Izumi Suganuma

Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic stromal cells in spheroid culture

OBJECTIVE To determine the effect of dienogest (DNG) on the expression of aromatase and cyclooxygenase-2 (COX-2) and the production of prostaglandin E(2) (PGE(2)) in human endometriotic stromal cells (ESCs). DESIGN Experimental study in vitro. SETTING University hospital. PATIENT(S) Seventeen patients with ovarian endometrioma. INTERVENTION(S) ESCs from chocolate cyst linings of ovaries were treated with DNG. MAIN OUTCOME MEASURE(S) Expression of aromatase and COX-2 evaluated in spheroid cultures of human ESCs by real-time quantitative polymerase chain-reaction and immunocytochemistry, production of PGE(2) quantified by enzyme-linked immunosorbent assay (ELISA), and nuclear factor kappa B (NF-κB) DNA-binding examined by ELISA and immunocytochemistry. RESULT(S) The pharmaceutical actions of DNG on the expression of aromatase and COX-2 and the production of PGE(2) were examined using spheroid cultures of human ESCs. More aromatase, COX-2, and PGE(2) were expressed in spheroid cultures than in conventional ESCs monolayers. In the spheroid cultures, DNG (10(-7) M) and progesterone (10(-7) M) inhibited the expression of aromatase, COX-2, and PGE(2). DNG also inhibited NF-κB DNA-binding activity and reduced the immunocytochemical protein expression of aromatase, COX-2, and NF-κB p50 nuclear localization. CONCLUSION(S) Because DNG inhibits aromatase and COX-2 expression as well as PGE(2) production in ESCs, these pharmacologic features might contribute to a therapeutic effect of DNG on endometriosis.

Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain

OBJECTIVE To examine whether long-term administration of dienogest following gonadotropin-releasing hormone agonist (GnRH-a) therapy would prolong the relief of pelvic pain while reducing the amount of irregular uterine bleeding. STUDY DESIGN This was a prospective, non-randomized clinical trial. Among the patients suffering from chronic pelvic pain associated with recurrent endometriosis, Group G (n=38) received GnRH-a for 4-6 months and then dienogest (1 mg/day) for 12 months. The dose of dienogest was increased to 1.5 or 2 mg/day when a patient had uncontrollable uterine bleeding {n=15 (39%)}. Group D (n=33) received only dienogest (2 mg/day) for 12 months. Pelvic pain was assessed using a visual analog scale (VAS). Uterine bleeding was semi-quantified using a pictorial blood loss assessment chart (PBAC). RESULTS In Group G, GnRH-a significantly reduced the VAS score for pelvic pain, and alleviation was maintained during the 12-month therapy with dienogest. There was no significant difference in pain reduction between Group G and Group D. The PBAC score during the first 6 months on dienogest was significantly smaller in Group G than in Group D. CONCLUSION Treatment with a GnRH-a followed by long-term dienogest therapy maintains the relief of endometriosis-associated pelvic pain achieved with GnRH-a therapy for at least 12 months. This regimen reduces the amount of irregular uterine bleeding that often occurs during the early phase of dienogest therapy.

Antiproliferative and apoptotic effects of norethisterone on endometriotic stromal cells in vitro

OBJECTIVES Low-dose estrogen-progestin (LEP) agents are often used for relieving endometriosis-associated chronic pelvic pain, but a direct effect of LEP on endometriotic lesions remains to be demonstrated. The objective of this study is to investigate the antiproliferative and apoptotic effects of the synthetic progestin norethisterone (NET) against human endometriotic stromal cells (ESCs). STUDY DESIGN Ovarian endometrioma specimens were obtained at laparoscopy from 19 patients with endometriosis, and ESCs were isolated. The antiproliferative effect of compounds against cultured ESCs was evaluated by measuring the inhibition of [(3)H]thymidine incorporation. The ability of compounds to induce apoptosis in the cultured cells was evaluated by the measurement of caspase 3/7 activity and by nuclear staining. The cytotoxicity of compounds was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the supernatant of the cell culture. RESULTS NET and progesterone (P4) at concentrations of greater than 10nM significantly inhibited [(3)H]thymidine incorporation in a dose-dependent manner. Co-treatment with 17β-estradiol at 0.1 ng/mL did not affect the inhibition of [(3)H]thymidine incorporation by NET. At concentrations greater than 100 nM, NET significantly increased caspase 3/7 activity and the numbers of apoptotic cells, whereas P4 did not. Treatment of ESCs for 24h with NET or P4 at concentrations of up to 1000 nM did not cause LDH leakage. CONCLUSIONS NET inhibits the proliferation of ESCs and induces their apoptosis. These results suggest a possible direct effect of NET on endometriotic lesions in patients with endometriosis.

Peroxisome proliferator-activated receptor gamma, coactivator 1α enhances local estrogen biosynthesis by stimulating aromatase activity in endometriosis.

CONTEXT Endometriosis is an estrogen-dependent disease, and estrogen is overproduced by abnormally elevated aromatase in endometriotic tissues. Peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC-1α) is a transcriptional coactivator-modulating steroid hormone. OBJECTIVE To investigate the effect of PGC-1α on aromatase activity in endometriosis. DESIGN Specimens from ovarian endometrioma (OE), endometrium with endometriosis (EE), and normal endometrium (NE) were analyzed for PGC-1α and aromatase expression. PGC-1α-dependent changes in aromatase expression in primary cultured stromal cells (SCs) were identified using luciferase and enzymatic assays, exon I-specific RT-PCR, and real-time PCR. Environmental stimulus-induced changes in PGC-1α were also examined. RESULTS PGC-1α was more highly expressed in OE than in EE and NE (P < .01). In OE, PGC-1α was coexpressed with aromatase, and their mRNA expressions were also correlated (r = 0.56, P = .02). PGC-1α was recruited to the nuclear receptor half-site between PI.3 and PII in the aromatase promoter. PGC-1α overexpression enhanced aromatase promoter activity (P < .01), mRNA expression (P < .05), and enzymatic activity (P < .01) in SCs from OE, but not in SCs from EE or NE. The levels of PI.3, PII, and exon II mRNA increased and transcriptional enhancement was abolished by mutation of the PGC-1α-interacting site. PGC-1α expression was enhanced in SCs from OE by tumor necrosis factor (TNF)-α (P < .05) but not by hypoxia or 17β-estradiol. CONCLUSIONS PGC-1α stimulated by TNF-α regulates aromatase expression and activity to promote local estrogen biosynthesis in OE, suggesting that PGC-1α is a promising candidate for novel targeted therapies in endometriosis treatment.

Autoamputation of a pedunculated, subserosal uterine leiomyoma presenting as a giant peritoneal loose body.

Peritoneal loose bodies (PLBs) are defined as fibrotic or calcified-free bodies within the peritoneal cavity; they commonly autoamputate from appendices epiploicae that have undergone torsion. Pedunculated, subserosal uterine leiomyomas (PSULs) are subserosal uterine leiomyomas connected to the uterus via a pedicle. In the present report, we describe the case of a PLB that originated from the autoamputation of a PSUL, confirmed based on histological evidence consistent with a uterine leiomyoma and the laparoscopic findings of a broken pedicle. This case clearly demonstrates the potential for a uterine leiomyoma to be the source of a PLB. Our findings contribute to the understanding of the etiological relationship between PLBs and uterine leiomyomas.

Medroxyprogesterone Acetate Enhances Monocyte-Endothelial Interaction Under Flow Conditions by Stimulating the Expression of Cell Adhesion Molecules

CONTEXT Monocyte adhesion to endothelial cells is an important initial event in atherosclerosis and is partially mediated by adhesion molecule expression on the cell surface. Although estrogens inhibit atherosclerosis development, effects of coadministered progestogen remain controversial. OBJECTIVE We examined the effects of progestogen on cytokine-stimulated human umbilical venous endothelial cell (HUVEC) expression of adhesion molecules. DESIGN In HUVECs, adhesion molecule mRNA levels were measured by real-time PCR. Protein expression was quantified by immunocytochemistry and ELISAs. To mimic the monocyte adherence to endothelial cells, we used a flow chamber system to assess progestogen effects on U937 monocytoid cell adherence to HUVEC monolayers. We also examined the suppression effects of adhesion molecules with small interference RNAs. RESULTS mRNA levels of adhesion molecules in HUVECs treated with medroxyprogesterone acetate (MPA) or 17β-estradiol + MPA were 1.7- to 2.5-fold higher than those in the control. MPA increased the protein expression of E-selectin, P-selectin, and intercellular adhesion molecule-1 compared with that for the control (83.0 ± 0.7, 34.8 ± 1.2, and 5.4 ± 0.0 ng/mL, respectively), whereas other progestogens or 17β-estradiol additive to progestogens did not significantly change expression. MPA significantly increased U937 monocytoid cell adherence compared with the control (56.0 ± 1.5 vs 46.5 ± 3.5 adherent cells per 10 fields) but did not increase adherence to HUVECs with knocked down intercellular adhesion molecule-1. CONCLUSIONS MPA increases cell adhesion molecule expression on HUVECs, causing increased numbers of monocytoid cells to adhere to HUVECs. These MPA effects may be a risk factor for atherogenesis on endothelial cells in postmenopausal women receiving hormone replacement therapy.

Clear Cell Carcinoma Arising from Cesarean Section Scar Endometriosis: Case Report and Review of the Literature

Introduction. The incidence of endometriosis affecting skin tissue represents only 0.5–1.0% of all endometriosis cases. A malignancy in the abdominal wall arising from endometriosis following cesarean section is even rarer; only 21 cases have previously been reported. The therapeutic strategy has not been determined because of the limited cases. We report a case of clear cell adenocarcinoma arising in the abdominal wall from endometriosis tissues following cesarean section and review previous literature to achieve the optimal treatment and better prognosis. Case Presentation. A 60-year-old woman presented with a growing mass at the left side of a cesarean section scar. Radical resection of the abdominal wall mass was performed. Histopathological examination showed a clear cell adenocarcinoma. Benign endometrium-like tissues were found adjacent to the cancer lesion in the excised specimen, suggesting malignant transformation from endometriosis of the abdominal wall. Discussion. Local resection was performed in 10 cases (47.6%) and total abdominal hysterectomy or oophorectomy was conducted in 11 cases (52.4%). No malignant lesions were observed in either the uterus or adnexa that were resected. These cases may be expected to increase with increasing incidence of cesarean section. The significance of the extensional resection should be further elucidated.

Usefulness of moistening seprafilm before use in laparoscopic surgery.

Purpose:Seprafilm is an ideal synthetic adhesion barrier, but its insertion into the abdomen in laparoscopic surgery is difficult because of its stiff and brittle nature. We tested the usefulness of a novel technique of moistening Seprafilm before use to increase its flexibility before insertion through a trocar during laparoscopic surgery. Methods:Laparoscopic pelvic surgeries that were followed by insertion of Seprafilm were evaluated in 67 women. A piece of Seprafilm (1/6 or 1/4 the size of a full sheet) was placed on gauze moistened with saline solution to soften it. The prepared piece was then rolled, inserted with forceps through a 12-mm trocar port, and placed at the intended site. Results:A total of 245 pieces of Seprafilm sheets were pretreated and inserted using a 12-mm trocar port with a success rate of 100% and placed correctly with a success rate of 80.0% (196 of the 245 pieces). The mean total time required for placement of all pieces per surgery was 601±248 seconds. Conclusions:This is a simple and effective technique that enables the film to be applied securely without breaking and without the need for special equipment.

(18)F-fluorodeoxyglucose positron emission tomography/computed tomography-positive lymph node endometriosis masquerading as lymph node metastasis of a malignant tumor.

Endometriosis is defined as the presence of endometrium-like tissues at extrauterine sites, most commonly in the abdominal cavity. Lymph node endometriosis is a rare but clinically important type of endometriosis that can mimic lymph node metastasis of a malignant tumor. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is a useful tool for diagnosing malignant tumors, although it occasionally shows false positive results in tissues with high metabolic activity caused by severe inflammation. In the present report, we describe a case of lymph node endometriosis that mimicked lymph node metastasis of a malignant tumor and showed a positive result on 18F-FDG PET/CT. The findings of the present case suggest that lymph node endometriosis could present as swollen lymph nodes with 18F-FDG PET/CT-positive results and provide important information for determining an appropriate treatment strategy.