive Immunology. Aili Sarapik, from the Department of Immunology, University of Tartu, Estonia, along with co-workers, performed immunoblot and mass spectrometry analysis of the sera of patients suffering from endometriosis and tubal factor infertility (TFI), and identified the candidate antigens. The following results were noted during the study: • Presence of IgG and IgA AEAs to several antigens with molecular weight varying between 10 to 200 kDa • Certain AEA reactions differed between the patient groups and a specific AEA was found to be linked to IVF implantation failure • IgA AEA to alpha-enolase (a 47-kDa protein) was extensive in patients with TFI, and linked to IVF treatment failure Based on the above findings, the researchers concluded that detection of the presence and spectra of AEA in endometriosis and TFI patients, could serve as an effective predictor for pregnancy outcome. Earlier, Randall et al (The Journal of Reproductive Medicine, 2009) conducted a study to evaluate the influence of surgically confirmed endometriosis, and peritoneal fluid and serum AEA on pregnancy outcome in patients undergoing zygote intrafallopian transfer (ZIFT), gamete intrafallopian transfer (GIFT), and IVF. Positive serum AEA was found to be statistically significant in patients who experienced miscarriage compared to those who delivered (P<0.0000), suggesting a link between endometriosis and miscarriage in ART patients. However, endometriosis did not significantly decrease the pregnancy potential.

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Another study by Tomassetti et al (Reproductive BioMedicine Online, 2006) evaluated the association between endometriosis and implantation failure or recurrent miscarriage after ART. It was reported that the probable explanation for the link could be the increased production of antiendometrial autoantibodies, and modifications in follicular and peritoneal fluid cytokines and immune cells. The aetiology of recurrent implantation failure, one of the major causes of unsuccessful ART, is poorly elucidated. Research has documented the potential role of embryonic chromosomal aberrations and maternal immunological, endocrinal, and thrombophilic abnormalities in both recurrent implantation failure and recurrent miscarriages. Although various therapeutic strategies have been tested to correct the disturbances, there is lack of sufficient evidence to recommend any treatment option in routine clinical practice. Further validation on the current study findings, which suggests the probable influence of anti-endometrial antibodies on implantation failure, would aid in better understanding of the underlying pathophysiological mechanisms. This could in turn help to develop or modify the diagnostic and treatment strategies, thereby improving the IVF outcomes in patients with infertility due to endometriosis.

References 01. Sarapik A, Haller-Kikkatalo K, Utt M, Teesalu K, Salumets A, Uibo R. Serum anti-endometrial antibodies in infertile women - potential risk factor for implantation failure. Am J Reprod Immunol. 2010 May;63(5):349-57. 02. Randall GW, Bush S, Gantt PA. Serum and peritoneal fluid antiendometrial antibodies in assisted reproduction. J Reprod Med. 2009 Jun;54(6):353-60. 03. Tomassetti C, Meuleman C, Pexsters A, et al. Endometriosis,

recurrent miscarriage and implantation failure: is there an immunological link? Reprod Biomed Online. 2006 Jul;13(1):58-64.

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June - July 2010

NEWS Elevated Expression of Macrophage Migration Inhibitory Factor Noted in Endometriosis Patients Elevated macrophage migration inhibitory factor (MIF) in women with endometriosis is indicative of disease progression as well as endometriosis-associated pain and infertility. Now, a recent study published in The Journal of Obstetrics and Gynaecology Research further substantiates this understanding by demonstrating the increased expression of MIF in both eutopic and ectopic endometrial tissues of subjects with endometriosis. Wei Lin from the Department of Obstetrics and Gynaecology, Qilu Hospital, Shandong University, China, and co-workers, compared the expression levels of MIF in eutopic and ectopic endometria of endometriosis patients, with eutopic endometrium of women without the disorder. The researchers further evaluated the existence of variation in the MIF expression with regard to menstrual cycle, disease stage, and infertility status. The cDNA samples were obtained from 40 endometriosis patients and 15 controls following the isolation of total RNA and reverse transcription. Real-time fluorescent quantitative polymerase chain reaction was used to amplify the cDNA samples in order to determine the MIF expression levels. Immunohistochemistry analysis was performed for both the endometriosis tissues and the normal specimens. The key study findings are as follows: • Enhanced MIF expression in eutopic and ectopic endometria in endometriosis-affected subjects, when compared to normal eutopic endometria (P<0.01) • Increased MIF concentration in the eutopic endometria of the endometriosis group, in both proliferative and secretory phases, in contrast to the controls (P<0.05) • Cycle phase-dependent expression of MIF mRNA and increased level of expression in both the groups in the proliferative phase, when compared to the secretory phase (P<0.05) • No substantial link between MIF expression and the American Fertility Society disease staging of endometriosis (P>0.05) • Increased MIF levels in sterile patients compared to non-sterile women in the endometriosis group (P<0.05) An earlier retrospective study by Akoum et al (Fertility

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and Sterility, 2006) reported similar findings and also noted an increased expression of MIF at specific phases of the menstrual cycle in the intrauterine endometrium of patients with endometriosis. The study conducted on 45 endometriosis and 25 normal subjects showed the elevated levels during the mid-secretory phase as well as in the late secretory phase before menstruation, especially in infertile endometriosis patients. These recent study findings suggest the putative role of MIF in the pathophysiology of endometriosis. MIF, a pro-inflammatory mediator, has been demonstrated to be involved in tumorigenesis as well as in diverse inflammatory and autoimmune diseases pathogenesis. The factor is speculated to play a pivotal role in modulating the physiological processes of endometrial tissue regeneration and disintegration during menstrual cycles. Further elucidation of its functional role and the differential expression pattern with regard to menstrual cycle, infertility, and disease stages may aid in developing novel diagnostic and screening strategies for this debilitating gynaecological condition and associated infertility.

References 01. Lin W, Chen S, Li M, Wang B, Qu X, Zhang Y. Expression of macrophage migration inhibitory factor in human endometriosis: relation to disease stage, menstrual cycle and infertility. J Obstet Gynaecol Res. 2010 Apr;36(2):344-51. 02. Akoum A, Metz CN, Al-Akoum M, Kats R. Macrophage migration inhibitory factor expression in the intrauterine endometrium of women with endometriosis varies with disease stage, infertility status, and pelvic pain. Fertil Steril. 2006 May;85(5):1379-85.

Dysregulated Activin-A Concentrations Play Crucial Role in Endometriosis-associated Infertility The adhesion of the trophoblast to the uterine wall through cell adhesion molecules (CAMs) is a crucial initial step, necessary for implantation, and then, placentation. The regulation of CAMs, such as integrins and extracellular matrix ligands, is most probably governed by cytokines, hormones, and growth factors. A new study has reported that dysregulated local levels of activin-A, a cytokine growth factor belonging to the beta superfamily, may

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reduce both the production of trophoblast CAM as well as adhesion, which could in turn lead to implantation failure. The findings, published in the Human Reproduction journal, could partly explain the association of endometriosis with infertility. Chelsea J Stoikos from the Department of Obstetrics and Gynaecology, Monash University, Australia, and coworkers, studied the secretory phase uterine washings obtained from subjects with and without endometriosis (EOS) to measure activin-A concentrations and investigate its impact on trophoblast cell adhesion. Integrin antibody and cell-matrix adhesion assays were used to measure adhesive molecules, while the examination of activin receptor expression on trophoblast (HTR8) cells was by RT-PCR. The researchers verified the localization of betasubunit in endometrial tissues. The dimeric activin-A in uterine washings (EOS patients=23; controls=14) was assessed with enzyme-linked immunosorbent assay. The study findings are listed below.

June - July 2010

It was observed that activin-A, which is expressed in high levels by epithelial and stromal cells during the endometrial phase, is secreted into the uterine cavity in increasing amounts during the secretory phase. The scientists further noted the modulatory influence of activin-A in embryonic trophoblast differentiation and adhesion. During the entire pregnancy, the growth factor was found to be expressed by the maternal decidua in high levels. The current study findings, providing insights into the mechanisms underlying implantation failure in endometriosis, will drive more research into an area that has great clinical implications in the management of infertile patients .

References 01. Stoikos CJ, Salamonsen LA, Hannan NJ, O’Connor AE, Rombauts L, Dimitriadis E. Activin-A regulates trophoblast cell adhesive properties: implications for implantation failure in women with endometriosis-associated infertility. Hum Reprod. 2010 May 10.

• HTR8 cells expressed activin receptors • In a concentration-dependent manner, Smad2 was activated by activin-A. Activin receptor inhibitor blocked this effect • Treatment with 50 ng/mL of activin-A for 24 hours reduced οοtrophoblast cell surface integrins (alpha 1, 2, 3, 5; beta 1, 2, 4; and alphavbeta 5) cell binding to the ECM ligands, collagen IV, οο fibronectin, and collagen I (P<0.05) • Activin-A in the range of 42 to 8481 pg/mL was noted in 56.5% and 21.4% of EOS and control washings, respectively

[Epub ahead of print] 02. Florio P, Rossi M, Sigurdardottir M, et al. Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin-A. Steroids. 2003 Nov;68(10-13):801-7.

Study Validates Safety and Improved Outcomes with Laparoscopic Colorectal Resection

The scientists concluded on the regulatory potential of activin-A for trophoblast cell adhesion and implicated its role in implantation failure in endometriosis-associated infertility. In an earlier review, Florio et al (Steroids, 2003) suggested that endometrial cells produce several peptide hormones and growth factors like activin-A under the effect of ovarian steroid hormones, promoting some of the following events: • Physiological growth and differentiation in endometrial cycle • Decidualisation, a vital preparative step for pregnancy establishment • Pathological growth and differentiation in conditions like cancer and endometriosis

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The use of laparoscopic and laparoscopy assisted surgery for bowel resection in young endometriosis patients trying to conceive is a matter of debate. Now, the first randomised trial published in the Annals of Surgery reports laparoscopy as a safe intervention, contributing to increased pregnancy rates, as well as symptomatic and quality of life improvements, compared to open surgery. Emile Darai from the Department of Gynecology and Obstetrics, Hôpital Tenon, Université Pierre et Marie Curie, France, and colleagues, compared the effectiveness between laparoscopically assisted surgery and open colorectal resection with regard to perioperative complications, symptomatic improvement, fertility, and quality of life. The non-inferiority trial was carried out by randomising 52 colorectal endometriosis patients to endure laparoscopy assisted or open colorectal resection. The median follow-up conducted over a period of 19 months considered improvement in dyschesia as the

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primary end point. Key study findings were as follows:

June - July 2010

Link between Increased Leptin Levels and Endometriosis Identified

• Overall improvement in the following digestive, gynaecologic and general symptoms οοDyschesia (P<0.0001) οοDiarrhoea (P<0.01) οοBowel pain and cramping (P<0.0001) οοDysmenorrhoea (P<0.0001) οοDyspareunia (P<0.0001) οοBack pain (P=0.001) οοAsthenia (P=0.0001) • No significant variation in the symptom delta values and quality of life between the groups • Reduced median blood loss in laparoscopic patients (P<0.05) • Improved pregnancy rate in laparoscopic group (P=0.006) with a cumulative pregnancy rate of 60% • Higher number of complications, particularly grade 3 (P=0.03), in the open surgery group (P=0.04)

Leptin and adiponectin protein hormones are speculated to play a crucial role in the pathogenesis of endometriosis, one of the leading causes of infertility. A new cross-sectional study, published in the recent issue of Gynecological Endocrinology, confirms that increased leptin levels in the peritoneal fluid (PF) contribute to the initiation and development of pelvic endometriosis. However, the study results did not support the theory of influence of increased adiponectin concentrations on endometriosis-associated infertility.

An earlier study conducted by Minelli et al (Archives of Surgery, 2009) validated laparoscopic colorectal resection as an effective procedure that can be adopted as a primary intervention for managing symptomatic colorectal infiltrating endometriosis. Although, the risk for major postoperative complications was found to be high in patients undergoing the procedure, it was reported to yield good treatment outcomes with regard to disease recurrence. Bowel endometriosis, one among the severe forms of endometriosis, is associated with an incidence rate of 5.3% to 12% amongst all endometriosis patients. Medical therapy for this debilitating condition is found to be ineffective or of transient benefit, with a recurrence rate of 76%. Although laparoscopy is validated as a safe and effective procedure, appropriate patient selection is vital for surgical management of the disease. Hence, the precise radiological evaluation and accurate anamnesis, besides clinical examination, plays a vital role in the successful performance of colorectal endometriosis resection.

References 01. Darai E, Dubernard G, Coutant C, Frey C, Rouzier R, Ballester M. Randomised trial of laparoscopically assisted versus open colorectal resection for endometriosis: morbidity, symptoms, quality of life, and fertility. Ann Surg. 2010 Jun;251(6):1018-23. 02. Minelli L, Fanfani F, Fagotti A, et al. Laparoscopic colorectal resection for bowel endometriosis: feasibility, complications, and clinical

Nitin Pandey and co-workers from the All India Institute of Medical Sciences, New Delhi, determined leptin and adiponectin concentrations in serum and PF samples of 50 infertile women (22-41 years of age) undergoing therapeutic and/or diagnostic laparoscopy for endometriosis. Based on the endoscopy results, patients with endometriosis were categorised as test group (n=15), while those without the disease as controls (n=35). The study excluded patients on leuprolide or danazol therapy and those with diabetes, polycystic ovarian syndrome, and thyroiditis. The assessment of the concentration of the two proteins with enzyme linked immunosorbent assay (ELISA) kits showed the following results: • Median leptin levels in PF were considerably higher in the test group compared to controls (27.7 versus 15.6 ng/mL; P=0.019), and the protein level remained high even after BMI-normalization (P=0.004). • Median leptin and adiponectin levels in the serum remained similar in both the groups. These findings confirmed the role of PF leptin in the initiation and development of pelvic endometriosis; however, researchers suggested that further validation in fertile women could provide definitive results. Certain previous studies have also reported a positive correlation between PF leptin levels and endometriosisrelated infertility. In one such study by Barcz et al (Gynecological Endocrinology, 2008), it was noted that PF leptin levels did not correlate with endometriosis stage, and was considerably high in infertile patients, suggesting its role in the pathophysiology of infertility.

outcome. Arch Surg. 2009 Mar; 144(3):234-9; discussion 239.

Contrary to recent study findings with regard to

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adiponectin, some of the previous studies have reported a decrease in the adiponectin levels in the PF of endometriosis patients. A study by Takemura et al (American Journal of Reproductive Immunology, 2005) noted a substantial decrease in adiponectin concentrations of patients with stage III/IV endometriosis, when compared to those in early stages of the disease and in patients without endometriosis. The researchers also concluded on the putative role of the protein as an anti-endometriotic factor due to its anti-angiogenic, antifibrotic, and anti-inflammatory properties. The varying signs and symptoms of endometriosis make its diagnosis complex. Currently adopted imaging techniques could fail in detecting small ovarian endometriomas, adhesions, and peritoneal lesions, which demand surgery for definitive diagnosis. Laparoscopy, although considered as the gold standard for endometrial screening, is invasive in nature. With further research on the current findings, leptin and adiponectin estimates could serve as appropriate protein markers for diagnosing pelvic endometriosis, as well as determining the disease stage, thereby avoiding the need for diagnostic surgery.

References

June - July 2010

for the existing and new generation infertility treatments. Sachiko Matsuzaki from the Centre Hospitalier Universitaire de Clermont-Ferrand, Gynécologie Obstétrique et Médecine de la Reproduction, France, along with co-workers, evaluated the adhesion molecules’ mRNA and/or protein expression levels in unexplained infertility patients (n=9), infertile subjects with endometriosis (n=151) and uterine fibromas (n=41), and healthy fertile controls (n=57). Techniques, such as immunohistochemistry, laser capture microdissection, and RT-PCR, were utilised for the analysis. The following results were noted during the study: • E-cadherin and catenin mRNA expression levels in the microdissected epithelial cells isolated from the subjects of all the groups were comparable throughout the menstrual cycle • Total β-catenin, E-cadherin, and dephosphorylated catenin protein expression were considerably low or nil in the glandular and luminal epithelia cells in mid-secretory endometrium of the controls. The expressions were however higher in infertile patients with endometriosis and those with unexplained infertility than controls

01. Pandey N, Kriplani A, Yadav RK, Lyngdoh BT, Mahapatra SC. Peritoneal fluid leptin levels are increased but adiponectin levels are not changed in infertile patients with pelvic endometriosis. Gynecol Endocrinol. 2010 May 26. [Epub ahead of print] 02. Barcz E, Milewski L, Radomski D, et al. A relationship between increased peritoneal leptin levels and infertility in endometriosis. Gynecol Endocrinol. 2008 Sep;24(9):526-30. 3.

Based on these findings, the researchers suggested that the activation of Wnt/β-catenin signaling pathway in addition to altered down-regulation of catenin and E-cadherin protein expression during the implantation window could be one of the potential pathophysiological mechanisms of endometriosis-associated infertility.

03. Takemura Y, Osuga Y, Harada M, et al. Concentration of adiponectin in peritoneal fluid is decreased in women with endometriosis. Am J Reprod Immunol. 2005 Oct;54(4):217-21.

Study Reports Link between Impaired E-Cadherin and β-Catenin Expression and Endometriosisassociated Infertility Numerous studies have linked adhesion molecules, E-cadherin and β-catenin, to endometriosis development; however, the role of these molecules in infertility is unclear. Now, a recent study reports that altered downregulation of E-cadherin and β-catenin expression, in the mid-secretory endometrium could play a role in infertility in endometriosis patients. The findings of the study, published in the recent issue of The Journal of Clinical Endocrinology & Metabolism, could be a potential target

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The E-cadherin/β-catenin complex has been reported to play a crucial role in epithelial cell-cell adhesion events and the preservation of endometrial tissue integrity. Studies have also documented cadherin’s participation in fertilization. A study by Rufas et al (Molecular Human Reproduction, 2000) reported that cadherin molecules are localised on oocyte and spermatozoa plasma membrane, and could be involved in the oocytespermatozoa recognition process prior to gamete fusion and fertilization. The recent findings, demonstrating lower endometrial expression of E-cadherin and β-catenin in infertile patients during the window of implantation, emphasises their importance in conception. With further investigation, these proteins could help in understanding the molecular basis of fertilization and diagnosing infertility associated with endometriosis.

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June - July 2010

References 01. Matsuzaki S, Darcha C, Maleysson E, Canis M, Mage G. Impaired Down-Regulation of E-Cadherin and {beta}-Catenin Protein

PDTC could represent a novel therapeutic approach for endometriosis.

Expression in Endometrial Epithelial Cells in the Mid-Secretory Endometrium of Infertile Patients with Endometriosis. J Clin Endocrinol Metab. 2010 Apr 21. 02. Rufas O, Fisch B, Ziv S, Shalgi R. Expression of cadherin adhesion molecules on human gametes. Mol Hum Reprod. 2000 Feb;6(2):163-9.

Study Demonstrates Therapeutic Application of Pyrrolidine Dithiocarbamate against Endometriosis The increased activation of nuclear factor-kappaB (NF-κB), a pro-inflammatory transcription factor, is documented in endometrial lesions and peritoneal macrophages of endometriosis patients. Now, a recent in vitro study reports that pyrrolidine dithiocarbamate (PDTC), an anti-oxidant and a potent inhibitor of NF-κB, could serve as a novel therapeutic strategy for endometriosis. The findings of the study are published in the recent issue of the journal, Fertility and Sterility. Jing-jing Zhang, from the department of Obstetrics and Gynecology, Affiliated Hospital of Medical College, Qingdao University, People’s Republic of China, and coworkers, determined the activity of PDTC on endometriotic and normal endometrial stromal cells using molecular biology techniques such as Western blot analysis, RT-PCR, and electrophoretic mobility shift assay. On assessment, the following results were documented: • The nuclear factor-kappaB activation was strongly inhibited by PDTC in the endometriotic stromal cells, when compared to normal endometrial stromal cells. • The endometriotic stromal cell pre-treatment with PDTC weakened the tumour necrosis factor-α-induced expressions of matrix metalloproteinase-9, CD44s, and vascular endothelial growth factor. However, a reversal in tumour necrosis factor-α-reduced expression of tissue inhibitor of metalloproteinase-1 was noted.

Earlier, a similar study by Celik et al (Human Reproduction, 2008) evaluated the effect of PDTC on the development of endometriosis in rat models. The researchers surgically induced endometriosis in these rat models and assessed the effect of PDTC on the volume and viability of implants after three weeks. It was noted that the implant volumes post-treatment reduced to some extent in the PDTC group, but increased in the control group. Additionally, expression levels of CD31, a proliferating cell nuclear antigen, and Ki67 considerably reduced in the PDTC group. Numerous studies have revealed that the activation of NFκB plays a critical regulatory role in the pro-inflammatory response of endometrial stromal cells of endometriosis patients. The protein has shown to induce the expression of several genes regulating the immune and inflammatory responses, contributing to the pathogenesis of endometriosis. In vitro and in vivo studies have shown that NF-kappaB-mediated gene transcription stimulates invasion, inflammation, proliferation, angiogenesis, and apoptosis inhibition of the endometriotic cells. A recent study by González-Ramos et al (Fertility and Sterility, 2010) concluded that the inhibition of NFκB activation could serve as a promising therapeutic strategy for the upcoming therapies that target the different cell functions such as invasion, inflammation, proliferation, angiogenesis, and apoptosis, implicated with endometriosis development.

References 01. Zhang JJ, Xu ZM, Dai HY, et al. Application of the nuclear factorkappaB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study. Fertil Steril. 2010 Jun 18. [Epub ahead of print] 02. Celik O, Hascalik S, Elter K, Tagluk ME, Gurates B, Aydin NE. Combating endometriosis by blocking proteasome and nuclear factor-kappaB pathways. Hum Reprod. 2008 Nov;23(11):2458-65. 03. González-Ramos R, Van Langendonckt A, Defrère S, et al. Involvement of the nuclear factor-kappaB pathway in the

Based on these findings, the researchers concluded that

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pathogenesis of endometriosis. Fertil Steril. 2010 Feb 24.

goserelin 3.6 mg depot

a real advance STERILE & CONVENIENT* READY-TO-USE PRE-FILLED SYRINGE* ENSURES DELIVERY OF 100% DOSE * EACH TIME * Zoladex Product Monograph

Abbreviated Prescribing Information COMPOSITION: Each prefilled syringe contains goserelin acetate equivalent to 3.6 mg peptide base in a sustained release depot. It is supplied as a single dose SafeSystem™ syringe applicator (with a protective sleeve in a sealed pouch t 6 10 which contains a desiccant) to be administered every 4 weeks. CLINICAL PHARMACOLOGY: Zoladex (D-Ser(Bu ) Azgly LHRH) is a synthetic analogue of naturally occurring LHRH. On chronic administration Zoladex results in inhibition of pituitary LH secretion leading to a fall in serum estrogen and testosterone concentrations in women and men, respectively. Initially, there may be a transient increase in serum sex steroid hormone concentration. By around 21 days after the first depot injection, estrogen or testosterone concentrations fall to within castrate range and remain suppressed with continuous treatment every 28 days. This inhibition leads to breast or prostate tumour regression and symptomatic improvement in the majority of patients. The bioavailability of Zoladex is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no tissue accumulation. Zoladex is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given monthly in a depot formulation, this change will have minimal effect. Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure. INDICATIONS: Prostate Cancer. Zoladex is indicated in the management of prostate cancer suitable for hormonal manipulation. Breast cancer. Zoladex is indicated in the management of breast cancer in premenopausal and perimenopausal women suitable for hormonal manipulation. Endometriosis. In the management of endometriosis, Zoladex alleviates symptoms, including pain and reduces the size and number of endometrial lesions. Uterine fibroids. In conjunction with iron therapy in the hematological improvement of anaemic patients with fibroids prior to surgery. Endometrial thinning. Zoladex is indicated for the prethinning of the uterine endometrium prior to endometrial ablation or resection. Assisted reproduction. Pituitary downregulation in preparation for superovulation. DOSAGE AND ADMINISTRATION: Adults: One 3.6 mg depot of Zoladex injected subcutaneously into the anterior abdominal wall, every 28 days. No dosage adjustment is necessary for patients with renal impairment. No dosage adjustment is necessary for patients with hepatic impairment. No dosage adjustment is necessary in the elderly. Children: Zoladex is not indicated for use in children. CONTRA-INDICATIONS: Hypersensitivity to Zoladex or other LHRH analogues. Pregnancy and Lactation. PRECAUTIONS: Zoladex is not indicated for use in children as safety and efficacy have not been established in this group of patients. Males: Use in patients at particular risk of developing ureteric obstruction or spinal cord compression should be considered carefully and patients monitored during first month of therapy. Females: Exclude pregnancy before treatment. Non-hormonal contraception should be employed during therapy. Loss of bone mineral density, which may recover on cessation of therapy. Caution in women with known metabolic bone disease. Increase in cervical resistance, requiring care if dilating the cervix. Currently, there are no clinical data on the effects of treating benign endometriosis conditions with Zoladex for periods in excess of six months. An increase in benign pituitary tumours has been observed in male rats following long-term repeated dosing. (Relevance to man not established). Pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach observed in mice following long term repeated dosing with human dose (relevance to man is unknown). There is no evidence that Zoladex results in impairment of ability to drive or operate machinery. PREGNANCY AND LACTATION Although reproductive toxicology in animals gave no evidence of teratogenic potential, Zoladex should not be used in pregnancy as there is a theoretical risk of abortion or foetal abnormality if LHRH agonists are used during pregnancy. Potentially fertile women should be examined carefully before treatment to exclude pregnancy. Non hormonal methods of contraception should be employed during therapy. The use of Zoladex during breast feeding is not recommended. SIDE EFFECTS Rarely, hypersensitivity, skin rashes, generally mild. Arthralgia. Changes in blood pressure. Occasional mild bruising at injection site. Males: Hot flushes, decrease in potency, infrequently breast swelling and tenderness. Temporary increase in bone pain, isolated case of ureteric obstruction and spinal cord compression have been recorded. Females: Hot flushes and sweating, change in libido, headaches, mood changes including depression, change in breast size. Temporary increase in signs and symptoms. Degeneration of 0 fibroids. PRESENTATION A sterile depot containing goserelin 3.6mg (as acetate) as a SafeSystem™. PRECAUTION FOR STORAGE: Store below 25 C. Consult the full Prescribing Information before prescribing.

Zoladex is a registered trademark of AstraZeneca group of companies.

For further information, please write to:

AstraZeneca Pharma India Limited, ‘Avishkar’, Off Bellary Road, PB No.2483, Bangalore-560 024, India. MA/MH/ZOL/BKT/014/JULY/2010 Not to be used after June 2012

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