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Research question The recently developed in-vitro activation (IVA) approach provides a promising infertility treatment for patients with premature ovarian insufficiency. The IVA method promotes growth of residual ovarian follicles following ovarian tissue fragmentation leading to Hippo signalling disruption, together with in-vitro incubation with Akt stimulators. As poor ovarian response (POR) patients with decreased ovarian reserve (DOR) have multiple secondary follicles, this study tested whether Hippo signalling disruption alone using in-vitro ovarian cortical fragmentation, followed by autologous grafting, was sufficient to promote follicle growth. Design A case series study. Results In 9 out of 11 POR patients with DOR treated with a simplified IVA procedure, increases in antral follicle numbers in multiple growth waves were detected following FSH treatment. Subsequent injection with human chorionic gonadotrophin allowed retrieval of more mature oocytes for IVF (median antral follicle counts before and after IVA per ovarian stimulation: 1.0 versus 2.6) with 68.7% fertilization rates and 56.9% showing high-quality embryonic development. One natural conception and 16 embryo transfers in five patients resulted in one live birth, two ongoing pregnancies and one miscarriage. Three additional patients and the miscarriage patient have cryopreserved embryos for future transfer. Conclusions The present drug-free IVA approach may be suitable for POR patients with DOR, as it increased the number of antral follicles. The procedure also eliminated the need for 2-day incubation with drugs and required only one surgery. This approach could allow the retrieval of more oocytes in middle-aged women to achieve higher pregnancy rates and deserves proper evaluation in future randomized controlled trials.

Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner’s syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.

Aim The aim of this study was to investigate whether the consecutive administration of recombinant thrombomodulin (r-TM) for 4 days improves maternal and fetal conditions and physiological outcomes in an N′-nitro-L-arginine-methyl ester hydrochloride-induced and low-dose endotoxin-induced pre-eclampsia (PE). Methods r-TM or saline was administrated i.v. to normal pregnant and experimental PE rats for 4 days. The maternal condition, vascular endothelial growth factor receptor-1 (VEGFR-1), fetal conditions, uteroplacental blood flow (UPBF), and oxygenation in the placenta and fetal brain was evaluated on gestational day 21. Results Significant increases in the mean arterial blood pressure, VEGFR-1 values and fetal death rate were observed in PE rats compared with control rats, while maternal and fetal bodyweight and fetal brain weight were substantially lower. Hypoperfusion and hypo-oxygenation in both the placenta and fetal brain tissues occurred in PE rats. Although r-TM failed to improve hypertension and affect the differences in maternal bodyweight between the groups, r-TM significantly improved hypoperfusion and fetal and maternal conditions, including VEGFR-1 values (6.5 ± 4.0 vs 2.2 ± 2.7 ng/mL, PE vs PE with r-TM, respectively; P

Problem Premature ovarian insufficiency (POI) is a clinical syndrome defined by the loss of ovarian activity before 40 years old. An autoimmune mechanism is suggested to be involved in the development of POI. Therefore, we examined the relationship between peripheral blood regulatory T (Treg) cells and autoantibodies in POI. Method of study Thirty POI patients and 23 control women were enrolled in the study. Using flow cytometry, we measured the abundance of CD4+ T, CD4+ CD69+ T, CD8+ T, CD8+ CD69+ T, naive Treg, effector Treg, and FOXP3+ effector T cells in peripheral blood. Antinuclear and anti-thyroglobulin antibody (Tg-Ab) titers were measured in POI patients. Results The number of CD4+ T or CD4+ CD69+ T cells was significantly higher in POI patients (P = 0.045, and P = 0.030), and there were significantly fewer effector Treg cells in POI patients (P = 0.016) than in the controls. There were significant negative correlations between effector Treg cells and Tg-Abs (r = -0.584, P = 0.0282), and between effector Treg cells and CD4+ CD69+ T cells (r = -0.415, P = 0.0226) in POI patients. Conclusion This is the first report of decreased numbers of effector Treg cells and increased CD4+ CD69+ activated T cells in peripheral blood in POI, suggesting that POI is an autoimmune disease.

Exposure to 3,3'-iminodipropionitrile (IDPN) causes persistent neurotoxicity, while its reproductive toxicity in female rats is transient, indicating that gonadotropin-releasing hormone (GnRH) neurons and gonadotrophs receive little or no damage from IDPN and that the transient gonadal toxicity may be also observed in males. To clarify these points, the acute toxic effects of IDPN on hypothalamic-pituitary-gonadal axis of male rats were examined histologically, biochemically and serologically. A single intraperitoneal injection of IDPN (1000 mg/kg body weight) induced signs of neurotoxicity within a day; nevertheless, GnRH neurons were not affected throughout the experimental period. Four days after IDPN treatment, the plasma level of testosterone but not gonadotropins decreased and active caspase 3-immunopositive spermatids increased; both parameters returned to normal levels afterwards. Data from our studies revealed that while IDPN had little or no toxic effect on GnRH neurons or gonadotrophs it was transiently toxic to gonads in both sexes.

Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.

Heat shock protein 27 (hsp27) is expressed by squamous cell carcinoma of the uterine cervix. Results from an earlier study by our group indicted that hsp27 may be a diagnostic marker for cervical intraepithelial neoplasia (CIN) and carcinoma. p16 expression is known to be elevated in intraepithelial uterine cervical cancer and grades 2 and 3 lesions (CIN2, CIN3), but has also been reported to be negative in 5-20% of cervical cancer and CIN lesions. The aim of our study was to confirm immunohistochemically the expression of hsp27 and p16 in cervical lesions. Formalin-fixed, paraffin-embedded cervical tissue specimens obtained between 2002 and 2010 were investigated for hsp27 and p16 expression. Positive staining was detected for hsp27 in 63% of normal cervical tissues, 47% of CIN1 lesions, 75% of CIN2 lesions, 92% of CIN3 lesions, and 100% of squamous cell carcinomas (SCC); the corresponding rates for p16 positivity were 29, 47, 67, 92, and 75%, respectively. Positive staining for both hsp27 and p16 was observed in 6% of normal cervical tissues and in 19% of CIN1, 18% of CIN2, 85% of CIN3, and 75% of SCC specimens. Hsp27 or p16 positivity had a sensitivity of 95.6 or 84.7% and a specificity of 37.2 or 70.5%, respectively, for the identification of CIN3 or SCC lesions; when both hsp27 and p16 were assessed, both the sensitivity and specificity were improved. In conclusion, both hsp27 and p16 immunohistochemistry is a useful tool for the diagnosis of CIN3 lesions or cervical SCC.

Conjoined twinning is a unique complication of monochorionic pregnancy. This report describes the clinical findings in two cases of conjoined twins, and discusses their management. One case involved thoracopagus complicating a triplet pregnancy, and the other involved cephalothoracopagus, in which the outcome was intrauterine fetal death due to abruptio placentae after amniocentesis. Recent improvements in ultrasound imaging have facilitated the diagnosis of conjoined twins as early as the first trimester. Although many mothers opt to terminate pregnancy when conjoined twins are diagnosed, a few do not, as in the cases described. In such cases, pregnancy management, including accurate determination of the degree of organ fusion and psychological follow up, are important. On the basis of the two present cases, we present a systematic flow diagram for management of conjoined twin pregnancy from the time of diagnosis until delivery.

Aim: Anxiety and depression are common in cancer patients, because diagnosis of cancer raises the fear of death. Although mental problems are often overlooked in cancer patients, it is important to control psychological distress, improve the quality of life, encourage patients to express requests about cancer therapy appropriately, and reduce the burden on family members. Material & Methods: There were 214 patients admitted to the Department of Obstetrics and Gynecology of St. Marianna University Hospital for treatment of cancer between January 2007 and December 2008. At 2 weeks after learning the diagnosis of cancer, these patients completed a Hospital Anxiety and Depression Scale (HADS) questionnaire, and their psychological characteristics were investigated in relation to age, tumor type and time after learning the diagnosis. The cut-off value for intervention to manage maladjustment and major depression was set at a HADS score of 11. Results: The HADS score was 11 in 118 of the 214 patients (55.1%). The HADS score for anxiety was higher in younger patients, while the HADS score for depression was higher in older patients. There were no significant correlations between the HADS score and the type of gynecologic cancer (cervical cancer, endometrial cancer and ovarian cancer) or the time after learning the diagnosis. Conclusion: Assessment based on the HADS score revealed a high prevalence of psychological problems after announcement of the diagnosis of gynecologic cancer. This emphasizes the importance of psychiatric intervention when patients are informed of their condition.

Formation of a fistula to a digestive organ is an extremely rare phenomenon in cases of ovarian carcinoma. We report a case of ovarian clear-cell carcinoma complicated by formation of a sigmoid colon fistula, and review the related literature. A 61-year-old woman, who had undergone hysterectomy and right salpingo-oophorectomy due to myoma and an ovarian tumor, developed bloody bowel discharge and abdominal distention. Computed tomography revealed a huge pelvic tumor with a thickened wall and internal gas. As the patient also had severe anemia and peritonitis, emergency laparotomy was performed, and intraoperatively it was noted that the tumor was tightly attached to the sigmoid colon, and contained bloody pus. Left salpingo-oophorectomy was performed and pathological examination of the specimen revealed fistula formation between the ovarian tumor and the sigmoid colon. The tumor was diagnosed as left ovarian clear-cell carcinoma, but no diverticulum or direct tumor invasion was evident around the fistula. The patient was given chemotherapy with paclitaxel and carboplatin, and she is now doing well after 9 months with no evidence of tumor recurrence. Although fistulation to the digestive tract is very rare in cases of ovarian cancer, it must be diagnosed and treated promptly because severe inflammation can make it potentially life-threatening.

Leiomyosarcoma (LMS) of the fallopian tube is exceedingly uncommon. So far as we investigated, only eighteen cases of LMS of the fallopian tube have been reported. Here we report a nineteenth case which was International Federation of Gynecology and Obstetrics stage IIIc LMS of the fallopian tube successfully treated with intraperitoneal cisplatin followed by prolonged oral etoposide. A 70-year-old female was introduced to our institute due to intrapelvic tumor and ascites. Because of elevated serum lactate dehydrogenase and CA125 as well as the findings of pelvic magnetic resonance imaging and computerized tomography, the patient was suspected to have ovarian cancer. In laparotomy, the large pelvic tumor was seemed to originate from the right fallopian tube. Pathologically, the patient was diagnosed as stage IIIc fallopian tube LMS. At the end of the operation, cisplatin was given intraperitoneally followed by prolonged oral etoposide. Although a lot of dissemination was noted throughout the peritoneal cavity, the patient is alive without any evidence of recurrence for more than 6 years since the initial operation. In this uncommon entity, a cisplatin- and etoposide-based regimen could be considered.

Water intoxication may be induced by the use of intrauterine fluid overload in hysteroscopic surgery. We report a patient with a uterine myoma and anemia (Hb, 9.3 g/dl), who developed severe hyponatremia during a hysteroscopic myomectomy. The submucosal myoma was resected using a monopolar resectoscope following 6 courses of GnRH agonist therapy. The procedure was performed by a combination of lumbar and intravenous anesthesia. The total amount of 3% solbitol was 27,000 ml and the duration of the procedure was 75 minutes. Severe hyponatremia (104 mEq/l) was diagnosed during the procedure, although there were no abnormal symptoms and vital signs. The serum Na level recovered to a normal level following the administration of diuretics. This case suggests that hyponatremia may occur during extensive resection of non-protruding submucosal myomas. Therefore, frequent measurements of intake and output of fluids and measurement of the serum Na level are required to prevent severe hyponatremia during hysteroscopic procedures for such cases.

Objective It has been reported that an ovarian tumor is diagnosed during pregnancy in 0.21-1.24% of cases. Patients with ovarian tumor who underwent surgery in pregnancy from 2004 to 2008 were reviewed.Design During these 5-years, there were 3,837 deliveries in our hospital, and 16 of which underwent surgery due to an ovarian tumor. A retrospective analysis of these cases was performed.Results Laparoscopic surgery was performed in 9 patients, while the remaining 7 patients underwent open abdominal surgery. The tumor was determined to be malignant in 2 patients. The mean patient age at the time of surgery was 31.4 years, and the median number of gestational age at surgery was 16 weeks. The median value for the maximal tumor diameter was 9 cm. Overall, among the patients with ovarian tumors complicating their pregnancy, the pathological diagnosis was a mature cystic teratoma in 9 patients, which was the predominant type, followed by an endometriotic cyst in 3 patients and a malignant tumor in 2 patients. These malignant tumors consisted of an immature teratoma (G2) and a yolk sac tumor, and these patients are currently undergoing chemotherapy.Conclusion Patients should be examined for the possible presence of an ovarian tumor early in gestation. Once a tumor is present and indication of operation is judged to be appropriate, it is necessary to carefully determine the best time and method for the surgery in each individual patient.

CapsuleSuccessful pregnancy and delivery after endoscopic revision of a uterine bicornis bicollis and septate vagina.AbstractInternal genital abnormalities which occur in fetuses are often diagnosed after menarche with symptoms of dysmenorrhea. We report a patient who was diagnosed with uterine bicornis bicollis and a septate vagina. She achieved a successful pregnancy and delivery after undergoing endoscopic surgery in childhood.

The CAG repeat lengths weighted by X-inactivation ratios were significantly shorter in 58 Japanese patients with premature ovarian failure (POF) than in 42 age-matched control females with normal menses. The results suggest that short CAG repeats with a relatively high androgen receptor function may constitute a susceptibility factor for the development of POF.

TGP (thermo-reversible gelation polymer) is a high molecular compound that has so-gel transmitting temperature of 221C Since solid cancer tissue grows in this polymer three-dimensionally, and fibroblasts scarcely grow in it, TGP is suitable for chemosensitivity assays for solid tumors. In this study, a chemosensitivity test using TGP was applied to recurrent gynecologic cancer patients in order to evaluate its utility and efficacy. In some ovarian cancer cases, expression of anticancer drug resistance-related proteins was also analyzed.Recurrent tumor tissues were surgically obtained with informed consent. After these tissues were minced and incubated for 4 days with CDDP, mitomycin C, 5-fluorouracil, paclitaxel, and CPT-11, the sensitivity against these drugs was estimated. Western blotting was performed in 8 recurrent ovarian cancer tissues in order to analyze the expression of Bcl-2, MRP2, BCRP, and GST-pi.The total evaluability rate of this assay was 90.6% (29/32). Sensitive drugs could be determined in 5 of 7 ascites samples (71.4%) and in 2 of 3 intra-tumoral fluid samples (66.7%). The overall clinical response rate of chemotherapy determined by these results was 50.0%. There were significant correlations between the IC50 of CDDP and Bcl-2, BCRP, GST-pi, and between that of 5-FU and MRP 2.Although this was a preliminary study, the chemosensitivity test using this new material appears to be useful for designing 'made-to order' salvage chemotherapy for pretreated recurrent gynecologic patients. In order to overcome multidrug resistance, the mechanisms of multidrug resistance should be further investigated.

In this study, the preliminary analyses were conducted of enzymatic activities of uridine phosphorylase (UP) and thymidine phosphorylase (TP) in normal tissues and cancer tissues of the uterine cervix. The study was performed on 27 patients of cervical cancer, treated first in our hospital. Normal cervical tissues obtained from 15 patients undergoing hysterectomy for benign diseases were used as controls. The supernatant of the homogenated cervical tissues and the stroma (5-FU and ribose-1-P or deoxyribose-1-P) were analyzed by high performance liquid chromatography, and then the UP and TP activities calculated. TP activity was significantly greater than UP activity (P < 0.0001). Both UP and TP showed significantly greater activity in cancer tissues than in normal tissues (P < 0.0001). In the TP activity of the cancer tissues, there was no significant difference among the histological types, while the TP activity tended to be significantly higher in the cases with lymph node metastasis. These results showed that the TP-mediated route seemed important as the 5FU metabolic pathway in the uterine cervical tissues, and TP enzymatic activity might be associated with lymph node metastasis.

The significance of cyclooxygenase-2 (COX-2) expression in ovarian cancer has been discussed. In this study, we found increased expression of COX-1 mRNA and protein in three out of 10 ovarian cancer cell lines. Prostaglandin E 2 (PGE 2 ) production was elevated in these three cell lines, but not in other seven cell lines. COX-2 protein was not detected in any of the cell lines. Cytosolic prostaglandin E synthase (cPGES) mRNA and protein were detected in all 10 cell lines. Membrane-associated PGES-1 (mPGES-1) was detected in some of the ovarian cell lines, but its presence did not correspond with PGE 2 production. In contrast, mPGES-2 mRNA and protein were detected in all 10 cell lines. A nonselective COX inhibitor (indometacin) and a selective COX-1 inhibitor (SC-560) strongly inhibited PGE 2 production by the three cell lines, while selective COX-2 inhibitors (NS-398 and rofecoxib) did not inhibit PGE 2 production. In addition, increased expression of COX-1, not COX-2 protein was observed in the mass of ovarian cancer tissues from 22 patients when compared with that in normal tissue. These findings suggest that COX-1 might be a major enzyme regulating PGE 2 production in ovarian cancer cells.

We successfully established a novel ovarian granulosa tumor cell line (HSOGT). The tumor tissue of the ovary was derived from a 25 year-old Japanese woman under her consent. The cell line was maintained for over 14 months, subcultured more than 73 times, and had a population doubling time of 18.9 hours. Phase contrast microscopy displayed a pavement-like arrangement without contact inhibition. The chromosome number showed a wide distribution of aneuploidy and the mode was 83; many marker chromosomes were observed. The HSOGT was also successfully xenotransplanted into nude mice. The cell line produced estradiol and has preserved some characters of granulosa cells with stable growth in vitro. We firmly believe that this cell line will be a most useful tool for endocrinological investigation of human granulosa cells.

背景:便秘症のカルチノイド症候群を呈した卵巣甲状腺腫性カルチノイドの1例を経験し, その腫瘍発生の検索のために二重染色による免疫組織化学的な検索を行った.症例:48歳, 女性. 画像診断で右卵巣に手拳大の腫瘤を認め, 成熟型奇形腫が疑われ摘出手術を施行し, 甲状腺腫性カルチノイドと診断された. 捺印細胞像では, コロイド様の無構造物質を背景に, 腫瘍細胞はシート状集塊または散在性, 一部濾胞構造, 腺管様構造, 索状配列を示していた. 細胞は比較的小型の類円形から円柱形で, 細胞質はレース状ないし顆粒状でライトグリーンに淡染し, 核は類円形, 核縁は薄く, クロマチンは軽度増量し, やや粗顆粒状で均等分布していた. 組織学的に腫瘍はカルチノイド, 甲状腺腫およびそれらの移行部分から構成されていた. 免疫組織化学的に移行部分はthyroglobulin, chromogranin A両者に陽性を示した.結論:本例の診断に大切なことは, カルチノイドに特徴的な細胞所見と, 甲状腺腫としてのコロイドを含む濾胞構造に着目したことであった. また免疫組織化学的染色結果から, 本腫瘍発生は, 腫瘍細胞が多分化能を持っていることと密接な関係があると考えた.

We examined the prevalence of anti-nuclear antibodies (ANA) in 32 consecutive patients with premature ovarian failure with and without chromosomal abnormalities. Blood samples were taken for karyotype determination as well as detection of autoantibodies, X-terminal microdeletions and spontaneous follicular growth. The correlation between ANA positivity and the age at onset of amenorrhoea, as well as the presence of karyotype abnormalities, X-terminal microdeletions and follicular growth was determined. Ten of the 24 patients with normal karyotype and none of the 8 patients with karyotype abnormalities were ANA positive. ANA were found more frequently in patients with premature ovarian failure with normal karyotypes than in control amenorrhoeic patients (42 versus 6, P < 0.01). ANA were found in 77% (10/13) of premature ovarian failure patients with normal karyotypes who developed amenorrhoea at or under the age of 30 years, but not in the patients who developed amenorrhoea later in life. Follicular growth was evident in 50% (5/10) of karyotypically normal patients with ANA, 71% (10/14) of karyotypically normal patients without ANA and 38% (3/8) of patients with karyotype abnormalities. X-terminal microdeletions were not found in any of the patients studied. These results suggest that patients with premature ovarian failure and ANA are an aetiologically and clinically distinct group.

Objective: To report successful ovulation induction in a woman with premature ovarian failure (POF) resulting from a partial Xq deletion. Design: An uncontrolled study. Setting: University hospital. Patient(s): A 27-year-old woman with 46,X,del(X)(q22) who had hypergonadotropic secondary amenorrhea. Intervention(s): Injections of hMG (225 IU/d) for 8 consecutive days after endogenous gonadotropin suppression with a long-acting GnRH agonist (900 μg/d) for 12 weeks, together with cyclic sex steroid replacement therapy. Main Outcome Measures: Serum concentrations of E 2 and P as well as ultrasonography. Result(s): Folliculogenesis and ovulation. Conclusion(s): Ovulation induction is possible in patients with POF caused by X chromosome aberrations.

OBJECTIVE: The liquid embolic agent n-butyl cyanoacrylate (NBCA) is a tissue adhesive used as an immediate and permanent embolic agent when mixed with oil-based contrast medium. In this study, the preservation of fertility with TAE using NBCA for massive haemorrhage during pregnancy or the peripartum period and the utility of this therapy were investigated. METHODS: Cases from January 2005 to October 2010 in which TAE was performed for massive haemorrhage in pregnant women, particularly during the peripartum period, were investigated. RESULTS: TAE was performed in 27 pregnant women. The embolic agent used was GS only in five cases, NBCA only in 19 cases, and additional embolization with NBCA when the effect with GS was insufficient in three cases, one each of abruptio placentae, cervical pregnancy, and uterine atony.A comparison of mean blood loss when each embolic agent was used for haemostasis showed a significant difference between cases in which GS only was used and cases in which NBCA only was used. In a comparison of mean transfusion volume, a significant difference was seen between cases in which both GS and NBCA were used and cases in which NBCA only was used. In a postoperative follow-up survey, menses resumed in eight patients, including four patients who later became pregnant and three who delivered. CONCLUSIONS: TAE with NBCA, which has an embolic effect unrelated to clotting dysfunction for massive haemorrhage during the peripartum period, is a minimally invasive and very effective treatment method for patients with severe DIC.

Erratum to: J Assist Reprod Genet (2012) 29:465–468 DOI 10.1007/s10815-012-9786-y The original version of this article unfortunately contained a mistake. Dr. C-R Tzeng's address was incorrect. Korea should be changed to Taiwan. The online version of the original article can be found under http://dx.doi.org/10.1007/s10815-012-9786-y.

The objective of this clinical trial was to examine the efficacy of a supplement containing natural S-(-)equol, a daidzein metabolite, in reducing menopausal symptoms.In this multicenter, double-blind placebo-controlled trial, 160 equol nonproducing, postmenopausal Japanese women who experienced at least 1 hot flush/day were randomly assigned to consume 10 mg/day S-(-)equol (n=77 women) or placebo (n=83 women) for 12 weeks. Participants completed a standardized menopausal symptom checklist and rated five common menopause symptoms by a visual analog scale at baseline, week 12, and week 18 (6-week postintervention). Physical, blood, and urine examinations were conducted. One hundred twenty-six women completed the study.At baseline, daily hot flush frequency was 2.9±2.1 for the S-(-)equol group and 3.2±2.4 for the placebo group. After the 12-week intervention, the S-(-)equol group had a greater decrease from baseline in hot flush frequency compared with the placebo group (-1.9±1.8/day, -58.7%, vs. -1.0±2.0/day, -34.5%, p=0.009). The severity of hot flushes and neck or shoulder muscle stiffness significantly decreased in the S-(-)equol group compared with the placebo group. No changes in clinical parameters or serious adverse effects were reported.This is the first trial to show beneficial effects of a 10-mg natural S-(-)equol supplement consumed daily for 12 weeks on major menopausal symptoms, specifically, hot flushes and neck or shoulder muscle stiffness, in postmenopausal Japanese women. This supplement offers a promising alternative for management of menopausal symptoms.

Background: Diagnosis of cancer causes psychological distress. The present study investigated the safety and efficacy of fluvoxamine therapy in gynecologic cancer patients with either adjustment disorder or major depression after cancer was diagnosed. Methods: Screening with the Hospital Anxiety and Depression Scale (HADS) was conducted at least 2 weeks after notification of the diagnosis of cancer in 214 gynecologic cancer patients hospitalized between January 2007 and December 2008. The HADS cutoff score was set at 11 points or greater. Informed consent to the study was obtained from 10 patients, and fluvoxamine was administered for 8 weeks. As primary end points, the safety and efficacy of fluvoxamine were evaluated using the HADS and the SF-36. As a secondary end point, the Clinical Global Impression was determined. Results: The total HADS score, the anxiety score, and the depression score were significantly reduced after 6, 4, and 6 weeks of treatment, respectively. The SF-36 revealed significant improvement in vitality, mental health, and role (emotional) after 8 weeks of treatment. In the 5 patients with adjustment disorder, only the HADS anxiety score was significantly reduced after 4 weeks. In the 5 patients with major depression, the total HADS score, the anxiety score, and the depression score were significantly reduced after 6, 8, and 6 weeks, respectively. According to the SF-36, the adjustment-disorder groups showed significant improvement in mental health after 8 weeks of treatment, whereas the major-depression group showed significant improvement in vitality and role (emotional) after 8 weeks. No adverse events occurred in any subject. Assessment of the Clinical Global Impression suggested that fluvoxamine improved psychological distress in all 10 subjects. Conclusions: The present findings suggest that fluvoxamine is useful for alleviating psychological distress, including adjustment disorder and major depression, in gynecologic cancer patients. Management of psychological distress after diagnosis of cancer is important.

Recently, accumulating evidence has suggested that tumors, including ovarian cancer, are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. The emergence of drug resistance is one of the most difficult problems in the treatment of ovarian cancer, which has been explained recently by the potential of CSCs to have superior resistance against anti-cancer drugs than conventional cancer cells. In this study, we expanded this line of study to examine whether this phenomenon is also observed in clinical specimens of ovarian cancer cells. In total we could analyze 28 samples out of 60 obtained from ovarian cancer patients. The clinical samples were subjected to testing of the expression of side population (SP) as a CSC marker, and according to the presence of SP (SP+) or absence of SP (SP−), clinicopathological significances were analyzed. Although there was no statistical significance, there were more SP+s in recurrent cases as well as in ascitic and peritoneal dissemination than in primary tumor of the ovary. There was no correlation between SP status and FIGO staging. In 19 cases of those who could be followed more than 6 months from initial therapy, there were 8 cases of recurrence or death from disease, and all of these were SP+. On the other hand, in 11 cases of disease-free survivors, 6 were SP+. There was a significant difference in prognosis between SP+ and SP− (p = 0.017). Although this study was limited, it revealed that SP could be contained more in recurrent or metastatic tumors than in primary tumors, and also that the presence of SP could be a risk factor of recurrence in ovarian cancer. Therefore, a novel therapeutic strategy targeting SP could improve the prognosis of ovarian cancer.

Objective: To report a case of full-term delivery after uterine artery embolization with N-butyl cyanoacrylate for abruptio placentae. Design: Case report. Setting: University hospital. Patient(s): A 35-year old woman, gravida 2 para 0, at 32 weeks’ and 4 days’ gestation. Intervention(s): Transcatheter arterial embolization with N-butyl cyanoacrylate (NBCA). Result(s): An emergency cesarean section was performed for abruptio placentae. The neonate died on day 0. After the cesarean section, a hematoma was found at the uterine incision that continued to increase. Therefore, pelvic angiography was performed, and extravasation was observed from the uterine arteries. NBCA was used for embolization, and the extravasation stopped rapidly. Total transfusion volume was 10,190 mL. Nine months after the cesarean section, the patient became pregnant naturally and delivered a boy by elective cesarean section. Conclusion(s): For treatment of shock caused by perinatal hemorrhage, which is a major cause of perinatal mortality, even if clotting abnormalities are present, transcatheter arterial embolization using NBCA can provide effective hemostasis. Moreover, in patients who would otherwise require a hysterectomy, fertility can be preserved. (Fertil Steril� 2011;95:290.e9–e11. � 2011 by American Society for Reproductive Medicine.)

Clear cell adenocarcinoma of the ovary often shows resistance to anticancer agents. We investigated new molecules to use when developing molecular-targeting therapy for clear cell adenocarcinoma of the ovary. RMG-I cells without invasive potential and RMG-V cells with invasive potential (derived from clear cell adenocarcinoma of the ovary) were subjected to complementary deoxyribonucleic acid microarray analysis. Caveolin-1, a molecule involved in cellular motility and invasion, showed differing expression between the two cell lines. An RNA interference experiment using the published siRNA for caveolin-1 was carried out. The results showed suppression of RMG-V cell infiltration by siRNA, but proliferation of the cancer cells was also suppressed. In other words, RMG-V cell infiltration may have been suppressed simply because cell proliferation was suppressed by RNA interference. These findings suggested that POU6F1 might be a transcription factor involved in the proliferation of ovarian cancer cells. Clear cell adenocarcinoma of the ovary shows little response to standard therapy. The results of the present study suggest that the transcription factor POU6F1 could be a new molecular target for treatment of this cancer.

Objective: The aim of this study was to determine whether self-assessed health changed over the last decade in association with menopausal symptoms among community-dwelling Japanese women. Methods: Cross-sectional surveys of 50-year-old women living in Northern Kawasaki were conducted in 1998 (n = 1,492) and 2008 (n = 1,274). Data obtained from a questionnaire were self-assessed health, menopause awareness, 1-year recall of 10 subjective symptoms (Simplified Menopausal Index), and sociodemographic, lifestyle, and health characteristics. The prevalence of poor self-assessed health, menopause awareness, and subjective symptoms was compared between the surveys. Results: The percentage of premenopausal women increased from 51.7% in the 1998 survey to 64.8% in the 2008 survey (P < 0.001). The prevalence of menopause awareness decreased from 36.8% in the 1998 survey to 31.7% in the 2008 survey (P = 0.006). The prevalence of poor self-assessed health decreased from 13.9% in the 1998 survey to 10.8% in the 2008 survey (P = 0.013). Multiple logistic regression analysis showed that participants of the 2008 survey had a significantly lower risk for having poor self-assessed health than did participants of the 1998 survey. Menopause awareness, comorbidity, and body mass index of 18.5 kg/m 2 or lower or 25.0 kg/m 2 or greater were significantly associated with increased risk for having poor self-assessed health. The impact of menopause awareness on self-assessed health was 2.2 to 2.4 times greater in participants without comorbidity than in those with comorbidity. Conclusions: There was a significant improvement in self-assessed health in parallel with a significant downward secular trend in the prevalence of menopause awareness among community-dwelling Japanese women. Women who felt themselves affected by menopause tended to perceive their own health as poor.

Although radical hysterectomy is the standard surgical treatment for patients with stage IB and II cervical cancer, it does not improve the prognosis of high-risk patients even if postoperative radiotherapy is added. There is therefore a need to establish some other therapeutic regimen. In the present retrospective study, the efficacy of concurrent nedaplatin after radical hysterectomy in high-risk stage IB to II cervical cancer was analyzed. From 1995 through 2005, patients with an International Federation of Gynecology and Obstetrics stage of IB2 and II cervical cancer who were given only radiotherapy (RT; n = 17) or postoperative concurrent chemoradiotherapy with biweekly nedaplatin at 70 mg/m(2) (p-CCRT; n = 13) were entered. All of the patients had at least one of the following risk factors: lymphovascular space infiltration, positive lymph nodes, or parametrial invasion. There was no significant difference between the RT and p-CCRT groups with regard to mean age and risk factors, except that more patients in the p-CCRT group had positive lymph nodes (P < 0.05). Five-year progression-free survival and overall survival after RT versus p-CCRT were 76.0% versus 83.3%, and 81.9% versus 83.3%, respectively. Although many patients in the p-CCRT group had positive lymph nodes, there was no significant difference in either PFS or OS. No grade 4 myelosuppression or other severe side effects were seen in the p-CCRT group. As CCRT with nedaplatin might have some benefit, a randomized control trial should be conducted in the future.

Objectives To determine the prevalence and characteristics of climacteric symptoms and related factors among 50-year-old Japanese women. Methods A self-administered questionnaire was mailed to all 50-year-old women ( n = 3166) in three northern wards of Kawasaki City regarding 10 menopausal symptoms (hot flashes, sweats, insomnia, depression, palpitation, chills, irritation, headache, fatigue, and stiff shoulders) as well as demographic, lifestyle, psychological, socio-economic and physical factors. The questionnaire included closed-ended questions about symptoms over a 1-year recall time frame. The response rate was 55%, and women with current illness, a history of gynecological or endocrinological disorders and those on HRT were eliminated. We finally analyzed data from 1169 (37%) women. Results The prevalence of hot flashes was 36.9%. These, together with sweats, insomnia and depression, were associated with menstrual status. All four symptoms were also associated with lifestyle and socio-psychological factors. Psychological stress (unease or anxiety) was associated with all 10 symptoms investigated. The two most prevalent symptoms, namely, fatigue (64.7%) and stiff shoulders (75.4%) were associated with psychological and lifestyle factors. Conclusions Hot flashes were experienced by more women in the present community-based study than in most previous studies of Japanese women. We found that hot flashes (‘hoteri’ in Japanese) are related to menstrual status. Symptoms both related and unrelated to menstrual status were associated with lifestyle, psychological factors and BMI.

A novel serous surface papillary carcinoma of the ovary (SSPC) cell line, HYKSSPC, was established successfully. Carcinoma cells were obtained from ascitic fluid of a 60-year-old Japanese woman. The population doubling time was 51.4 h. A phase contrast micrograph showed a pavement stone-like arrangement without contact inhibition. The chromosome number showed a wide distribution of aneuploidy, and the mode was in 46–47. An immunocytochemical study showed that CA1 25, BerER4 and cytokeratin were positive and that CEA, calretinin and thrombomodulin were negative. This cell line preserved some characters of the adenocarcinoma while growing in vitro. A chemosensitivity test revealed that HYKSSPC cells were sensitive to CDDP (cis-platinum), 5-fluorouracil, mitomycin C, paclitaxel and irinotecan. To our knowledge, HYKSSPC is the first established cell line derived from SSPC, and it may offer some useful information for investigating this disease.

A cell line designated HTLS was established from the retroperitoneal liposarcoma. The HTLS line showed stable proliferation without interruption for 2 years and subcultivated over 35 times. The cells were elongated fibrous and spindle in shape, and neoplastic and pleomorphic features. The multinucleated giant cells with fine cytoplasm were seen. The cells proliferated slowly and the population doubling time was about 90 hours. The chromosome number showed a wide distribution of aneuploidy, the mode was hyperdiploid range (51-52), and many marker chromosomes were observed. The cells were transplantable into the submucosa of immunesuppressed hamster's cheek pouch and produced liposarcoma, while were not transplantable into subcutis of nude mice

Despite recent advances in the application of chemotherapy to ovarian cancer, the development of alternative therapies that retain activity against drug-resistant-tumors remains a high priority. We analyzed a number of cultured ovarian cancer cell lines of different tissue types for the presence or absence of sensitivity to various anticancer drugs as well as expression patterns of oncogene products (erbB-2, EGFR, bcl-2). As a result, we identified oncogene products that were related to resistance. Using 9 cultured cell lines of ovarian cancers (serous, mucinous, endometrioid, clear, undifferentiated), sensitivities to anticancer drugs were investigated using the MTT assay. The phenotypes of oncogene products expressed by the above cultured cell lines were analyzed by Western blotting. The oncogene products involved in resistance to anticancer drugs were identified by multivariate analysis. Positive correlation between the resistance to anticancer drugs and the oncogene products was obtained by multivariate analysis for (a) CDDP and erbB-2 (b) · p-16 and erbB-2, and (c) MMC and EGFR. Correlation between resistance to anticancer drugs and expression of certain oncogene products was obtained in ovarian cancers, suggesting that sensitivity to anticancer drugs could be predicated prior to chemotherapy.

A cell line designated HUUCLEC was established from a human uterine cervical lymphoepithelial carcinoma obtained from a 61-year-old Japanese woman. The cell line has grown slowly without interruption and serial passages were successively carried out 60 times within 3 years. The cultured cells were spindle or round in shape, showing anaplastic and pleomorphic features, a pavement cell arrangement and multilayering without contact inhibition. The population doubling time of the HUUCLEC line was 72 hours while the chromosomal number varied widely and showed aneuploidy. The modal chromosomal number was stable at the triploid range and marker chromosomes were present; the Ebstein-Barr virus was absent in the cultured cells.

Study Objective: To compare adrenergic-sympathetic responses during pelvic laparoscopic surgery with CO 2 insufflation0259 0201 with those during laparotomy. Design. Propective study (Canadian Task Force classification II-1). Setting. Tertiary care university hospital. Patients. Twenty-one infertile women with a clinical diagnosis of endometriosis. Interventions. Plasma norepinephrine (NE) and epinephrine (E) levels were measured in patients undergoing laparoscopic or open pelvic surgery. Measurements and Main Results. During laparoscopic surgery, increases in NE and E levels were correlated with arterial tension of CO 2 (PaCO 2 ) and were greater in patients with a larger increase in PaCO 2 than in those undergoing laparotomy. Hemodynamic changes were also more evident during laparoscopic surgery, with larger PaCO 2 increases. Conclusions. The PaCO 2 increases due to CO 2 insufflation are associated with adrenergic-sympathetic activation and hemodynamic changes during laparoscopic pelvic surgery.

A 24-year-old female with significant ovarian hypertestosteronism, who responded well both to gonadotropin releasing hormone (GnRH) agonist and cyclic administration of estrogen and gestagens in terms of suppressing circulating testosterone levels is reported. The patient's menstrual periods had been regular since menarche at the age of 12 until she became amenorrheic at the age of 20. She visited our facility in November 1988 after receiving three cycles of estrogen and gestagen replacement therapy from a previous physician which caused withdrawal bleeding. Clomiphen citrate reportedly failed to induce apparent ovulation. On her first visit with us, she was 160 cm tall weighing 47 kg with apparent hoarseness but not with hirsutism. Pelvic examination revealed significant clitoromegaly but otherwise normal external and internal genitalia. Laparoscopic examination disclosed that her uterus appeared to be normal with bilateral ovaries relatively small (4 x 4 x 3 cm) without tumorous or polycystic appearance. Histological examination of her ovaries obtained at laparoscopy showed several primary follicles with mild infiltration of the stromal cells. No thickened tunica albuginea or cystic formation were observed. These findings did not support either polycystic ovary or hyperthecosis. Serum testosterone (T) levels were extremely high (7.1 ng/ml), while serum androstenedione levels were only slightly above normal range (3.1 ng/ml). Urine 17-KS excretion was slightly increased (6.1 mg/day), while 17-OHCS output was within normal range (4.0 mg/day). Basal serum LH and FSH levels were within normal range and LH pulse frequency was reduced to 1 in 4 hours. Administration of dexamethasone 1 mg/day for 2 days did not suppress circulating T and free T levels but lowered serum cortisol concentration and urine excretion of 17-OHCS. Blood glucose and insulin levels were within normal limits and their responses to oral glucose administration were normal. Abdominal and pelvic ultrasonography and computed tomography as well as adrenal scintigraphy did not reveal any tumorous lesions in bilateral adrenals and ovaries. Administration of GnRH agonist, Buserelin 900 micrograms/day, suppressed circulating T concentrations to 0.7 ng/ml in 8 days, while it had no significant effects on DHEA and DHEA-S levels. After 16 weeks of Buserelin administration, ovulation was successfully induced by hMG administration. Cyclic estrogen and gestagen replacement therapy by Kaufmann's schedule for 2 cycles also suppressed serum T levels to normal, female range. Thus, the present case represents non-neoplastic, non-PCO, ovarian hypertestosteronism which responded well both to GnRH agonist and estrogen and gestagen replacement therapy in terms of lowering circulating T levels.

Brain metastases of gynecological malignancies are rare, but the incidence is increasing. Patients with brain metastases have a poor prognosis, therefore early detection and optimal management is necessary. In order to determine a new biomarker, we aimed to identify proteins that associated with brain metastases. We investigated proteins associated with brain metastases of gynecological malignancies in three patients who underwent surgical resection (stage IIb cervical cancer, stage Ib endometrial cancer, and stage IIIb ovarian cancer). Proteomic analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples of the primary tumors and brain metastases, which were analyzed by liquid chromatography with tandem mass spectrometry. Thereafter, candidate proteins were identified by the Scaffold system and Mascot search program, and were analyzed using western blotting and immunohistochemistry. As a result, a total of 129 proteins were identified. In endometrial and ovarian cancers, western blotting revealed that the expression of alpha-enolase (ENO1) and triosephosphate isomerase (TPI-1) was higher and the expression of Transgelin-2 (TAGLN2) was lower in metastatic tumors than in primary tumors. On the other hand, the expression of TPI-1 and TAGLN2 was lower in metastatic tumors than in primary tumors in cervical cancer. Immunohistochemistry confirmed that ENO1 expression was elevated in the metastatic tumors compared with the primary tumors. In conclusion, the present study showed that FFPE tissue-based proteomics analysis can be powerful tool, and these findings suggested that ENO1, TPI-1, and TAGLN2 may have a role in the development and progression of brain metastasis from gynecological malignancies.

Fertility issues should be addressed to all patients in reproductive age before cancer treatment. In men, cryopreservation of sperm should be offered to all cancer patients in reproductive age regardless of the risk of gonadal failure. In women, the recommendation of fertility preservation should be individualized based on multiple factors such as the urgency of treatment, the age of the patient, the marital status, the regimen and dosage of cancer treatment.

Background Patients with gynecologic cancer have a high risk of venous thromboembolism (VTE) like patients with other cancers. However, there is little information on risk factors for VTE during gynecologic surgery and no uniform preventive strategy. Our objectives were to identify risk factors for perioperative VTE in gynecologic patients and establish methods for prevention. Methods We analyzed 1,232 patients who underwent surgery at the Department of Obstetrics and Gynecology of St. Marianna University School of Medicine between January 2005 and June 2008. We investigated (1) risk factors for preoperative VTE, (2) use of an inferior vena cava (IVC) filter, and (3) risk factors for postoperative VTE. Results There were 39 confirmed cases of perioperative VTE (3.17%), including 25 patients with preoperative VTE and 14 with postoperative VTE. Thirty-two patients had cancer and seven patients had benign diseases. Twenty-two of the 32 cancer patients (68.7%) had preoperative VTE, while postoperative VTE occurred in 10 cancer patients. Multivariate analysis indicated that ovarian cancer, tumor diameter ≥10 cm, and previous of VTE were independent risk factors for preoperative VTE. Among ovarian cancer patients, multivariate analysis showed that an age ≥50 years, the presence of heart disease, clear cell adenocarcinoma, and tumor diameter ≥20 cm were independent risk factors for preoperative VTE. The factors significantly related to preoperative VTE in patients with benign disease included previous VTE, age ≥55 years, tumor diameter ≥20 cm, and a history of allergic-immunologic disease. Thirteen of the 25 patients (52%) with preoperative VTE had an IVC filter inserted preoperatively. Postoperative screening (interview and D-dimer measurement) revealed VTE in 14/1,232 patients (1.14%). Multivariate analysis indicated that cancer surgery, a history of allergic-immunologic disease, and blood transfusion ≥2,000 ml were independent risk factors for postoperative VTE. Conclusions Perioperative VTE is often fatal and preventive measures should be taken in the gynecologic field, especially when patients have the risk factors identified in this study. Since VTE is often present before surgery, preoperative screening is important and use of an IVC filter should be considered.