Carcinoma in Situ ; metabolism ; pathology ; Cystadenocarcinoma, Serous ; metabolism ; pathology ; Fallopian Tube Neoplasms ; metabolism ; pathology ; Fallopian Tubes ; metabolism ; pathology ; Female ; Humans ; Neoplasm Invasiveness ; Ovary ; pathology ; Tumor Suppressor Protein p53 ; metabolism

OBJECTIVEOvarian fibrosis is characterized by excessive proliferation of ovarian fibroblasts and deposition of extracellular matrix (ECM) and it is one of the principal reasons for ovarian dysfunction. This review aimed to investigate the pathogenetic mechanism of ovarian fibrosis and to clarify the relationship between ovarian diseases and fibrosis.

DATA SOURCESWe searched PubMed for English language articles published up to November 2016. The search terms included ovarian fibrosis OR fibrosis, ovarian chocolate cyst OR ovarian endometrioma, polycystic ovarian syndrome (PCOS), premature ovarian failure, ECM, matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), transforming growth factor-beta 1 (TGF-β1), connective tissue growth factor (CTGF), peroxisome proliferator-activated receptor gamma (PPAR-γ), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and combinations of these terms.

STUDY SELECTIONArticles were obtained and reviewed to analyze the pathogenic mechanism of ovarian fibrosis and related ovarian diseases.

RESULTSMany cytokines, such as MMPs, TIMPs, TGF-β1, CTGF, PPAR-γ, VEGF, and ET-1, are involved in ovarian fibrogenesis. Ovarian fibrogenesis is associated with various ovarian diseases, including ovarian chocolate cyst, PCOS, and premature ovarian failure. One finding of particular interest is that fibrogenesis in peripheral tissues around an ovarian chocolate cyst commonly causes ovarian function diminution, and therefore, this medical problem should arouse widespread concern in clinicians worldwide.

CONCLUSIONSPatients with ovarian fibrosis are susceptible to infertility and tend to have decreased responses to assisted fertility treatment. Thus, protection of ovarian function should be a priority for women who wish to reproduce when making therapeutic decisions about ovarian fibrosis-related diseases.

Animals ; Cytokines ; metabolism ; Female ; Fibrosis ; complications ; diagnosis ; etiology ; metabolism ; Humans ; Infertility, Female ; etiology ; Ovary ; pathology

The endoplasmic reticulum (ER) is the principal organelle responsible for several specific cellular functions including synthesis and folding of secretory or membrane proteins, lipid metabolism, and Ca storage. Different physiological as well as pathological stress conditions can, however, perturb ER homeostasis, giving rise to an accumulation of unfolded or misfolded proteins in the ER lumen, a condition termed ER stress. To deal with an increased folding demand, cells activate the unfolded protein response (UPR), which is initially protective but can become detrimental if ER stress is severe and prolonged. Accumulating evidence demonstrates a link between the UPR and ovarian development and function, including follicular growth and maturation, follicular atresia, and corpus luteum biogenesis. Additionally, ER stress and the UPR may also play an important role in the ovary under pathological conditions. Understanding the molecular mechanisms related to the dual role of unfolded protein response in the ovarian physiology and pathology may reveal the pathogenesis of some reproductive endocrine diseases and provide a new guidance to improve the assisted reproductive technology. Here we review the current literature and discuss concepts and progress in understanding the UPR, and we also analyze the role of ER stress and the UPR in the ovary.
Animals ; Apoptosis ; Calcium ; metabolism ; Endoplasmic Reticulum ; metabolism ; pathology ; Female ; Humans ; Lipid Metabolism ; Ovarian Diseases ; metabolism ; pathology ; therapy ; Ovary ; metabolism ; pathology ; Unfolded Protein Response

OBJECTIVE: To examine the expression of G protein-coupled estrogen receptor (GPER) and Gankyrin in ovarian endometriosis (OEM) and to evaluate its clinicopathological significance.
 METHODS: Immunohistochemistry was conducted to determine the expression and distribution of GPER and Gankyrin in matched ectopic and eutopic endometrium of OEM and the normal endometrium. The association of these two proteins with the stages of OEM was also investigated.
 RESULTS: The positive rate for GPER protein in paired ectopic and eutopic endometrium of OEM and the normal endometrium were 63.6%, 51.5% and 21.2%, respectively. There was significant difference in matched ectopic and eutopic endometrium from OEM compared with the control endometrium (P<0.0125). No statistical significance was found between ectopic and eutopic endometrium from OEM (P>0.0125). The positive rate for Gankyrin protein were 69.7%, 36.4% and 9.1%, respectively. Significant difference in Gankyrin protein was found between ectopic and eutopic endometrium of OEM, ectopic and normal endometrium or eutopic and normal endometrium (P<0.0125). Higher positive expression rate for GPER was also observed in eutopic endometrium from OEM during proliferative phase in comparison to secretory phase (P<0.05). There was no significant difference in Gankyrin between proliferative and secretory phase (P>0.05). These two proteins were positively correlated with the revised American Society for Reproductive Medicine (rASRM) stages of OEM. Both of them were found to be significantly higher in advanced stages (III-IV) compared with those in early stages (I-II, P<0.05). Moreover, a significant positive correlation was found between GPER and Gankyrin proteins in ectopic endometrium of OEM (rs=0.640, P<0.01). 
 CONCLUSION GPER and Gankyrin might be involved in the pathogenesis of OEM, which could possibly facilitate the formation of ectopic lesions.
Case-Control Studies ; Endometriosis ; metabolism ; Endometrium ; pathology ; Female ; Humans ; Immunohistochemistry ; Ovary ; pathology ; Proteasome Endopeptidase Complex ; metabolism ; Proto-Oncogene Proteins ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, G-Protein-Coupled ; metabolism

OBJECTIVETo investigate the variation in expression of ARHI, STAT3 and E2F1 and the correlation among them during carcinogenesis of ovarian serous carcinoma.

METHODSImmunohistochemical staining was used to detect the expression of ARHI, STAT3 and E2F1 in samples of 25 normal ovaries, 35 ovarian serous cystadenomas, 18 borderline serous cystadenomas and 56 ovarian serous carcinomas. The variation in expression of the three genes and relationship among them were analyzed.

RESULTSARHI expression was detected in 22 of 25 (88.0%) normal ovaries and 30 of 35 (85.7%) cystadenomas, but only in 10 of 18 (55.6%) borderline serous cystadenomas and 22 of 56 (39.3%) ovarian serous carcinomas, significantly lower than that in the normal ovaries and ovarian serous cystadenomas (P < 0.05). STAT3 expression was found in 14 of 18 (77.8%) borderline serous cystadenomas and 49 of 56 (87.5%) ovarian serous carcinomas, significantly higher than that in the normal ovaries and ovarian serous cystadenomas (P < 0.05). To compare with E2F1 expression in the normal ovaries, serous cystadenomas and borderline serous cystadenomas, E2F1 expression in 46 of 56 (82.1%) ovarian serous carcinomas was significantly higher (P < 0.05). It was found that the expression of ARHI was inversely correlated with that of STAT3 and E2F1.

CONCLUSIONOur findings indicate that ARHI expression is down-regulated, but STAT3 and E2F1 expressions are up-regulated, with an inverse correlation between ARHI and STAT3 in the carcinogenesis of ovarian serous carcinoma.

Adult ; Aged ; Cystadenocarcinoma, Serous ; metabolism ; pathology ; Cystadenoma, Serous ; metabolism ; pathology ; E2F1 Transcription Factor ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Middle Aged ; Ovarian Neoplasms ; metabolism ; pathology ; Ovary ; metabolism ; pathology ; STAT3 Transcription Factor ; metabolism ; rho GTP-Binding Proteins ; metabolism

OBJECTIVETo investigate ovarian follicular damage induced by chemotherapeutic agents and gonadotropin- releasing hormone receptor (GnRHR) expression in the damaged ovaries in rats.

METHODSTwo groups of adult SD rats were subjected to intraperitoneal injection of a single-dose cyclophosphamide and saline, respectively, and 8 weeks later, the ovaries were taken for observing the ovarian damages. The distribution of GnRHR was detected with immunohistochemistry, and RT-PCR was used to determine the expression of GnRHR mRNA in the rat ovaries.

RESULTSMassive primordial follicular loss occurred in the ovaries of rats exposed to cyclophosphamide with also evident stromal ovarian blood vessel damages and focal fibrosis. Both the protein and mRNA expressions of GnRHR were detected in normal rat ovaries, but in rats exposed to cyclophosphamide, the expressions were significantly lowered in the ovaries (P<0.05).

CONCLUSIONLow-level GnRHR expressions in the ovaries of rats with cyclophosphamide exposure suggest microenvironment disturbances in the damaged rat ovaries in advanced stage of chemotherapy.

Animals ; Cyclophosphamide ; adverse effects ; Female ; Humans ; Ovary ; drug effects ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley ; Receptors, LHRH ; metabolism

OBJECTIVETo detect the expression of Toll-like receptor 9 (TLR9) in ovarian cancer, and to explore their clinical significance.

METHODSWestern blot method and immunohistochemical staining were used to examine the expression of TLR9 in the ovarian cancer, paracancerous tissues and normal ovarian tissues, obtained during operation from 30 ovarian carcinoma patients and 30 normal non-tumor patients. The relationships of TLR9 with pathological grade, clinical stage, and metastasis of ovarian cancer were statistically analyzed.

RESULTSThe percentage of positive cells expressing TLR9 protein in human ovarian cancer tissues, paracancerous tissues and normal ovarian tissues were 80.0%, 36.7% and 20.0%, respectively. The protein expression level of TLR9 was gradually descending (P < 0.01). The highly expressed TLR9 significantly correlated with the degree of tumor differentiation, an advanced FIGO stage and lymph node metastasis. The Western blot results showed that TLR9 protein expression in ovarian cancer, paracancerous tissues and normal ovarian tissues were 0.803 ± 0.072, 0.411 ± 0.087 and 0.113 ± 0.065, respectively. The expression of TLR9 in ovarian cancer was significantly higher than that in normal tissue and paracancerous tissues (P < 0.01).

CONCLUSIONSTLR9 has a higher expression in ovarian cancer tissues. TLR9 expression has a close relationship with pathological grades of ovarian cancer, suggesting that TLR9 plays an important role in the development and progression of ovarian cancer through immunologic mechanisms.

Adult ; Blotting, Western ; Carcinoma, Endometrioid ; metabolism ; pathology ; Case-Control Studies ; Cystadenocarcinoma, Mucinous ; metabolism ; pathology ; Cystadenocarcinoma, Serous ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Neoplasm Staging ; Ovarian Neoplasms ; metabolism ; pathology ; Ovary ; metabolism ; Toll-Like Receptor 9 ; metabolism

OBJECTIVETo study the characteristics of the metabolic syndrome (MS) in patients with polycystic ovary syndrome (PCOS).

METHODSOral glucose tolerance test (OGTT) was performed in 336 patients with PCOS, and the serum levels triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and testosterone were measured.

RESULTSThe total incidence of MS was 18.8% in these 336 patients with PCOS. The incidence of MS increased with percent body fat (%BF) and lipid accumulation product (LAP) in patients with PCOS. The patients at child-bearing age appeared to have a higher incidence of MS than those in puberty. The muscle distribution coefficient, age, body mass index, and the metabolic parameters were all higher in patients with MS than in those without MS. The bilateral lower limb muscle strength were lower in patients with MS than in those without, but the level of testosterone showed no significant difference between them.

CONCLUSIONThe risk of MS increases with BF%, age and LAP in patients with PCOS.

Adolescent ; Adult ; Body Composition ; Body Mass Index ; Female ; Humans ; Metabolic Syndrome ; metabolism ; pathology ; Obesity ; metabolism ; Polycystic Ovary Syndrome ; metabolism ; pathology ; Risk Factors ; Young Adult

OBJECTIVETo investigate the expressions of metastasis-associated in colon cancer-1 (MACC1), hepatocyte growth factor (HGF), and C-met proteins in epithelial ovarian cancer and their significance.

METHODSThe expressions of MACC1, HGF and C-met in 20 specimens of normal ovarian tissues, 19 specimens of benign epithelial ovarian tumor and 52 specimens of epithelial ovarian cancer were measured by immunohistochemistry and Western blotting. The correlations of the expressions of MACC1, HGF and C-met protein to the clinicopathologic characteristics of epithelial ovarian cancer were analyzed, and the correlations between the expressions of the 3 proteins were also evaluated.

RESULTSThe positivity rates of MACC1, HGF and C-met proteins were 73.1%, 63.5% and 78.8% in epithelial ovarian cancer with relative expressions of 0.72∓0.05, 0.64∓0.04 and 0.79∓0.04, respectively, showing significant differences from those in normal ovarian tissues and benign ovarian tumors (P<0.05). In epithelial ovarian cancer, the up-regulation of MACC1, HGF and C-met expressions were associated with advanced FIGO stage, poor differentiation and lymph node metastasis (P<0.05). MACC1 expression was positively correlated to HGF (r=0.350, P=0.011) and C-met expressions (r=0.429, P=0.002), and the latter two was also positively correlated (r=0.487, P=0.000).

CONCLUSIONSMACC1 may serve as a potential biomarker for advanced ovarian cancer. Deregulation of MACC1, HGF and C-met proteins may synergistically participate in the malignant progression of epithelial ovarian cancer.

Adult ; Aged ; Biomarkers, Tumor ; metabolism ; Female ; Hepatocyte Growth Factor ; metabolism ; Humans ; Middle Aged ; Neoplasms, Glandular and Epithelial ; metabolism ; pathology ; Ovarian Neoplasms ; metabolism ; pathology ; Ovary ; metabolism ; pathology ; Proto-Oncogene Proteins c-met ; metabolism ; Transcription Factors ; metabolism

OBJECTIVE: To examine the association among malondialdehyde (MDA), superoxide dismutase (SOD) and incidence of apoptosis of granulosa cells in follicular fluid with the outcome of in vitro fertilization-embryo transfer (IVF-ET). METHODS: We recruited 51 women undergoing an IVF-ET programme for tubal factor infertility. The women with endometriosis or endocrine diseases and those with male factor infertility were excluded. All the 51 patients underwent a long gonadotropin-releasing hormone (GnRH) agonist protocol for pituitary downregulation followed by controlled ovarian hyperstimulation with rFSH. Granulosa cells were isolated from all aspirated follicular fluid using gradient centrifugation at oocyte retrieval. The level of MDA and the activity of the SOD were measured by the thiobarbituric acid(TBA)and the chemiluminescence method, respectively. The apoptosis was studied by flow cytometry using propidium iodide. RESULTS: Twenty-six out of the 51 patients (51.0%) were pregnant after IVF-ET. Non-pregnant patients showed significantly higher MDA level [(1.7±0.72) nmol/(g × prot) vs. (1.1±0.56) nmol/(g × prot), P<0.05)], higher incidence of apoptosis (24.8%±6.57% vs.19.0%±5.59%, P<0.05) and lower SOD level [(3.5±1.08)×10(3)NU/(g × prot) vs. (4.4±0.99)×10(3)NU/(g × prot), P<0.05)] in the granulose cells and lower good-embryo rate (54.9±20.22% vs. 65.9±16.16%, P<0.05) compared with the pregnant patients. No correlation was detected among SOD and the number of retrieved oocytes, oocyte maturity, embryo quality, fertilization, or cleavage. A significant negative correlation was detected between MDA and fertilization rate (r=-0.425, P=0.002). No significant correlation was detected between MDA and age, the number of retrieved oocytes, oocyte maturity, cleavage, or good-embryo rate. A significant negative correlation was detected between the incidence of apoptosis and the number of retrieved oocytes (r=-0.286, P=0.042), mature oocytes (r=-0.330, P=0.020) and good-embryo rate (r=-0.311, P=0.026). There was significant negative correlation between MDA and SOD levels (r=-0.471, P<0.001); and significant positive correlation between MDA level and incidence of apoptosis (r=0.475, P<0.001). CONCLUSION Oxidative stress may induce apoptosis in granulose cells and subsequently lower oocyte quality and lead to poor outcome of IVF-ET.
Adult ; Apoptosis ; physiology ; Embryo Transfer ; Female ; Fertilization in Vitro ; Granulosa Cells ; metabolism ; pathology ; Humans ; Malondialdehyde ; metabolism ; Ovary ; cytology ; metabolism ; Oxidative Stress ; Pregnancy ; Pregnancy Rate ; Superoxide Dismutase ; metabolism ; Treatment Outcome