Genome-Wide Gene Expression Profiling Reveals the Direct Effect of Dienogest on Ovarian Endometriotic Stromal Cells.

Endometriosis affects up to 10% of women of reproductive age, causing dysmenorrhea, chronic pelvic pain, and infertility. The current key drug for endometriosis is dienogest, a progestin with high specificity for the progesterone receptor. To reveal the direct anti-endometriotic effect of dienogest on ovarian endometriotic cells, we investigated the genome-wide gene expression profiles of ovarian endometriotic stromal cells with (Dienogest group) or without dienogest treatment (Control group) and compared the groups' gene expression profiles. We performed a gene ontology (GO) analysis and Ingenuity pathway analysis using these data. To validate the microarray data, we performed real-time RT-PCRs and immunohistochemistry for the differentially expressed genes between the two groups. Of 647 genes differentially expressed between the two groups, 314 genes were upregulated and 333 were downregulated in the Dienogest group versus the Control group. The GO analysis showed that the regulation of macrophage chemotaxis, the collagen catabolic process, and the proteoglycan biosynthetic process are the main biological processes closely associated with the differentially expressed genes. We identified 20 canonical pathways that were most significantly differentially expressed in the Dienogest group versus the Control group. We observed that matrix metalloproteinases (MMPs) are the genes in these pathways that are most closely associated with dienogest treatment. Of components involved in the regulation of macrophage chemotaxis, colony-stimulating factor 1 and macrophage-stimulating 1 are potential upstream regulators of MMPs and were observed herein to be suppressed by dienogest. Our results suggest that dienogest may thus exert its anti-endometriotic effect by directly suppressing MMPs.

Adult granulosa cell tumors of the ovary: a retrospective study of 30 cases with respect to the expression of steroid synthesis enzymes.

OBJECTIVE: Some, but not all, granulosa cell tumors are characterized by estrogen production. This study was designed to determine whether there are clinical or pathological variations in granulosa cell tumors in relation to the expression of sex steroid synthesis enzymes. METHODS: Clinical symptoms, serum hormonal values, and histology of 30 granulosa cell tumor patients who underwent surgery between 2002 and 2014 were retrospectively reviewed. RESULTS: Most patients presented with abnormal genital bleeding including abnormal menstrual cycles. Eight of 16 patients older than 50 years had endometrial hyperplasia and one had endometrial cancer. Serum 17ß-estradiol (E2) levels tended to be higher in patients over 50 years of age (p=0.081). Serum follicle-stimulating hormone (FSH) levels were low in all patients irrespective of serum E2 levels. Magnetic resonance imaging revealed a thicker endometrium in older as compared to younger patients (p<0.05). Tumor cells in the majority of cases were positive for inhibin α and P450 aromatase, irrespective of age and serum E2 levels. P450 17α-hydroxylase (P450c17) expression varied among cases. P450c17 was strongly positive in luteinized tumor cells and weakly positive in theca cells and fibroblasts. High E2 levels were associated with P450c17-positive cells in the tumor (p<0.05). CONCLUSION: The expression of hormone-synthesizing enzymes divides granulosa cell tumors into 2 distinct types; tumors with P450c17-positive cells show elevated serum E2 and related clinical symptoms, while tumors without these cells show symptoms related to FSH suppression by inhibin.

The frequent shift to intermediate flora in preterm delivery cases after abnormal vaginal flora screening.

The effect of screening and treatment for abnormal vaginal flora on the reduction of preterm deliveries remains controversial. We evaluated whether this screening and treatment reduces the preterm delivery rate for general-population pregnant women. Pregnant women of the Intervention group (n = 574) underwent the screening test and the treatment of vaginal metronidazole during the early second trimester, and those of the Control group (n = 1,161) did not. We compared the preterm delivery rate between these two groups. We also compared the profiles of vaginal flora of the preterm delivery cases with those of the pregnant women with a normal course. There was no significant difference in the preterm delivery rate between these two groups. However, in the preterm delivery cases, a frequent shift to intermediate flora was observed not before but after the screening in the Intervention group. This shift may explain why most of the previous studies failed in regard to the prevention of preterm deliveries.

[A case of large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix successfully treated by postoperative CPT-11+CDDP chemotherapy after non-curative surgery].

A 31-year-old woman, gravida 3 para 3, visited a local clinic because of post-coital bleeding. She was diagnosed as having a uterine-cervical tumor and was referred to our hospital. Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix was pathologically shown by biopsy. The patient was initially treated by radical hysterectomy. Postoperative pathological examination revealed a direct invasion to the parametrium and the positive resection margin. Postoperatively, she was treated by CPT-11+CDDP. One course of treatment was 60mg/m² of CPT-11 administered on day 1, 8 and 15, and 60 mg/m² of CDDP on day 1, with an intermission after administration for 7 days. Six courses were carried out. This treatment resulted in complete remission. A follow-up at the outpatient clinic revealed the patient had been tumor-free for one year and three months after the first treatment. We suggest that postoperative chemotherapy with CPT-11+CDDP might be useful in the treatment of patients with LCNEC of the uterine cervix.

Clinical features of ovarian large-cell neuroendocrine carcinoma: Four case reports and review of the literature.

The objective of the present study was to present 4 recently encountered ovarian large-cell neuroendocrine carcinoma (LCNEC) cases, and to evaluate their clinicopathological features in the context of the previously reported 29 LCNEC cases. First, we described the clinical features of 4 recently encountered cases. Routine H&E staining and immunohistochemistry for CD56, synaptophysin and chromogranin A were performed on sections of both the LCNEC and epithelial carcinoma components. Clinical data for the total of 33 LCNEC cases were summarized, and the Kaplan-Meier survival curve was estimated. Our cases were observed in women aged 42-81 years. One case is clinically classified as FIGO stage IV with multiple metastases, and the others are classified as FIGO stages Ic, IIc and IIIb by post-surgical findings. Pathological features, assessed by H&E staining, were similar to lung LCNEC, and at least one neuroendocrine marker was positive staining in both LCNEC and the epithelial component. One case was pure type LCNEC and the others were mixed carcinoma. Paclitaxel/carboplatin chemotherapy was performed for all cases and 3 of the 4 treatments were effective. The prognoses of our cases were as follows: 1 in stage Ic died from the disease after only 2 months, but the others survived, with or without recurrence, for 32-64 months, whereas the total 5-year survival of the 33 LCNEC cases was 34.9%. In summary, our 3 LCNEC cases revealed ordinary chemo-sensitivity, resulting in a better prognosis than those previously described, apart from 1 case which exhibited aggressive behavior. For the future, a retrospective survey to elucidate the prognostic factors and prospective clinical studies to evaluate the efficacy of treatment modalities of ovarian LCNEC are necessary, particularly for aggressive LCNEC cases.