Wataru Isono

Uterine artery pseudoaneurysm after cesarean section: case report and literature review.

Uterine artery pseudoaneurysm (UAP) occurs rarely and can develop after various gynecologic or obstetric procedures. The delayed diagnosis of this disease often results in life-threatening hemorrhage. Herein is described a case of UAP after cesarean section. The patient visited our emergency outpatient department 99 days after cesarean section because of abnormal uterine bleeding, which was diagnosed as UAP using color Doppler ultrasonography and contrast medium-enhanced computed tomography. Selective transcatheter arterial embolization was performed to resolve the lesion without complications. We also conducted a review to identify the demographic etiology of UAP. A PubMed search yielded 57 cases reported in the English literature. The most frequent cause of UAP was cesarean section, which accounted for 47.4% of all cases. The mean interval between the incident and the symptoms was approximately 2 weeks, regardless of cause. At analysis of 17 cases diagnosed within a day, it became evident that the definitive diagnosis was made at angiography (41.2%), computed tomography (29.4%), or color Doppler ultrasonography (29.4%). Almost all cases (94.1%) were conservatively treated with transcatheter uterine artery embolization. Consideration of UAP in the differential diagnosis is crucial for proper treatment before rupture and to preserve fertility.

SIRT3 positively regulates the expression of folliculogenesis- and luteinization-related genes and progesterone secretion by manipulating oxidative stress in human luteinized granulosa cells.

SIRT3 is a member of the sirtuin family and has recently emerged as a vital molecule in controlling the generation of reactive oxygen species (ROS) in oocytes. Appropriate levels of ROS play pivotal roles in human reproductive medicine. The aim of the present study was to investigate SIRT3 expression and analyze the SIRT3-mediated oxidative response in human luteinized granulosa cells (GCs). Human ovarian tissues were subjected to immunohistochemical analysis to localize SIRT3 expression. Hydrogen peroxide and human chorionic gonadotropin were used to analyze the relationship between ROS and SIRT3 by quantitative RT-PCR and Western blotting. Intracellular levels of ROS were investigated by fluorescence after small interfering RNA-mediated knockdown of SIRT3 in human GCs. To uncover the role of SIRT3 in folliculogenesis and luteinization, mRNA levels of related genes and the progesterone concentration were analyzed by quantitative RT-PCR and immunoassays, respectively. We detected the expression of SIRT3 in the GCs of the human ovary. The mRNA levels of SIRT3, catalase, and superoxide dismutase 1 were up-regulated by hydrogen peroxide in both COV434 cells and human GCs and down-regulated by human chorionic gonadotropin. Knockdown of SIRT3 markedly elevated ROS generation in human GCs. In addition, SIRT3 depletion resulted in decreased mRNA expression of aromatase, 17β-hydroxysteroid dehydrogenase 1, steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, and 3β-hydroxysteroid dehydrogenase in GCs and thus resulted in decreased progesterone secretion. These results have the important clinical implication that SIRT3 might play a positive role in the folliculogenesis and luteinization processes in GCs, possibly by sensing and regulating the generation of ROS. Activation of SIRT3 function might help to sustain human reproduction by maintaining GCs as well as oocytes.

Prediction model for the incidence of emergent cesarean section during induction of labor specialized in nulliparous low-risk women

Aim:  This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS).

CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase.

Liver X receptors (LXRs) monitor endogenous sterol levels to maintain whole-body cholesterol levels and regulate inflammatory responses. Recent studies have demonstrated that LXRs may inhibit cellular proliferation, but the underlying mechanism remains unclear. Cell cycle and apoptosis regulator 2 (CCAR2), previously known as DBC1/KIAA1967, is a transcriptional regulator that regulates cellular proliferation and energy metabolism by inhibiting sirtuin 1 (SIRT1) deacetylase. Based on the findings that CCAR2 regulates several nuclear receptors, including the estrogen receptors and androgen receptor, we aimed to identify the underlying mechanism of CCAR2 regulation of LXRα. We found that CCAR2 formed a complex with LXRα in a ligand-independent manner in HepG2 cells, and in vitro pull-down assays, it revealed a direct interaction between the amino terminus of CCAR2 and the AF-2 domain of LXRα. Thereby, CCAR2 attenuates the ligand-dependent transcriptional activation function of LXRα. RNA interference-mediated depletion of endogenous CCAR2 potentiated the expression of the LXRα target genes ATP-binding cassette transporter A1 and G1, and the abrogation of CCAR2 resulted in decreased cellular proliferation. Moreover, competitive immunoprecipitation studies revealed that the LXRα downregulation involves the inhibition of SIRT1-LXRα complex formation. Therefore, these results clearly indicate a novel mechanism in which CCAR2 may regulate the transcriptional activation function of LXRα due to its specific inhibition of SIRT1 and serve to regulate cellular proliferation.

Diameter of dominant leiomyoma is a possible determinant to predict coexistent endometriosis

OBJECTIVE To identify the frequency and assess risk factors for unexpected discovery of peritoneal endometriotic implants in patients who underwent myomectomy or hysterectomy for symptomatic uterine leiomyomas. STUDY DESIGN We retrospectively collected medical records of 829 patients with symptomatic leiomyomas in The University of Tokyo Hospital. All the patients underwent abdominal or laparoscopic surgeries between January 2001 and December 2010 and the presence or absence of endometriosis during surgery was analyzed. Possible determinant to predict coexistent endometriosis was statistically investigated. RESULTS In total, 105 leiomyoma cases (12.7% in 829 patients) were diagnosed with endometriosis. Patients with small dominant leiomyomas were significantly complicated by peritoneal endometriotic implants (small leiomyomas were classified as < 8 cm). The patients with both diagnoses were more likely to be infertile and at age 39 years or younger than those with leiomyoma alone. CONCLUSIONS Women undergoing myomectomy or hysterectomy with both endometriosis and leiomyomas have several different clinical features compared with women with only leiomyomas. The size of largest leiomyoma may provide an important clue for coexistent endometriosis. Women with substantial infertility despite a smaller leiomyomas burden may be more likely to have a surgical indication for concomitant endometriosis.

The Emerging Role of FOXL2 in Regulating the Transcriptional Activation Function of Estrogen Receptor β: An Insight Into Ovarian Folliculogenesis.

Germline mutations of the fork-head transcriptional factor forkhead box L2 (FOXL2) predispose embryos to autosomal-dominant blepharophimosis–ptosis–epicanthus inversus syndrome with primary ovarian insufficiency in female patients, but the mechanisms of FOXL2 in ovarian follicular development remain elusive. Estrogens produced by ovarian granulosa cells and estrogen receptor (ER) α and ERβ play fundamental roles in ovarian pathophysiology, and a previous study revealed that ERα and ERβ physically interact with FOXL2. However, the underlying functions of these interactions have not been investigated. Herein, we report an ERβ-specific repressive function of FOXL2. Histological examination demonstrated that FOXL2 expression tends to be intense during early follicular development. Immunoprecipitation revealed that ERβ and FOXL2 interact in a ligand-independent manner. In vitro pull-down assays revealed a direct interaction between FOXL2 and the activation function (AF)-1/2 domain of ERβ. The expression of FOXL2 represses the ligand-dependent transcriptional activation of ERβ, but FOXL2 does not influence the ligand-dependent transcriptional activation of ERα. Consistent with these results, RNA interference-mediated depletion of FOXL2 stimulates the expression of the ERβ-downstream gene p450 aromatase. The convergence between FOXL2 functions and ERβ-mediated transcription in the ovary suggests the putative mechanism of FOXL2 in early-phase follicular development, which may be partially attributed to the regulation of ERβ-dependent gene expression.

Administration of Oral Contraceptives Could Alleviate Age-Related Fertility Decline Possibly by Preventing Ovarian Damage in a Mouse Model

Age-related fertility decline is hypothesized to occur mainly by the spontaneous exhaustion and deterioration of the ovarian follicle, and the accumulation of ovarian tissue damage resulting from the ovulation cycle may play roles in the process. In this study, we hypothesized that suppressing ovulation would exert protective effects against age-related fertility decline. To test this hypothesis, we established a mouse model in which oral contraceptives (OCs) were administered daily. Female C57BL/6N mice were administered OCs daily from the age of 2 months to 12 months as an ovulation suppression mouse model. Mouse fecundity was investigated by counting oocyte number after ovarian stimulation and by examining live fetuses after mating. We found that compared with control mice administered vehicle alone, 12-month-old mice administered 2-fold dose OCs used for treating humans exhibited a significantly greater average oocyte number after ovarian stimulation (8.5 ± 0.6 vs 5.9 ± 0.6, P < .01). In addition, spontaneous conception with living fetuses after mating was strikingly increased in 12-month-old mice administered OCs relative to controls (6.0 ± 1.2 vs 0.4 ± 0.3, P < .01). In the histological examination of mouse ovarian tissues, we did not detect a significant difference in ovarian follicle number, but reduced amount of brownish foamy fibrous tissues, which might reflect ovarian tissue damage, was detected in aged mice administered OCs. These results suggest the possibility that long-term OC administration might alleviate age-related fertility decline, and the improvement mechanism could be attributed to the prevention of ovarian tissue damage by suppressing ovulation.

Prediction of the operative time for hysteroscopic myomectomy for leiomyomas penetrating the intramural cavity using leiomyoma weight and clinical characteristics of patients

To preoperatively predict the operative time (OT) for hysteroscopic myomectomy for G1 or G2 leiomyoma based on leiomyoma weight.

The efficacy of non-assisted reproductive technology treatment might be limited in infertile patients with advanced endometriosis in their 30s: Optimization of infertility treatment

To determine the efficacious treatment for infertile couples, we assessed the impact of infertility factors including endometriosis on assisted reproductive technology (ART) and non‐ART treatment, and the effect of age in infertility treatment outcomes was also investigated.

Endophytic-Type Endometrial Cancer with Adenomyosis Successfully Diagnosed with Hysteroscopic Endometrial Biopsy Using an 8.3-mm Operative Resectoscope: A Case Report

In order to diagnose endometrial cancer preoperatively, outpatient endometrial biopsy with a curette is frequently performed owing to its convenience. However, in some cases, gynecologists fail to diagnose endometrial cancer via outpatient endometrial biopsy because of the cancer’s distribution in the uterus and its consistency. A 57-year-old Japanese woman (gravida 4 para 4) presented with a 6-month history of light but intermittent postmenopausal vaginal bleeding. A malignant uterine tumor was strongly suspected after imaging using ultrasound examination and magnetic resonance imaging; however, a precise pathological diagnosis was not achieved despite multiple outpatient endometrial biopsies with the aid of office hysteroscopy. Based on an endometrial biopsy obtained using a cutting loop electrode on an 8.3-mm operative resectoscope, we reached a diagnosis of endophytic-type endometrial cancer, which is in accordance with the final pathological diagnosis after abdominal hysterectomy. Three months after her first visit to our hospital, total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic/para-aortic lymph node dissection were performed. Macroscopically, the endometrium was atrophic, and there was no obvious mass in the uterine cavity; however, microscopically, the cancer cells mainly existed in the deep myometrium and the final diagnosis was International Federation of Gynecology and Obstetrics (FIGO) stage IB endometrial cancer. Operative biopsy of the uterine endometrium and deep myometrium using hysteroscopy confirmed an accurate preoperative diagnosis of uterine endometrial cancer specifically of the endophytic type.