To the Editor:
We would like to thank Dr. Fassbender et al. for their fine article (1). The aim of the review study was to show the diagnostic performance of noninvasive or semi-invasive tests for endometriosis. This article provides an overview of various markers and their place in early detection. We greatly appreciated this paper, but there are also some other biomarkers that should be discussed.
Stem cell theory opens the latest advanced avenue for the etiology of many diseases, including endometriosis. Stem progenitor cells may serve as early markers and also detect recurrence. The endometrium contains endometrial/stem progenitor cells, and these stem cells are present in the peritoneal cavity in women that have retrograde menstruation. Bone marrow is another origin. Bone marrow mesenchymal stem cells (MSC) circulate to the endometrium and reprogram into the endometrial MSC. Positive immunostaining for stem cell markers such as CD9, CD34, c-Kit, Oct-4, Musashi-1 was detected in isolated epithelial and stromal cells in eutopic and ectopic endometrium (2). It has been reported that Oct-4 may stimulate the migration activity of endometrial cells (3). Moreover, these markers may also identify the patients that carry the risk of developing ovarian cancer.
Another biomarker is increased telomerase activity. Telomeres are noncoding tandemly repeated DNA sequences that are vital for maintaining chromosomal integrity and cell stability. Telomerase is a reverse transcriptase that can prevent telomere shortening, allowing the cells to overcome apoptosis and to divide indefinitely. Its expression correlates with cell proliferation (4). It has been reported that increased endometrial expression of telomerase triggers the development and severity of endometriosis (4). Alterations in pathways involved in telomere-length homeostasis could influence the survival of ectopic endometrial and hematopoietic stem cells (4).
There is also a need for genomic biomarker testing for early diagnosis of endometriosis. It is well known that genetic abnormalities may also play a role in endometriosis development modifying stromal-epithelial interactions, peritoneal environment, immune surveillance, cell adhesion and proliferation, apoptosis, and angiogenesis (2). Genomic imbalances in 3p, 5q, 7p, 9p, 11q, 16q, 17p, 17q, 18q, 19p, and 19q were found in endometriosis (2). The presence of microsatellite instability may lead to malignant transformation in endometriosis (5).
In summary, early diagnosis is important in endometriosis. A noninvasive test is needed in both asymptomatic and symptomatic disease. It would be better if other recent biomarkers such as stem cells, increased telomerase activity, and genomic profiling were discussed in the text. We think these markers are promising early markers, and women who have no symptoms or minimal to mild disease may also be identified in the future.
Fatma Ferda Verit, M.D.
Orkun Cetin, M.D.
Suleymaniye Maternity, Research and Training Hospital, Department of Obstetrics and Gynecology, Infertility Research and Treatment Center, Istanbul,Turkey
1. Fassbender A, Vodolazkaia A, Saunders P, Lebovic D, Waelkens E, De Moor B, et al. Biomarkers of endometriosis. Fertil Steril 2013;99:1135-45.
2. Silveira CG, Abrão MS, Dias JA Jr, Coudry RA, Soares FA, Drigo SA, et al. Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells. Hum Reprod 2012;27:3187-97.
3. Chang JH, Au HK, Lee WC, Chi CC, Ling TY, Wang LM, et al. Expression of the pluripotent transcription factor OCT4 promotes cell migration in endometriosis. Fertil Steril 2013;99:1332-9.
4. Hapangama DK, Turner MA, Drury JA, Quenby S, Saretzki G, Martin-Ruiz C, et al. Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length. Hum Reprod 2008;23:1511-9.
5. Fuseya C, Horiuchi A, Hayashi A, Suzuki A, Miyamoto T, Hayashi T, et al. Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis. Hum Pathol 2012;43:1964-72.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.07.009
The authors respond:
We sincerely appreciate the commentary of Dr. Fatma Ferda Verit on our paper “Biomarkers of endometriosis” (1). We are especially grateful for their reporting on stem cells markers and telomeres activity as possible biomarkers. Due to the submission of this paper in October 2012, we were not able to include the references mentioned by Dr. Fatma Ferda Verit. We indeed agree that stem cells might be important in the future for endometriosis biomarker research.
In their commentary, Dr. Fatma Ferda Verit discussed and mentioned four extra papers (2-5), which are quite important in endometriosis research, but related to the pathogenesis of endometriosis, in contrast with other studies cited in our review paper (1) that are already in phase II of biomarker development for endometriosis (1).
Silveira and coworkers analyzed chromosomal imbalances and stemness-related protein expression markers (CD9, CD34, c-Kit, Oct-4, Musashi-1) in endometriotic lesions (n=20) (2). In ectopic endometrium, an average of 68 genomic imbalances was detected per sample. DNA losses were mainly involved 3p,5q,7p,9p,11q,16q,18q,19q. The expression of stemness-related markers suggested that endometriosis arises as a clonal proliferation with the putative involvement of stem cells (2). The limitation of this study is the small sample size.
The group of Fuseya analyzed 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma (4). In two cases, a decreased expression of mismatch repair proteins [human mutL homolog 1 and 2] and microsatellite instability was observed both in endometriosis and carcinoma lesions. Their findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis (4).
Chang and colleagues showed that the expression of OCT4 was significantly higher in human ectopic endometrial tissues (n=58) (adenomyosis and chocolate cysts), compared with eutopic endometriotic (n=36) and normal uterine tissues (n=12) (5). The level of OCT4 messenger RNA in endometriotic tissues was positively correlated with the expression of genes associated with cell migration (5).
We would also like to stress that our paper, “Biomarkers of endometriosis,” was written as a guideline for future research and as a basis for consensus regarding standard operating procedures and steps to take to develop a successful clinical test.
Dr. Fatma Ferda Verit and colleagues further cited a paper by Hapangama (3), suggesting that aberrant endometrial expression of telomerase mediates alterations in cell fate that enhance proliferation, contributing to the pathogenesis of endometriosis (3). Immunostaining for telomerase was significantly increased during the implantation window and in the premenstrual endometria of women with endometriosis (n=29) (P < 0.0001). This was associated with a loss of stromal and vascular ERbeta immunostaining (P < 0.05) (3). This is an interesting finding, which is more related to the pathogenesis of endometriosis than to biomarker development for endometriosis.
Amelie Fassbender, Ph.D.,a Alexandra Vodolazkaia, Ph.D., M.D.,a Philippa Saunders, Ph.D.,b
Dan Lebovic, M.D.,c Etienne Waelkens, Ph.D., M.D.,d Bart De Moor, Ph.D.,e and Thomas D’Hooghe, Ph.D., M.D.a,f,g
a Department of Development and Regeneration, Sexual, Pelvic, Reproductive, and Family Studies, University Hospital Gasthuisberg, Leuven, Belgium; b MRC Centre for Reproductive Health, Queen’s Medical Research Institute, Edinburgh, Scotland; c Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Middleton, Wisconsin; d Department of Cellular and Molecular Medicine, Campus Gasthuisberg, Leuven, Belgium; e Department of Electrical Engineering (ESAT-SCD), Katholieke Universiteit Leuven, Leuven, Belgium; f Leuven University Fertility Centre, Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium; and g Division of Reproductive Biology, Institute of Primate Research, Karen, Nairobi, Kenya
1. Fassbender A, Vodolazkaia A, Saunders P, Lebovic D, Waelkens E, De Moor B et al. Biomarkers of endometriosis. Fertil Steril 2013;99:1135-45.
2. Silveira CG, Abrao MS, Dias JA, Jr., Coudry RA, Soares FA, Drigo SA et al. Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells. Hum Reprod 2012;27:3187-97.
3. Hapangama DK, Turner MA, Drury JA, Quenby S, Saretzki G, Martin-Ruiz C et al. Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length. Hum Reprod 2008;23:1511-9.
4. Fuseya C, Horiuchi A, Hayashi A, Suzuki A, Miyamoto T, Hayashi T et al. Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis. Hum Pathol 2012;43:1964-72.
5. Chang JH, Au HK, Lee WC, Chi CC, Ling TY, Wang LM et al. Expression of the pluripotent transcription factor OCT4 promotes cell migration in endometriosis. Fertil Steril 2013;99:1332-9 e5.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.07.010