The material covered in this Seminar is based on an extensive search of published work, participation in expert meetings, and many years of research on the subject. A systematic MEDLINE search was done with key words “endometriosis”, “infertility”, “gene expression”, and “proteomics”, up to June, 2004, restricted to papers published in English.
SeminarEndometriosis
Section snippets
Theories of pathogenesis
The most widely accepted theory on the pathogenesis of endometriosis (panel 1), proposed in the 1920s,16, 17 is that the disorder originates from retrograde menstruation of endometrial tissue sloughed through patent fallopian tubes into the peritoneal cavity. The presence of disease in the pelvis has been attributed to attachment of endometrial fragments to the epithelium of the peritoneum, invasion of the epithelium, establishment of a blood supply, and generation of a suboptimum immune
Genetics
The heritable features of endometriosis were first recognised more than 20 years ago when the risk for first-degree relatives of women with severe endometriosis was reported to be six times higher than that for relatives of unaffected women.25 Familial aggregation has been shown in clinical25, 26 and population-based27 samples and in twin studies.28, 29, 30 Genetic dissection of complex traits is challenging, especially when different stages of disease exist and surgery is needed for diagnosis.
Environmental factors
The non-human primate model has provided important information about environmental factors and their potential influence on development of endometriosis. For example, rhesus monkeys exposed to whole-body proton irradiation have a higher frequency of endometriosis than controls (53% vs 26%).40 Also, rhesus monkeys exposed to 5–25 ppm dioxin per day for 4 years developed endometriosis that was dose-dependent in staging.41 Extrapolation to women was initially thought to be epidemiologically
Immune system
The immune system is believed to be involved in the pathogenesis of endometriosis,49 and a lack of adequate immune surveillance in the peritoneum is thought to be a cause of the disorder. There is much evidence of activation of peritoneal macrophages with increased cytokine production in women with endometriosis, although there is decreased phagocytic activity.49, 50 Sharpe-Timms and colleagues,51 using the proteomics approach of two-dimensional gel electrophoresis, found a protein they called
Evidence for infertility association with endometriosis
Studies in animals72, 73, 74, 75, 76 and some studies of patients,77, 78 but not others,79 support an adverse effect of endometriosis on pregnancy rates. Although several studies on assisted reproduction have suggested lower than normal rates of pregnancy among women with endometriosis, a meta-analysis of most such studies to date showed that the pregnancy rate in women with endometriosis was about half that in women with tubal-factor infertility, after control for confounding factors.80
Gene products aberrantly expressed in endometriosis
Panel 3 shows the genes currently known to be aberrantly expressed during the time of implantation and other times of the cycle in women with endometriosis, which are candidates for establishment of the disease or for implantation-based infertility.
Genomic changes
Altered DNA copy numbers have been detected in endometriosis lesions, by use of comparative genomic hybridisation.129 Another study130 with a similar approach also found several regions of genomic alteration in eutopic endometrium in patients with endometriosis compared with unaffected women, which suggests these changes as a pathogenetic mechanism. Two-colour fluorescence in-situ hybridisation has shown greater heterogeneity of chromosome 17 aneuploidy in endometriotic than in normal archival
Malignant disorders and endometriosis
Women with endometriosis are at increased risk of malignant tumours of the pelvis.132, 133 Endometriosis is found in significantly higher frequency in women undergoing surgery for endometroid, clear-cell, and mixed subtypes of ovarian cancers than in women with serous, mucinous, and other subtypes of cancers (21·1–26·3% vs 3·6–5·6%; p<0·001).134 The synchronous occurrence of endometriosis with ovarian cancer and clear-cell carcinoma (41%) and endometroid subtypes (38%) suggests transformation
Diagnosis and treatment
Several reviews have summarised in detail diagnosis and medical and surgical therapies for endometriosis.10, 11, 12, 13, 23, 81, 132, 147, 148, 149, 150, 151, 152, 153 The mainstay of diagnosis has been visualisation of lesions by surgery—laparoscopy or laparotomy. Treatment has two aims: relief of pain, amelioration of infertility, or both. Agents that have been classically used to treat endometriosis are listed in panel 4. Agents to suppress ovarian function and limit growth and activity of
Conclusion
Endometriosis remains an underdiagnosed disorder with substantial associated morbidity. Challenges for the future include non-invasive methods to diagnose the disorder, targeted drug discovery, and delineation of the genetics and genomics governing development of disease, contributions from the environment, and involvement of the immune system. For this debilitating disorder, the threshold for diagnosis and treatment should be low to improve the quality of life and fertility, if desired. The
Search strategy and selection criteria
Conflict of interest statement
LCG takes part in advisory board meetings and receives fees for speaking at conferences and symposia.
Role of the
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