Cigarette smoke increases progesterone receptor and homeobox A10 expression in human endometrium and endometrial cells: a potential role in the decreased prevalence of endometrial pathology in smokers

Cigarette smoking has long been tied to a multitude of poor health outcomes; however, in reproductive biology, smoking has shown several unintuitive findings. Smoking is associated with significantly decreased rates of endometriosis and endometrial cancer. Here, we show that treatment with cigarette smoke extract leads to increased mRNA and protein expression of homeobox A10 (HOXA10) and progesterone receptor (PGR) as well as more rapid decidualization of endometrial stromal cells in vitro. In vivo, mice exposed to cigarette smoke similarly showed increased expression of HOXA10 and PGR in the endometrium. Both HOXA10 and PGR drive endometrial differentiation and are suppressed in endometrial tumors and in endometriosis. The increased expression found upon exposure to cigarette smoke may provide a protective effect, mediating the decreased incidence of endometrial disease among smokers. This mechanism contrasts with the accepted paradigm that the effects of smoking on the uterus are secondary to ovarian alterations rather than direct effects on endometrium as demonstrated here.     

Endometriosis is associated with progesterone resistance in the baboon (Papio anubis) oviduct: evidence based on the localization of oviductal glycoprotein 1 (OVGP1)

Endometriosis has been associated with a reduced response to progesterone in both the eutopic and ectopic endometrium. In this study we evaluated OVGP1 and steroid receptor expression in oviducts of baboons with endometriosis during the midsecretory phase and determined whether progesterone resistance associated with endometriosis also occurs in the oviduct. Oviducts obtained during the window of uterine receptivity (Day 10 postovulation [PO]) from animals with induced and spontaneous disease were compared to control animals during the proliferative stage and in the implantation window as well as animals treated with the progesterone receptor (PGR) antagonist ZK 137.299 (ZK). OVGP1 was significantly higher in animals with endometriosis compared with Day 10 PO controls and was similar to that seen in the late proliferative phase and in ZK-treated animals. Baboons with spontaneous endometriosis also showed a similar persistence of OVGP1, which was correlated with the maintenance of estrogen receptor 1 (ESR1) in the epithelial cells of animals with endometriosis. However, epithelial cell height and the percentage of ciliation were not affected by endometriosis. These data imply that the normal antagonism of progesterone on ESR and OVGP1, which results in their downregulation during the window of implantation, is absent in animals with endometriosis. This was confirmed further when the action of PGR was antagonized in animals without disease, which also resulted in the persistence of ESR1 and OVGP1. These studies suggest that an aberrant oviductal environment may be an additive factor that contributes to endometriosis-associated infertility.     

Genome‐wide analysis of DNA methylation in endometriosis using Illumina Human Methylation 450 K BeadChips

Endometriosis is a common chronic gynecologic disorder characterized by the presence and growth of endometrial‐like tissue outside of the uterine cavity. Although the exact etiology remains unclear, epigenetic modifications, such as DNA methylation, are thought to contribute to the pathogenesis of endometriosis. Here, we used the Illumina Human Methylation 450 K BeadChip Array to analyze the genome‐wide DNA methylation profiles of six endometriotic lesions and six eutopic endometria from patients with ovarian endometriosis and six endometria of women without endometriosis. Compared with the eutopic endometria of women with endometriosis, 12,159 differentially methylated CpG sites and 375 differentially methylated promoter regions were identified in endometriotic lesions. GO analyses showed that these putative differentially methylated genes were primarily associated with immune response, inflammatory response, response to steroid hormone stimulus, cell adhesion, negative regulation of apoptosis, and activation of the MAPK activity. In addition, the expression levels of DNMT1, DNMT3A, DNMT3B, and MBD2 in endometriotic lesions and eutopic endometria were significantly decreased compared with control endometria. Our findings suggest that aberrant DNA methylation status in endometriotic lesions may play a significant role in the pathogenesis and progression of endometriosis.     

Aberrant methylation of the IL‐12B promotor region contributes to the risk of developing ovarian endometriosis

Studies have shown that aberrant expression of IL‐12p40, which is encoded by the interleukin‐12B (IL‐12B) gene, may be involved in the development of endometriosis. In this study, we investigated the role of aberrant methylation of the IL‐12B promoter region and its associated expression in the development of ovarian endometriosis. By using pyrosequencing, we analyzed the methylation level of the IL‐12B promoter region in eutopic and ectopic endometrium of patients with ovarian endometriosis and normal endometrium of control women. The expression of IL‐12B mRNA was detected by quantitative real‐time PCR. The results showed that the methylation level of the IL‐12B promoter region in ectopic and eutopic endometrium of patients with ovarian endometriosis was significantly lower than that in endometrium of women without endometriosis ( p < 0.001 and p = 0.041, respectively). In contrast, mRNA levels were significantly increased in ectopic and eutopic endometrium of patients with ovarian endometriosis compared to those in endometrium of women without endometriosis ( p < 0.001 and p = 0.042, respectively). Correlation analysis showed that the methylation level of the IL‐12B promoter region was negatively correlated with mRNA levels of IL‐12B ( p < 0.001). Our data suggested that aberrant methylation of the IL‐12B promoter region may be responsible for aberrant IL‐12B mRNA expression in endometrium tissue of women, which may be associated with the development of ovarian endometriosis in northern Chinese women.     

A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis

Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf?/? and Mmp9?/? mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.