The distinguishing cellular and molecular features of the endometriotic ovarian cyst : from pathophysiology to the potential endometrioma-mediated damage to the ovary

background: Clinical data suggest that the presence of an ovarian endometrioma may cause per se damage to the surrounding otherwise healthy ovarian tissue. However, the basic research has so far done a limited job in trying to understand the potential detrimental effect of an endometrioma presence in the context of the ovarian physiology.We have reviewed the literature with the aim of characterizing the pathophysiology of the endometrioma focusing mostly on factors and mechanisms potentially affecting the surrounding, otherwise normal, ovarian tissue. methods: Comprehensive searches of PUBMED were conducted to identify human studies published from 1991 to 2013 in the English language on the cellular and molecular characterization of the various endometrioma components. results: An endometrioma contains free iron, reactive oxygen species (ROS), proteolytic enzymes and inflammatory molecules in concentrations from tens to hundreds of times higher than those present in peripheral blood or in other types of benign cysts. The cyst fluid causes substantial changes in the endometriotic cells that it baths from gene expression modifications to genetic mutations The physical barrier between the cyst contents and the normal ovarian tissue is a thin wall composed of the ovarian cortex itself or fibroreactive tissue.ROS potentially permeating the surrounding tissues and proteolytic substances degrading the adjacent areas are likely to cause the substitution of normal ovarian cortical tissue with fibrous tissue in which the cortex-specific stroma is reduced. The fibrosis is associated with smooth muscle metaplasia and followed by follicular loss and intraovarian vascular injury. Follicular density in tissue surrounding the endometriotic cyst was consistently shown to be significantly lower than in healthy ovaries but this pathological change does not appear to be caused by the stretching of surrounding tissues owing to the presence of a cyst. conclusions: There is sufficient molecular, histological and morphological evidence, in part deriving from knowledge of the pathophysiology, to support a deleterious effect of the endometrioma on the adjacent ovarian cortical tissue, independent of the mere mechanical stretching owing to its size

The endometriotic tissue lining the internal surface of endometrioma : hormonal, genetic, epigenetic status, and gene expression profile

Ovarian endometriomas are found in a consistent proportion of patients with endometriosis and are associated with a more severe form of the disease. The endometriotic tissue lining the inside of the endometrioma has been extensively studied over the years mostly for the need to compare the molecular and cellular characteristics of eutopic and ectopic endometria. Several aspects of hormonal regulation, response to local inflammation, carcinogenesis, and modifications of the local environment have been investigated in order to characterize also the processes associated with peritoneal endometriosis. In this review, we have summarized the current knowledge of pathophysiology of endometrioma, with a particular focus on the cellular components lining the internal surface of the cyst in order to provide a comprehensive overview of the hormonal, genetic, epigenetic, and gene expression profiles of this essential part of the cyst

An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis

Background: Although endometriosis may benefit from primary prevention measures, the epidemiological risk factors identified are equivocal. Two genome-wide association studies (GWAS) have been conducted for endometriosis in two different ethnic populations but results are still to be replicated consistently and across various ethnicities. To confirm the association of GWASderived susceptibility loci, we conducted a replication Italian case-control study and a meta-analysis. Methods: An independent set of 305 laparoscopicallyproven endometriosis patients and 2710 controls were recruited. Four SNPs-CDKN2BAS rs1333049, rs7521902 close to WNT4, rs12700667 in an inter-genic region on 7p15.2 and fibronectin 1 rs1250248-were selected for this association study. Results: Rs1333049 risk allele G frequency resulted significantly higher in endometriosis patients compared with controls (OR 1.32, 95% CI 1.11 to 1.57), confirming the role of this locus also in the Caucasian population. The meta-analysis showed that rs7521902 was associated with endometriosis at a genome-wide significance (pmeta=2.23 710-9) while for rs1250248, a genome-wide significant pmeta value of 3.89 710-9 was detected only in association with severe forms. An epistatic interaction between rs7521902 and rs1250248 (OR 1.56, p=1.19 710-2) was found especially in presence of ovarian disease (OR=2.15, p=3.12 710-4). Conclusions: We confirm WNT4, CDKN2BAS and FN1 as the first identified common loci for endometriosis

Endometrial stromal progesterone receptor-A/progesterone receptor-B ratio: no difference between women with and without endometriosis

The aim of the present study was to investigate whether alterations of the P receptor\u2013A/P receptor\u2013B ratio could be considered an etiopathogenetic factor for endometriosis.We failed to observe statistically significant differences in both P receptor\u2013A/P receptor\u2013B messenger RNA and protein ratio between endometrial stromal cells derived from women with and without endometriosi

Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has potent anti-proliferative/ immunomodulatory effects on various tissues. Consistently, the enzyme that catalyzes the synthesis of 1,25(OH)2D3, 1\u3b1-hydroxylase (1\u3b1-OHase) and the vitamin D receptor have a widespread tissue distribution. Among site-specific functions, the hormone has been suggested to be involved in uterine physiology. However, molecular analysis of the vitamin D system in normal endometrium throughout the menstrual cycle as well as its regulation in the context of endometrial physiological and pathological events have received very limited attention. Thus, we have studied expression, localization and regulation of 1\u3b1-OHase in human cycling and early pregnant endometrium. The capacity for 1\u3b1-hydroxylation and the presence of vitamin D receptor in endometrial cells have also been evaluated. The functional significance of these findings has been tested by evaluating gene expression of the catabolic enzyme, vitamin D 24-hydroxylase, and of the adhesion protein, osteopontin. Finally, to verify any potential dysfunction of the vitamin D system in endometriosis, a reproductive disease characterized by immune-mediated anomalies, we have analyzed expression of 1\u3b1-OHase in both eutopic and ectopic endometrium of affected patients. Results obtained showed that the active form of the 1\u3b1-OHase gene was expressed in human endometrial stromal cells independent of the cycle phase but with a significant increase in early pregnant decidua. A similar profile was observed for the protein, which was abundantly expressed in the cytoplasm of both endometrial stroma and epithelial glands. Both cycling and early pregnant endometrial cells also expressed the vitamin D receptor. In the same cells, 1\u3b1-OHase mRNA levels were significantly stimulated by the pro-inflammatory cytokine interleukin (IL)-1\u3b2 (50 and 500 pg/ml) while addition of the active form of the hormone could modulate both CYP24 and osteopontin gene expression. The 1\u3b1-OHase gene was also expressed in ectopic endometrium and its levels were increased in proliferative phase cultures derived from patients with endometriosis. Human cycling endometrium may be included among the extrarenal sites able to synthesize vitamin D. The IL-1\u3b2-mediated induction of 1\u3b1-OHase gene and the hormonal modulation of osteopontin support a role for the hormone in the immunological mechanisms underlying uterine function. Abnormalities of this system are present in endometriosis