Endometriosis, often in the form of 'chocolate cysts' of the ovary, has been reported in sisters rather frequently and at least twice in mother and daughter(s). Hinson et al. (1981) reported 2 sisters with pelvic endometriosis and catamenial pneumothorax. Both were typical of reported cases of catamenial pneumothorax in that pneumothorax was always on the right, occurred only with menses, and had onset in the fourth decade. Hormonal suppression of menses helped the symptoms. Diaphragmatic perforations were found at surgery in 1 of the sisters.

The development of endometriosis is believed to result from immunologic defects and/or perturbations in cascades involving prostaglandins and the steroids estrogen and progesterone. Inflammation, a key feature of endometriotic tissue, is associated with increased levels of acute inflammatory cytokines such as IL1B (147720), IL6 (147620), and TNF (191160), which may enhance adhesion of shed endometrial-tissue fragments onto peritoneal surfaces. Proteolytic membrane metalloproteinases (see, e.g., MMP1; 120353) may further promote implantation of the fragments. Other inflammatory molecules that may play a role include MCP1 (158105), IL8 (146930), and RANTES (187011). Excessive formation of estrogen and prostaglandin and development of progesterone resistance have also emerged as clinically useful points of study involving 3 critical therapeutic targets: aromatase (CYP19A1; 107910), cyclooxygenase-2 (COX2; 600262), and progesterone receptor (PGR; 607311). In addition, specific epigenetic markers involving hypomethylation result in overexpression of the nuclear receptors steroidogenic factor-1 (NR5A1; 184757) and estrogen receptor-beta (ESR2; 601663). See review by Bulun (2009).

Endometriosis is a common gynecologic disorder that accounts for infertility in 10 to 15% of women of reproductive age; however, relatively little is known about its etiology and pathogenesis. Several studies have suggested that endometriosis has a multifactorial etiology including hereditary, hormonal, and immunologic factors (Olive and Schwartz, 1993; Brinton et al., 1997). At the cellular level, the disease is characterized by monoclonal growth and can exhibit features of malignant behavior, including local invasion and metastasis. To identify genomic changes involved in the development of endometriosis, Gogusev et al. (1999) examined a panel of 18 selected endometriotic tissues by comparative genomic hybridization (CGH), a molecular cytogenetic method that allows screening of the entire genome for chromosomal gains and/or losses. Recurrent copy number losses on several chromosomes were detected in 15 of 18 cases. Losses of 1p and 22q were each detected in 50% of the cases. Additional common losses included 7p (22%). To validate the CGH data, selective dual-color FISH was performed using probes for the deleted regions on chromosomes 1, 7, and 22 in parallel with the corresponding centromeric probes. Cases showing deletion by CGH all had 2 signals at 1p36, 7p22.1, and 22q12 in less than 30% of the nuclei, in comparison to the double centromeric labels found in more than 85% of the cells. The results were interpreted as indicating that genes localized to previously undescribed chromosomal regions play a role in the development and progression of endometriosis.

Treloar et al. (2005) sought to identify susceptibility loci for endometriosis using a positional-cloning approach starting with linkage analysis to identify genomic regions likely to harbor these genes. They conducted a linkage study of 1,176 families (931 Australian and 245 from the U.K.), each with at least 2 members, mainly affected sister pairs, with surgically diagnosed disease. They identified a region of significant linkage on 10q26 (maximum lod score = 3.09; genomewide P = 0.047) and another region of suggestive linkage on 20p13 (maximum lod score = 2.09). Minor peaks (with maximum lod scores greater than 1.0) were found on 8 other chromosomes.

Associations Pending Confirmation

Uno et al. (2010) performed a genomewide association study and a replication study using a total of 1,907 Japanese individuals with endometriosis (cases) and 5,292 controls, and identified a significant association of endometriosis with rs10965235 (p = 5.57 x 10(-12), odds ratio = 1.44), which is located in the CDKN2BAS gene (613149) on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA. By fine mapping, the SNP showing the strongest association was located in intron 16 of CDKN2BAS and was implicated in regulating the expression of p15 (see CDKN2B, 600431), p16 (see CDKN2A, 600160), and p14.

By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, Dinulescu et al. (2005) expressed an oncogenic Kras (190070) allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma (167000); 7 of 15 mice (47%) also developed peritoneal endometriosis. When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary.