TCDD induces the hypoxia-inducible factor (HIF)-1α regulatory pathway in human trophoblastic JAR cells.

The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development.

Endocrine disruptor, dioxin (TCDD)-induced mitochondrial dysfunction and apoptosis in human trophoblast-like JAR cells.

The endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to disrupt hormone signalling, reduce fertility, interfere with embryo development and cause spontaneous miscarriage in humans. The precise mechanisms of its effects on early implantation in humans are still unclear. In this study, we examined the relationship between mitochondrial function and dioxin-induced toxicity in JAR cells, a human trophoblast-like cell line. Several experiments were performed to address the effects of TCDD on cell viability, reactive oxygen species (ROS) generation, oxidative damage (indicated by the presence of lipoperoxides and oxidized DNA bases), mitochondrial DNA (mtDNA) copy number, ATP content, mtDNA mutations and the protein levels of p53, Bax, Bcl2, cytochrome c and caspase 3. Increased oxidative damage and mitochondrial dysfunction in TCDD-treated trophoblast-like cells was demonstrated. A 2.58-fold increase in lipid peroxides was detected in cells treated with 2 nM TCDD for 4 h. The oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine was significantly increased by TCDD treatment in a time-dependent manner. Meanwhile, reductions in mtDNA copy number and ATP content and an increase in mtDNA deletions were found. Furthermore, we observed increased apoptosis, p53 accumulation, Bax overexpression, cytochrome c release and sequential caspase 3 activation after TCDD exposure. These results indicate that oxidative damage and mitochondrial dysfunction may be responsible for the apoptotic effects of TCDD.

Should cystoscopy be routinely performed after laparoscopy-assisted vaginal hysterectomy?

This study was undertaken to determine the usefulness of routine intra-operative cystoscopy in documenting ureteral patency after laparoscopy-assisted vaginal hysterectomy (LAVH). There were eighty patients who underwent LAVH for benign tumors of the uterus (adenomyosis and myoma), uterine prolapse, persistent intraepithelial neoplasm of the cervix (CIN3) and cervical carcinoma in situ (CIS). Intra-operative cystoscopy with ureteral stenting was performed at the time of LAVH to evaluate the urinary tract. From among the 80 patients who underwent LAVH, 52 had myoma, 19 had adenomyosis, six patients had uterine prolapse, one had CIS and seven patients were diagnosed to have CIN3. Cystoscopy discovered one unsuspected bladder injury. Hematuria was the immediate complication caused by intraoperative cystoscopy. It was observed in ten patients. Urinary tract evaluation, including cystoscopy and ureteral stenting at the time of complex gynecologic surgery such as LAVH could be incorporated in the whole surgical procedure. It decreases morbidity associated with unrecognized injury.

Total laparoscopic hysterectomy (TLH) versus coagulation of uterine arteries (CUA) at their origin plus total laparoscopic hysterectomy (TLH) for the management of myoma and adenomyosis.

We tried to evaluate the relative feasibility, surgical duration and complications of total laparoscopic hysterectomy (TLH) versus coagulation of uterine arteries at their origin (CUA) plus total laparoscopic hysterectomy for the management of myoma and adenomyosis, and to compare the estimated blood loss for both procedures. A total of 123 patients underwent TLH or CUA plus TLH for the treatment of symptomatic myoma and adenomyosis. Sixty-four women underwent TLH, whilst 68 women underwent coagulation of uterine arteries at their origin plus TLH. The mean weight and volume of the uterus as determined following TLH was 288.1+/-102.4 gm (range 182.1 approximately 396.2 gm.) and 451+/-340.6 cm(3) (range 107.4 approximately 792), respectively. The mean weight of the uterus following CUA plus TLH was 269.1+/-151.7 gm (range 215.8 approximately 430.1) whilst the mean uterine volume was 472.7+/-377.8 cm(3) (range 93.7 approximately 851.2). No significant differences with respect to surgical duration (95 vs. 96.5 minutes TLH vs. CUA + TLH; p>0.05), blood loss (177.2+/-80.1 ml for TLH and 154.9+/-30.21 ml for CUA+TLH; p>0.05) and mean+/-SD preoperative (12.05+/-1.70 gm/dl for TLH and 12.14+/-1.38 gm/dl for CUA+TLH; p>0.05) and post-operative hemoglobin level (11+/-1.03 for TLH and 11+/-1.49 for CUA + TLH; p>0.05) were observed between the two study groups. The blood loss for TLH is comparable to that for the CUA plus TLH procedure.

Oxidative damage and mitochondrial DNA mutations with endometriosis.

Endometriosis, a frequently encountered disease in gynecology, is a considerable threat to the physical, psychological, and social integrity of women. Moreover, up to 50% of infertile patients have this disease. The etiology and pathogenesis of this important disease are poorly understood; it is defined as an ectopic location for endometrium-like glandular epithelium and stroma outside of the uterine cavity. It still remains an open question as to what extent the peritoneal environment influences the establishment and/or progression of endometriosis. As a result of such stress, a sterile, inflammatory reaction with the secretion of growth factors, cytokines, and chemokines is generated, which is especially deleterious to successful reproduction. Significantly higher amounts of oxidative damage were detected in endometriotic lesions than in controlled normal endometrium, including mitochondrial DNA (mtDNA) rearrangement, 8-OH-deoxyguanosine (8-OH-dG), and lipoperoxide contents. There were approximately sixfold increases in 8-OH-dG and lipoperoxides in chocolate cysts compared with normal endometrial tissues. A novel 5,335-bp deletion of mtDNA was identified in endometriotic tissue. According to these results, we propose that oxidative stress and mtDNA mutations might be anticipated in the initiation or progression of endometriosis. Only by understanding the mechanisms involved in the pathogenesis of endometriosis can we develop a basis for new diagnostic and therapeutic approaches.

Effects of standardized phytoestrogen on Taiwanese menopausal women.

OBJECTIVE: To investigate the effects of standardized soy extract on climacteric symptoms, lipid profiles, bone markers, and serum isoflavone concentration in healthy Taiwanese postmenopausal women. MATERIALS AND METHODS: A multicenter, open-labeled, randomized, prospective, comparative study design was used. A total of 130 outpatients who had undergone natural menopause were randomly administered either 70 mg or 35 mg soy extract daily for 24 weeks. RESULTS: The evidence suggests that the soy extract treatment that was administered to both groups for 1 month could help reduce climacteric scores (reductions of 19.66% [p<0.01] and 18.85% [p<0.01] in the 35 mg and 70 mg groups compared with baseline, respectively), and the efficacy was more potent after 6 months of treatment. Soy isoflavone significantly reduced the total cholesterol (reductions of 4.50% [p<0.01] and 3.06% [p<0.05] in the 35 mg and 70 mg groups, respectively) and low density lipoprotein cholesterol levels (reductions of 4.67% [p<0.05] and 5.09% [p<0.05] in the 35 mg and 70 mg groups, respectively) in patients with total cholesterol > 200 mg/dL after 6 months of treatment. In patients with high bone turnover (urinary deoxypyridinoline/creatinine > 7.4 nM/mM), soy extract treatment reduced the deoxypyridinoline/creatinine level by 10.53% (p<0.05) and 11.58% (p<0.05) in the 35 mg and 70 mg groups, respectively. Serum levels of isoflavone increased in both groups after 6 months of treatment. CONCLUSION: Soy extract is highly efficacious at relieving menopausal symptoms and demonstrates a positive effect on the cardiovascular system and skeleton.

Laparoscopic management of complicated adnexal masses in the first trimester of pregnancy.

OBJECTIVE: To describe our experiences with laparoscopic management of complicated adnexal masses in the first trimester of pregnancy. DESIGN: Retrospective clinical study. SETTING: A teaching hospital. PATIENT(S): Eleven patients with singleton pregnancy who underwent laparoscopic operation for complicated benign adnexal mass during their first trimester. INTERVENTION(S): Laparoscopic surgery for complicated adnexal masses. MAIN OUTCOME MEASURE(S): Technical feasibility and safety. RESULT(S): All of the patients had an uneventful recovery. Pregnancy was continued to term in nine patients (81.1%). Two patients (18.2%) had ongoing pregnancy at the time of writing. CONCLUSION(S): Operative laparoscopy for complicated adnexal masses performed during early pregnancy is safe and feasible.

Relationship of progesterone/estradiol ratio on day of hCG administration and pregnancy outcomes in high responders undergoing in vitro fertilization.

OBJECTIVE: To evaluate the predictive value of a serum P/E(2) ratio measured on the day of hCG administration regarding pregnancy outcomes in high responders undergoing IVF. DESIGN: Retrospective study. SETTING: Teaching hospital. PATIENT(S): Two hundred twenty-three infertile women classified as high responders in IVF-ET cycles. INTERVENTION(S): Eligible infertile women undergoing IVF were assigned to four groups according to serum P levels on the day of hCG administration: group 1, P2.0 ng/mL. The relationship of E(2) level and P/E(2) ratio on the day of hCG administration and pregnancy outcomes was analyzed. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rate. RESULT(S): Patients in group 4 had highest E(2) level and P/E(2) ratio, as well as lowest implantation and pregnancy rates. Using P for grouping, the sensitivity/positive predictive values (%/%) of P/E(2) ratio in the four groups were 15/66, 30/65, 30/60, and 25/41, respectively. CONCLUSION(S): Using the level of a single sex hormone on hCG day to predict pregnancy outcome in high responders undergoing IVF is confounding, whereas using a P/E(2) ratio on hCG day is theoretically reasonable. However, the low sensitivity and positive predictive value make the use of P/E(2) clinically unfeasible.

An increased serum progesterone-to-estradiol ratio on the day of human chorionic gonadotropin administration does not have a negative impact on clinical pregnancy rate in women with normal ovarian reserve treated with a long gonadotropin releasing hormone agonist protocol.

OBJECTIVE: To evaluate the relationship between serum P:E(2) ratio on the day of hCG administration and the clinical outcomes in infertile women with normal ovarian reserve treated with a long GnRH agonist (GnRH-a) protocol. DESIGN: Retrospective analysis of IVF-embryo transfer data. SETTING: University teaching hospital. PATIENT(S): One hundred thirty-nine infertile women with normal ovarian reserve, who received IVF-embryo transfer with a long GnRH-a protocol. INTERVENTION(S): Cycles were grouped according to whether premature luteinization (PL) appeared on the day of hCG administration. Premature luteinization was defined as a P:E(2) ratio >or=1.2 by using receiver operator characteristic analysis. MAIN OUTCOME MEASURE(S): Treatment cycle hormonal characteristics and clinical outcomes. RESULT(S): The P:E(2) ratio on the day of hCG administration was significantly higher in the PL (n = 41) compared with the non-PL (n = 98) group (2.4 +/- 1.5 and 0.6 +/- 0.3, respectively). The mean number of oocytes retrieved in the PL and non-PL groups were 4.2 +/- 2.8 and 12.7 +/- 6.6, respectively. However, the difference between the clinical pregnancy rates (PR) in the PL and non-PL groups was not statistically significant (29.3% vs. 34.5%). In a logistic regression analysis, the P:E(2) ratio showed no statistically significant correlation with pregnancy outcome. CONCLUSION(S): The increased serum P:E(2) ratio on the day of hCG administration, as an indicator of PL, has a poor predictive value on IVF outcomes in infertile women with normal ovarian reserve treated with a long GnRH-a protocol.

The influence of abdominal ultrasound-guided embryo transfer on pregnancy rate: a preliminary report.

To determine whether the use of abdominal ultrasound-guided embryo transfer improves the clinical pregnancy rate in patients undergoing in vitro fertilization, 50 fresh cycles with day 3 embryo transfer were studied; 27 patients were randomized to ultrasound-guided transfers, and 23 patients were randomized to clinical touch transfers. Although the clinical pregnancy rate was not statistically different (18.5% in the ultrasound-guided group vs. 17.4% in the clinical touch group), the use of abdominal ultrasound during the embryo transfer procedure provided a greater degree of confidence and satisfaction to both patients and physicians.

Low maternal serum levels of pregnancy-associated plasma protein-A during the first trimester are associated with subsequent preterm delivery with preterm premature rupture of membranes.

OBJECTIVE: To assess the relationship between the first-trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels and pregnancies complicated by preterm delivery. MATERIALS AND METHODS: The correlation between PAPP-A levels and gestational age at delivery was analyzed by linear regression. The probabilities of low PAPP-A multiples of the median (MoM) levels between preterm delivery and control population were analyzed by logit model. RESULTS: A positive correlation was noted between the first-trimester PAPP-A MoM levels and gestational age at delivery between 34-38 weeks (p < 0.001). Lower PAPP-A MoM level had a significantly higher likelihood of preterm delivery (p < 0.05). When preterm premature rupture of membranes (PPROM) and preterm labor (PTL) were analyzed separately, there was an increasing likelihood of PPROM with decreasing PAPP-A MoM levels (p < 0.05), but not for PTL with intact membranes. CONCLUSION: Low maternal serum PAPP-A levels during the first trimester may reflect a trophoblast invasion defect in the maternal-fetal interface, resulting in subsequent preterm delivery, particularly in those of PPROM.

Large cell neuroendocrine carcinoma of the uterine cervix associated with adenocarcinoma.

OBJECTIVE: Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive cervical neoplasm. In the present study, we present a 45-year-old woman with large cell neuroendocrine uterine cervical carcinoma with coexisting adenocarcinoma. CASE REPORT: A 45-year-old G2 P0 presented with vaginal bleeding for 7 months. On pelvic examination, a polypoid mass of the cervix was discovered. Biopsy of the lesion revealed large cell neuroendocrine carcinoma of the cervix. The patient underwent a radical hysterectomy, and then received concurrent chemotherapy and radiation therapy. She has remained disease free until the time of this writing. CONCLUSION: Patients with LCNEC of the cervix have had poor prognoses; hence aggressive multimodality treatment is recommended.

Laparoscopic electrodessication of an interstitial pregnancy.

OBJECTIVE: To report on the case of a woman who presented with lower abdominal pain and vaginal bleeding, and who was diagnosed with early interstitial pregnancy. DESIGN: Case report. SETTING: Medical center and teaching hospital. PATIENT: A 32-year-old woman with a previous history of ectopic pregnancy. INTERVENTION(S): Imaging study with ultrasonography and laparoscopy. MAIN OUTCOME MEASURE(S): Complete resolution of the ectopic pregnancy at the interstitial site of the amputated fallopian tube, and resumption of menstruation. RESULT(S): Other causes of internal bleeding were ruled out. Menstruation resumed 30 days after the procedure. CONCLUSION: An early interstitial pregnancy may be successfully managed with laparoscopic electrodessication.

Torsion of a uterine leiomyoma.

OBJECTIVE: To report a case of torsion of a pedunculated uterine leiomyoma. CASE REPORT: A 38-year-old female virgin presented at the emergency department with complaints of severe lower abdominal pain on November 30, 2005. A transabdominal sonogram revealed multiple uterine masses, including a pedunculated mass. With a preoperative diagnosis of torsion of a pedunculated subserosal leiomyoma, the patient underwent an abdominal myomectomy. On gross inspection, the resected myoma was ischemic, and both focal hemorrhage and necrosis were noted in the pathology report. CONCLUSION: Torsion of a pedunculated uterine myoma is rare but represents a surgical emergency to improve symptoms and avoid consumptive coagulopathy.

Sonographic appearance of fallopian tube carcinoma.

Fallopian tube carcinoma is the least common of gynecological malignancies. We report the case of a 56-year-old woman who presented with a 2 1/2-year history of intermittent vaginal bleeding and lower abdominal pain. Transvaginal sonography revealed a cystic lesion of the fallopian tube with papillary projections, distinct from the ovary and uterus. Doppler examination showed low vascular impedance (resistance index 0.50, pulsatility index 0.80). The suspicion of tubal malignancy was confirmed at surgery.

Primary peritoneal carcinosarcoma (malignant mixed mullerian tumor): Report of a case with five-year disease free survival after surgery and chemoradiation and a review of literature.

Malignant mixed mullerian tumors (MMMTs), also known as carcinosarcoma because they contain both carcinomatous and sarcomatous elements are aggressive tumors, which usually arise in the uterus and ovary. Extragenital carcinosarcomas are extremely rare and most cases develop from the peritoneum. To our knowledge, only 29 cases have been described in English literature. Here we report a case of a primary carcinosarcoma of the pelvic peritoneum with five-year disease-free survival after managing the patient with surgery, chemotherapy and radiotherapy.

Prevalence of cervical human papillomavirus in Taiwanese women.

PURPOSE: To define the prevalence rate of cervical human papilloma virus (HPV) using DNA oligonucleotide microarray and its correlation with risk factors in Taiwanese women in metropolitan Taipei. METHODS: Thirteen hundred and twenty healthy women, aged 21 - 65 yr without history of cervical intraepithelial neoplasia (CIN) or carcinoma were included in this prospective study. Pap smear and HPV typing using oligonucleotide microarray were performed for each woman. They were given a standardized questionnaire to obtain information about the risk factors of cervical cancer in Taiwan. RESULTS: The overall HPV positivity was 19.85% and multiple infections were found in 35.84% of the infected group, 7.92% of the whole study population. The younger the subject, the higher was the infection rate and multiple infection rates. The most common HPV types were 16, 18, 58, 52, 51 and 56, which is different from the western world. The sensitivity of the HPV DNA chip in detecting CIN and cervical carcinoma is 97.06%, and 100% in detecting CIN 2 or more lesions. Risk factors for HPV infection include earlier coitarche (P < 0.01), multiple sexual partners (P < 0.05), history of sexually transmitted disease (P < 0.05), two or more vaginal deliveries (P < 0.05) and infrequent use of condoms (P < 0.05). The association between oral contraception or cigarette smoking and HPV infection could not be determined because few women smoke or used oral contraception. There was no relationship between induced abortion and HPV infection. CONCLUSIONS: About one-fifth of adult women in metropolitan Taipei were cervical HPV positive. The popular HPV types and the risk factors of HPV infection in metropolitan Taipei are not the same as those in the western world. The sensitivity of the HPV DNA chip in detecting cervical neoplasia is very high.

First-trimester screening for Down syndrome in singleton pregnancies achieved by intrauterine insemination.

PURPOSE: To evaluate whether achieving a singleton pregnancy by IUI affects the results of first-trimester screening for Down syndrome compared to naturally conceived pregnancy. METHODS: Forty-nine IUI and 3059 naturally conceived singleton pregnancies were included in the study. Ovulation in IUI pregnancies was induced by clomiphene and human menopausal gonadotropin. Progesterone was given after insemination for 2 weeks. Down syndrome screening was performed using a combination of maternal age, fetal nuchal translucency, and maternal serum concentrations of free beta-hCG and PAPP-A during the period of 10-14 weeks' gestation. RESULTS: In IUI pregnancies, nuchal translucency thickness and the levels of PAPP-A were significantly higher. The values of free beta-hCG were not statistically different between the two groups. The screen-positive rate in IUI pregnancies was significantly higher (14.3% vs. 7.1%). CONCLUSIONS: Singleton pregnancies achieved by IUI have a higher screen-positive rate. Not only elder maternal age but also exogenous hormones given during the process of ovulation induction and after conception may play an important factor influencing positive screening results.

Pregnancy outcomes in unselected singleton pregnant women with an increased risk of first-trimester Down's syndrome.

BACKGROUND: The purpose of this study was to assess outcomes in pregnancies with a positive screen of first-trimester combined test (nuchal translucency, pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin). METHODS: Using a cut-off level of 1 in 270, 216 (7.1%) women had a positive screen. Among them, 187 delivered their babies in our hospital and the adverse outcomes, such as spontaneous abortion, intrauterine fetal demize, preterm prelabor rupture of the membranes, preterm labor, intrauterine growth restriction, gestational hypertensive disorders, placenta previa, chromosomal abnormalities and fetal structural anomalies, were identified and compared with the 2097 women who screened negative for Down's syndrome. RESULTS: Pregnancies with a positive screen had a significantly higher risk of adverse outcomes than those with negative screens (30.5% versus 15.3%; odds ratio 2.4; p < 0.001), especially for those complicated by spontaneous abortion (odds ratio 11.4; p < 0.05) and placenta previa (odds ratio 4.3; p < 0.05). CONCLUSIONS: Besides fetal chromosomal abnormalities and structural abnormalities, pregnancies with a positive screen for Down's syndrome in the first-trimester had a significantly higher incidence of subsequent adverse obstetric outcomes.