Journal of Ovarian Research - Latest Articles

Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats

Fang Wang — 2012-05-18T00:00:00Z

Background: The polycystic ovary syndrome (PCOS) affects approximately 6-10% of women ofreproductive age and is characterized by chronic anovulation and hyperandrogenism.However, a comprehensive understanding of the mechanisms that dictate androgenoverproduction is lacking, which may account for inconsistencies between measures ofandrogen excess and clinical presentation in individual cases. Methods: A rat model of PCOS was established by injecting dehydroepiandrosterone sulfoconjugate(DHEAS) into pregnant females. Rats were administered with DHEAS (60 mg/kg/d)subcutaneously (s.c.) for all 20 days of pregnancy (Group A), or for the first 10 days (GroupB), or from day 11 to day 20 (Group C). Controls were administered with injection oil(0.2 ml/day) s.c. throughout pregnancy (Group D). The litter rate, abortion rate, and offspringsurvival rate in each group were recorded. Serum androgen and estrogen were measured andthe morphological features of the ovaries were examined by light and electron microscopy inthe offspring of each group. Results: We found that rats injected with DHEAS throughout pregnancy (group A) lost fertility. Ratsinjected with DHEAS during early pregnancy (group B) exhibited more serious aberrations infertility than both Group C, in which rats were injected with DHEAS during late pregnancy(P < 0.05), and Group D (controls). There was a statistical difference of ovarian weightamong female offspring in Group B, C and D (P < 0.01). By light and electron microscopy, asignificant morphological difference among the female offspring in the three groups wasobserved. Conclusions: Our results indicate that androgen excess during pregnancy can decrease rat fertility. Excessandrogen at the early stage of pregnancy causes high reproductive toxicity, leading toabnormality of ovarian morphology and functions in female offspring.

Does ovary need D-chiro-inositol?

Rosalbino Isabella — 2012-05-15T00:00:00Z

Background: Polycystic Ovary Syndrome (PCOS) is a multifactorial pathology that affects 10% of thewomen in reproductive age being the main cause of infertility due to menstrual dysfunction.Since 1980, it is known that PCOS is associated with insulin resistance (IR). The recognitionof this association has prompted extensive investigation on the relationship between insulinand gonadal function, and has turned insulin sensitizer agent as the main therapeutic choice.In particular two different polyalcohol myo-inositol and D-chiro-inositol have been shown toimprove insulin resistance, hyperandrogenism and to induce ovulation in PCOS women. Inparticular, while data on myo-inositol and restored ovulation were consistent, data on Dchiro-inositol were not once the dosage was increased. Recently, a comparative study,proposed a D-chiro-inositol paradox in the ovary of PCOS patients hypothesizing that onlymyo-inositol has a specific ovarian action. In the present study we aim to further study therole played by D-chiro-inositol at ovarian lavel. Methods: A total of 54 women, aged <40 years and diagnosed with PCOS were enrolled in this study.Patients with insulin resistance and/or hyperglycaemia were excluded from the study. Patientswere randomly divided into 5 groups (n=10-12): a placebo group, and 4 groups (A-D) thatreceived 300-600-1200-2400 mg of DCI daily respectively. All treatments were carried outfor 8 weeks before follicle stimulating hormone (rFSH) administration. Results: Total r-FSH units increased significantly in the two groups that received the higher doses ofDCI. The number of immature oocytes was significantly increased in the three groups thatreceived the higher doses of DCI. Concurrently, the number of MII oocytes was significantlylower in the D group compared to placebo group. Noteworthy, the number of grade Iembryos was significantly reduced by DCI supplementation. Conclusions: Indeed, increasing DCI dosage progressively worsens oocyte quality and ovarian response.

Tubal ligation, hysterectomy and ovarian cancer: A meta-analysis

Megan Rice — 2012-05-15T00:00:00Z

PurposeThe purpose of this meta-analysis was to determine the strength of the association betweengynecologic surgeries, tubal ligation and hysterectomy, and ovarian cancer. Methods: We searched the PubMed, Web of Science, and Embase databases for all English-languagearticles dated between 1969 through March 2011 using the keywords "ovarian cancer" and"tubal ligation" or "tubal sterilization" or "hysterectomy." We identified 30 studies on tuballigation and 24 studies on hysterectomy that provided relative risks for ovarian cancer and ap-value or 95% confidence interval (CI) to include in the meta-analysis. Summary RRs and95% CIs were calculated using a random-effects model. Results: The summary RR for women with vs. without tubal ligation was 0.70 (95%CI: 0.64, 0.75).Similarly, the summary RR for women with vs. without hysterectomy was 0.74 (95%CI:0.65, 0.84). Simple hysterectomy and hysterectomy with unilateral oophorectomy wereassociated with a similar decrease in risk (summery RR = 0.62, 95%CI: 0.49-0.79 and 0.60,95%CI: 0.47-0.78, respectively). In secondary analyses, the association between tuballigation and ovarian cancer risk was stronger for endometrioid tumors (summary RR = 0.45,95%CI: 0.33, 0.61) compared to serous tumors. Conclusion: Observational epidemiologic evidence strongly supports that tubal ligation and hysterectomyare associated with a decrease in the risk of ovarian cancer, by approximately 26-30%.Additional research is needed to determine whether the association between tubal ligation andhysterectomy on ovarian cancer risk differs by individual, surgical, and tumor characteristics.

Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy

Andrew Wilson — 2012-04-24T00:00:00Z

Background: New treatment strategies are emerging to target DNA damage response pathways in ovarian cancer. Our group has previously shown that the class I biased HDAC inhibitor romidepsin (FK228) induces DNA damage response and has potent cytotoxic effects in ovarian cancer cells. Here, we investigated newly discovered HDAC inhibitors, thailandepsin A (TDP-A) and thailandepsin B (TDP-B), to determine the effects on cell viability, apoptosis and DNA damage response in ovarian cancer cells. Methods: FK228, TDP-A and TDP-B were tested in five ovarian cancer cell lines. Cellular viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Immunofluorescence assays were used to assess activated caspase 3. Western blots were performed to detect protein expression of PARP cleavage, pH2AX, P-glycoprotein and tubulin acetylation. Results: Treatment with TDPs decreased cell viability at nanonomolar concentrations in four of the five ovarian cancer cell lines studied. Similar to FK228, both TDP compounds exerted minimal effects on NCI/ADR-RES ovarian cancer cells. Across the four cell lines sensitive to the TDPs, TDP-B consistently had a greater inhibitory effect than TDP-A on cell viability. TDP-B also had relatively greater effects on promoting cell apoptosis and induction of pH2AX (a mark of DNA damage response), than TDP-A. These antitumor effects of TDP-B were of similar magnitude to those induced by an equal concentration of FK228. Similar to FK228, the nanomolar concentrations of the TDPs had little effect on tubulin acetylation (a mark of class II HDAC6 inhibition). Conclusions: The new small molecule HDAC inhibitors TDP-A and TDP-B are FK228 analogues that suppress cell viability and induce apoptosis at nanomolar drug concentrations. TDP-B showed the most similarity to the biological activity of FK228 with greater cytotoxic effects than TDP-A in vitro. Our results indicate that FK228-like small molecule class I HDAC-biased HDAC inhibitors have therapeutic potential for ovarian cancer.

The value of serum CA125 for the development of virtual follow-up strategies for patients with epithelial ovarian cancer: A retrospective study

Elizabeth Varughese — 2012-03-22T00:00:00Z

Background: Serum CA125 is routinely used in the follow up of ovarian cancer. The objective of the present study was to evaluate the usefulness of CA125 in the detection of ovarian cancer recurrence. Methods: This retrospective case study was carried out at a tertiary gynaecological cancer centre in Australia. Patients with all cell types of epithelial ovarian cancer (EOC) treated between 2003 and2010 were considered eligible. We excluded patients whose aim of treatment was palliative, had no follow-up, had no pre-operative CA125 reading or had pre-operative CA125 levels < 35 U/mL. After primary treatment, patients were followed up as per guidelines suggested by National Comprehensive Cancer Network (NCCN). We recorded if symptoms, findings from physical examination, imaging or serum CA125 levels led to the diagnosis of recurrence. An increase in CA125 levels to twice the postoperative nadir was considered as "doubling" at any time during follow up. Results: Analysis is based on 56 patients who completed primary treatment and who presented for a total of 274 follow-up episodes. Of those, 29 patients (52%) developed a recurrence within the follow up period. Recurrence was diagnosed by CA125 alone in 14 of 29 patients (48%). CA125 was not elevated in 7 patients (24%) who recurred. Doubling of CA125 from nadir was observed in 27/29 patients. Of those 27 patients the doubling from nadir occurred within the normal range of 35 U/ml in 3 cases and outside the normal range in 24 cases. Multivariate analysis suggests that doubling of serum CA125 (OR 5.10, p 0.036) and nadir CA125 > 10 U/ml (OR 2.86, p 0.01) remained the only independent factors to predict ovarian cancer recurrence. Conclusions: The present paper proposes the validation of a novel CA125 algorithm aiming to detect recurrent EOC. These data may allow us to investigate novel ways of follow up that do not require a patient's physical attendance at a clinic (virtual follow-up).

Struma Ovarii associated with Pseudo-Meig's syndrome and high serum level of CA 125; a case report

Nahid Mostaghel — 2012-03-21T00:00:00Z

Struma ovarii is a rare form of ovarian neoplasm in a form of mature teratoma and is composed predominantly of thyroid tissue. In the literature review, there has only been 10 cases of this tumor, associated with ascites and pleural effusion (Meig's Syndrome) and increased CA125 so far. In such cases, the tumor mimics malignant ovarian tumor. In this article, the case of a 72-year-old symptomatic woman with a pelvic mass, pleural and peritoneal effusion and high level of serum CA125 is presented. Cytological evaluation for the pleural fluid was performed. She underwent hysterectomy and bilateral salpingo-oophorectomy. The result of pathologic diagnosis is presented in this paper. The patient was well in postoperative period and paraclinical tests including CA 125 were normal as well.

The G protein-coupled estrogen receptor 1 (GPER/GPR30) does not predict survival in patients with ovarian cancer

Zuzana Kolkova — 2012-03-18T00:00:00Z

Background: Even though ovarian tumors are not generally considered estrogen-sensitive, estrogens may still have an impact on ovarian tumor progression. The recently identified trans-membrane estrogen receptor GPER is involved in rapid estrogen signaling. Furthermore, it binds selective estrogen receptor modulators with agonistic effect, which could explain tamoxifen controversies. Methods: GPER mRNA was assayed with quantitative real-time PCR (qPCR) in 42 primary ovarian tumors and 7 ovarian cancer cell lines. ERα and ERβ mRNA were analyzed for comparison. GPER protein was semi-quantified with densitometric scanning of Western blots and its tissue distribution analyzed with immunohistochemistry (IHC) in 40 ovarian tumors. In addition, IHC was evaluated in a tissue microarray (TMA) of 150 primary malignant ovarian tumors. Results: All tumor samples contained GPER mRNA. The content of mRNA was not different between benign and malignant tumors, but one third of malignant samples over-expressed GPER mRNA. The content of ERα mRNA was higher in malignant than in benign tumors, whereas ERβ mRNA was higher in benign than in malignant tumors. GPER mRNA was detected in all seven ovarian cancer cell lines with highest levels in TOV21G and TOV112D cells. Similar expression pattern was seen for ERβ mRNA. Western blot demonstrated GPER protein in all tumor samples. Semi-quantification showed no difference between benign and malignant tumors, but about one third of malignant samples over-expressed GPER protein. GPER staining was localized mainly in epithelial cells. In the TMA study we found no correlation between GPER staining and clinical stage, histological grade or patient survival. Conclusions: GPER mRNA as well as GPER protein is present in both benign and malignant ovarian tumor tissue. About one third of malignant tumors over-expressed both GPER mRNA and protein. This, however, correlated neither with histological or clinical parameters nor with patient survival.

MicroRNAs and ovarian function

Jason Baley — 2012-02-09T00:00:00Z

MicroRNAs (miRNAs) are a class of small non-coding RNAs which function in gene regulation with an important role in cell proliferation, maturation, and activity. The regulatory role of these small RNA molecules has recently begun to be explored in ovarian cells, uncovering their influence on gonadal development, steroidogenesis, apoptosis, ovulation, and corpus luteum development. This emerging area of research has extended and reshaped our understanding on how ovarian function is regulated. Here, we review the current understanding of miRNA biogenesis, the role and mechanism that miRNAs play in post-transcriptional gene expression regulation, and specifically the current evidence of miRNA involvement in ovarian development and function. Future comprehensive understanding of the role of miRNAs in the ovary in both physiological and pathological conditions may offer new treatment strategies for infertility and other ovarian disorders.

Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination

Takafumi Watanabe — 2012-02-01T00:00:00Z

Background: A crucial step in the metastatic spread of ovarian cancer (OC) is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3) from the non-metastatic FOC3 line. Methods: Molecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells. Results: After murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p < 0.01). IL-1β induced mesothelial cell β1-integrin, and an antibody to this subunit also inhibited the adhesion of MFOC3 to mesothelial cells in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate. Conclusions: These results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination.

Discovery of Dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer

Bjorn Nodin — 2012-01-27T00:00:00Z

Background: The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC). Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples. Methods: Immunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n = 32). A nuclear score (NS), i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS < = 3) and high (NS > 3) using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells. Results: DACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype, DACH2 remained an independent factor of poor prognosis. Conclusions: This study provides a first demonstration of DACH2 protein being expressed in human fallopian tubes and EOC, with the highest expression in serous carcinoma where DACH2 was found to be an independent biomarker of poor prognosis. Future research should expand on the role of DACH2 in ovarian carcinogenesis and chemotherapy resistance.