High rates of abnormalities in hysterosalpingography in couples with male factor infertility.

The rate of anatomical abnormalities in infertile couples with obvious male factor is unknown. For this purpose the authors retrospectively analyzed 376 hysterosalpingographies (HSG) of couples with severe male factor. Patients were subdivided into four groups according to the woman's age, and primary or secondary infertility: A--less than 35-years-old, primary infertility, B--less than 35-years-old, secondary infertility, C--35-years-old or more, primary infertility, and D--35-years-old or more, secondary infertility. Overall, abnormalities in HSG were demonstrated in 25.5% of the patients, and in 18, 21, 52, and 40 percent of patients in groups A, B, C and D, respectively. Age was found to be a significant independent risk factor (p < 0.05) while primary or secondary infertility was not. The adjusted odds ratio for woman who were 35-years-old or more to have any abnormalities in HSG were 3.7-fold greater (95% CI 2.2- 6.23), than women who were less than 35-years-old. In conclusion, relatively high rates of female mechanical abnormalities may be found even in infertile couples with obvious male factor and are significantly more prevalent in older women.

Temporal pattern of recurrence of stage I endometrial cancer in relation to histological risk factors.

OBJECTIVE: To study the temporal pattern of endometrial cancer recurrence in relation to histological risk factors in a large multicenter setting. METHODS: 843 patients with apparent stage I endometrial cancer were followed for a median time of 38 months, documenting all recurrences. Patients were stratified as high risk based on the presence of at least one of the established histological risk factors: high tumor grade, penetration to the outer half of the myometrium, lymphvascular space involvement, lower uterine segment involvement and non endometroid histology. Survival analysis, including Kaplan-Meier curves, log-rank tests and multi-variate Cox proportional hazard regression were used to evaluate the equality of recurrence-free distributions for different levels of risk. RESULTS: Recurrence was documented in 66 cases. The presence of one or more of the histological risk factors was associated with significantly shorter recurrence free survival, not attenuating over time (p < 0.001). Age-adjusted Cox regression model demonstrated a significantly decreased recurrence-free survival (HR = 2.8 95% CI 1.5, 5.1) in the presence of risk factors. CONCLUSIONS: In patients with stage I endometrial cancer, the presence of histological risk factors is associated with a significantly higher recurrence rate, which does not attenuate over follow up time. This may allow for a selective approach in the follow- up of endometrial cancer patients.

Serum retinol-binding protein-4 levels in polycystic ovary syndrome patients undergoing controlled ovarian hyperstimulation for in-vitro fertilization cycle.

AIMS: To determine serum retinol-binding rotein 4 (RBP-4) levels in polycystic ovary syndrome (PCOS) patients undergoing controlled ovarian hyperstimulation (COH) for an in vitro fertilization-embryo transfer (IVF-ET) cycle and the possible correlation to COH variables. PATIENTS AND METHODS: 11 consecutive PCOS patients undergoing our routine IVF flexible multidose gonadotropin-releasing hormone (GnRH)-antagonist protocol. Blood was drawn three times during the COH cycle: (1) day 1 or 2 of menstruation, and prior to gonadotropin administration (Day-S) (Day-S); (2) day of or prior to human chorionic gonadotropin (hCG) administration (Day-hCG); and (3) day of ovum pick-up (Day-OPU). Levels of estradiol and serum RBP-4 were compared among the three time points. Serum RBP-4 was measured with a commercial immunoassay. RESULTS: Results showed significantly lower levels of serum RBP-4 on Day-OPU and Day-hCG than on Day-S. Though significant correlations were observed between serum RBP-4 and body mass index, fasting glucose or glucose to insulin ratio, no correlations were found between serum RBP-4 and IVF treatment variables or pregnancy rate. CONCLUSION: While serum RBP-4 decreases during COH for IVF, there is apparently no correlation of serum RBP-4 levels with IVF treatment variables or outcome.

The possible influence of increased body mass index on the clinical efficacy of standard human chorionic gonadotropin dosage.

OBJECTIVES: To evaluate whether the efficacy of standard (10,000 IU) hCG dosage is BMI dependent. PATIENTS & METHODS: During the study period, body mass index (BMI) was recorded in 261 consecutive women enrolled in our ICSI program. Women in the 90th BMI percentile were compared with those in the 10th percentile. The number and percent of mature metaphase-II (M-II) oocytes were considered as the outcome measure. RESULTS: Mean BMI of the 10th and 90th percentile groups were 18.2 +/- 0.7 kg/m2 (n = 26) and 32.8 +/- 2.2 kg/m2 (n = 27), respectively. There were no differences between the groups in mean patients age, number of gonadotropin ampoules used, mean number of oocytes retrieved or the number and percentage of mature M-II oocytes. CONCLUSIONS: Standard (10,000 IU) hCG dosage is adequate to induce final oocyte maturation in IVF patients regardless of their BMI. This may imply that this hCG dosage is much higher than the dosage that is actually required.

A multicenter validation of computerized tomography models as predictors of non- optimal primary cytoreduction of advanced epithelial ovarian cancer.

AIMS: To compare the validity of four predictive models of preoperative computerized tomography (CT) scans in predicting suboptimal primary cytoreduction in patients treated for advanced ovarian cancer. PATIENTS AND METHODS: Preoperative CT scans of patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreductive surgery at one of four medical centers were reviewed by radiologists blinded to surgical outcome. The validity of each set of CT criteria previously published by Nelson, Bristow, Dowdy, and Qayyum as predictors of suboptimal cytoreduction was assessed. RESULTS: Data of 123 patients were evaluated. Optimal cytoreduction (largest diameter of residual tumor < or =1cm) was obtained in 90 (73.2%) patients. All CT models were able to significantly predict surgical outcome (p<0.02). The respective sensitivity, specificity, and accuracy of the CT models to predict sub-optimal cytoreduction was 64%, 64% and 64% for Nelson's criteria, 70%, 64% and 66% for Bristow's criteria, 79%, 60%, and 65% for Dowdy's criteria, and 67% 57% and 60% for Qayyum's criteria. CONCLUSIONS: Apart from Dowdy's criteria, the accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in this cross validation. This study underscores the difficulty in devising universally applicable selection criteria or models that reliably predict surgical outcome across institutions and surgeons.

The reproducibility of histological parameters employed in the novel binary grading systems of endometrial cancer.

OBJECTIVE: To compare the interobserver reproducibility and prognostic value of the FIGO grading system with the histological parameters employed in the various recently proposed binary grading systems of endometrial cancer. METHODS: Seventy two consecutive stage I endometrioid endometrial carcinomas from hysterectomy specimens were independently graded by two pathologists. Clinical data and outcome were obtained from the patients' records. The following histological parameters were evaluated: FIGO grade (dichotomized to grades 1 and 2 vs. grade 3), nuclear atypia, presence of more than 50% solid growth, diffusely infiltrative rather than expansive growth pattern, presence of tumor cell necrosis, and mitotic count. Interobserver agreement was measured by the kappa (k) statistics. Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard regression were used to evaluate the equality of survival distributions and to model the overall effects of the various predictor variables on survival. RESULTS: The interobserver reproducibility was as follows: FIGO grade, k=0.65; nuclear atypia, k=0.63; solid growth, k=0.51; infiltrative growth pattern, k=0.38; tumor necrosis, k=0.52; and mitotic index, k=0.44. In the comparison of the Kaplan-Meier curves, the following parameters were associated with a significantly poorer survival: FIGO grade 3, p=0.02; presence of more than 50% solid growth, p=0.01; and a high mitotic index, p=0.01. The other binary histological parameters were not significantly predictive of survival. CONCLUSIONS: The proposed novel binary grading parameters are not advantageous in terms of interobserver reproducibility and prognostic significance over dichotomization to FIGO grades 1 and 2 vs. grade 3. A simple binary grade based solely on presence of more than 50% solid growth has a comparable reproducibility and prognostic value.

Lower uterine segment involvement is associated with adverse outcome in patients with stage I endometroid endometrial cancer: results of a multicenter study.

OBJECTIVE: To quantify the relative risk associated with lower uterine segment involvement (LUSI) on outcome measures in patients with apparent stage I endometroid endometrial cancer. METHODS: A cohort of 769 consecutive patients with endometroid endometrial carcinoma apparent stage I, who underwent surgery in five gynecological oncology centers in Israel; 138 patients with and 631 without LUSI were followed for a median time of 51 months. Local recurrence, recurrence-free and overall survival were compared between the two groups. RESULTS: LUSI was associated with grade 3 tumor (p=0.002), deep myometrial invasion (p<0.001), and the presence of lymphvascular space involvement (p=0.01). There were 22 cases of local recurrences, 40 cases of distal recurrences and 80 patients died. Univariate survival analysis showed that patients with LUSI had trend toward lower regional recurrence-free survival (p=0.09), and significant lower distant recurrence-free survival (p=0.04) and lower overall survival (p=0.002). The Cox proportional hazards model demonstrated a significantly decreased overall survival (HR=2.3; 95% CI 1.3, 3.9; p=0.003) in cases with LUSI. CONCLUSIONS: In patients with apparent stage I endometroid endometrial cancer, the presence of LUSI is a poor prognostic factor, associated with a significantly higher risk of distal recurrence and death. The presence of LUSI warrants consideration when deciding upon surgical staging or postoperative management.

The outcome of patients with stage I endometrial cancer involving the lower uterine segment.

The objective of this study was to evaluate whether lower uterine segment involvement (LUSI) correlates with recurrence and survival in women with stage I endometrial adenocarcinoma and whether it is associated with poor prognostic histopathologic features. Three hundred seventy-five consecutive patients with endometrial carcinoma stage I compromised the study population. The patients were divided into two groups according to the presence of LUSI with endometrial carcinoma. The two groups were compared with regard to prognostic factors and outcome measures by using the Pearson chi(2) test, log-rank test, and Cox proportional hazards model. LUSI was present in 89 (24%) patients with stage I endometrial carcinoma. LUSI was significantly associated with grade 3 tumor (P = 0.022), deep myometrial invasion (P < 0.0001), and the presence of capillary space-like involvement (CSLI) (P = 0.003). Kaplan-Meier survival curves demonstrated that patients with LUSI had a lower recurrence-free survival (log-rank test; P = 0.009) and a worse overall survival (log-rank test; P = 0.0008). In the Cox proportional hazards model, only a trend toward higher recurrence rate (HR = 2.4, 95% CI 0.7, 8.2; P = 0.16) and a trend toward poorer overall survival (HR = 1.54, 95% CI 0.82, 2.91; P = 0.18) were noted when LUSI was present. In patients with stage I endometrial cancer, the presence of LUSI is associated with grade 3 tumor, deep myometrial invasion, and the presence of CSLI. A larger group of patients is necessary to conclude whether higher recurrence rate and poorer overall survival are associated with the presence of LUSI.

Early endometrial changes following successful implantation: 2 and 3-dimensional ultrasound study.

OBJECTIVE: To study of the possible role of ultrasound (US) measurements of the endometrium in the prediction of IVF outcome. PATIENTS AND METHODS: 28 infertile women underwent US measurements of endometrial thickness and volume on day of ET and two weeks later. US measurements were compared between day of ET and two weeks later, and between those who conceived and those who did not. RESULTS: While in the group of patients who conceived (n = 7) endometrial thickness and volume rose significantly between day of hCG and two weeks later, no differences were observed in patients (n = 21) who did not. CONCLUSION: The dynamic changes in endometrial volume and thickness between day of ET and two weeks later may predict IVF treatment outcome.

Luteal phase support for patients undergoing frozen-thawed embryo transfer cycles--the required progesterone dose.

OBJECTIVE: With the recent trend toward single-embryo transfer (ET), cryopreservation of extraneous embryos is becoming increasingly prevalent. Several replacement protocols for frozen-thawed ET exist, with no consensus regarding the dosage or delivery mode of progesterone. PATIENTS AND METHODS: Hormonal replacement with only estrogen and progesterone is the most frequently used protocol in women with and without functioning ovaries in our unit. Since August 2005, we have doubled the usual daily dose of progesterone for luteal support due to a high prevalence of patients experiencing withdrawal bleeding 11-13 days after ET. We compared the outcome of frozen-thawed ET cycles using different doses of progesterone for luteal support. RESULTS: While the prevalence of embryos that survived the thawing process was significantly higher in the earlier (69%) as compared to the later period (58%), positive b-hCG pregnancy rates (17.5% vs 44.8%, respectively) and clinical pregnancy rates per transfer (7.9% vs 41.4%, respectively) were significantly higher in the later period. CONCLUSION: We conclude that high-dose progesterone supplementation in the luteal phase of frozen-thawed ET cycles results in a significantly higher clinical pregnancy rate.

Lymphvascular space involvement compromises the survival of patients with stage I endometrial cancer: results of a multicenter study.

AIMS: To quantify the relative risk associated with lymphvascular space involvement (LVSI) on outcome measures in patients with apparent stage I endometrial cancer. METHODS: Six hundred and ninety nine consecutive patients with endometrial carcinoma apparent stage I, who underwent surgery in one of four gynecological oncology centers in Israel, comprised the study population. Forty cases with and 659 without LVSI were followed for a median time of 39 months. Recurrence free, disease specific and overall survival was compared between the two groups. The effect of LVSI, adjusted for other clinical and histo-pathological prognostic factors, was assessed by multivariate analysis. RESULTS: The univariate Kaplan-Meier procedure for survival analysis showed that patients with LVSI had lower recurrence free survival (p=0.0003), worse disease specific (p=0.0007) and overall survival (p<0.0001). Cox proportional hazards model demonstrated a trend toward shorter recurrence free survival (HR=2.0, 95% CI 0.9, 4.5; p=0.08), a worse disease specific survival (HR=2.8, 95% CI 1.1, 7.4; p=0.04) and decreased overall survival (HR=2.0, 95% CI 1.1, 3.8; p=0.03) in cases with LVSI. CONCLUSIONS: In patients with apparent stage I endometrial cancer the presence of LVSI, an independent poor prognostic factor, is associated with a two fold increased risk of death. The presence of LVSI warrants consideration when deciding upon post operative management.

GnRH agonist versus GnRH antagonist in ovarian stimulation: is the emperor naked?

OBJECTIVE: The aim of the study was to evaluate the influence of type of GnRH-analog used during controlled ovarian hyperstimulation (COH) on the outcome of in vitro fertilization (IVF) cycles. PATIENTS AND METHODS: All consecutive women aged < or = 35 years admitted to our IVF unit from January 2001 to December 2004 were enrolled in the study. Only patients undergoing up to their third IVF cycle attempt were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred, and clinical pregnancy rate were compared between women given GnRH-agonist or GnRH-antagonist during COH. RESULTS: Four hundred and eighty-seven consecutive IVF cycles were evaluated, 226 in the agonist group and 261 in the antagonist group. A clinical pregnancy was achieved in 93 patients in the agonist group (pregnancy rate 41.2% per cycle) and 66 patients in the antagonist grup (pregnancy rate 25.3%); this difference was statistically significant (p < 0.01). The agonist group also used significantly more gonadotropin ampoules, required longer stimulation, and had higher estradiol levels on the day of human chorionic gonadotropin administration. CONCLUSION: The midluteal long GhRH-agonist suppressive protocol should be the protocol of choice in young patients in their first three IVF cycle attempts.

Mild tricuspid regurgitation: a benign fetal finding at various stages of pregnancy.

OBJECTIVE: Tricuspid regurgitation (TR) may accompany various anatomical malformations and/or dysfunction of the fetal right heart. It may also appear in an anatomically healthy heart. With improved ultrasound modalities, more cases than the previously estimated prevalence of fetal TR in the low-risk population are being diagnosed. The objective of this study was to determine the prevalence of mild fetal TR in a low-risk obstetric population. METHODS: In 157 low-risk pregnant women (age range, 18-42 years) undergoing both early second-trimester and mid-trimester targeted organ scanning, including complete fetal echocardiography according to the five transverse planes technique, the apical four-chamber view was visualized using gray-scale, color Doppler and spatiotemporal image correlation (STIC) ultrasound modalities, with optimal acquisition parameters. RESULTS: Mild-to-moderate TR was discovered in the early second-trimester scan in 131/157 (83.4%) fetuses. No cases of cardiac malformation were found. All fetuses showed normal flow in the ductus venosus, including in one case diagnosed with moderate TR. Only in 39 (24.8%) cases was mild TR still evident at the second, mid-trimester scan. Neonatal echocardiography revealed mild TR in eight (5.1%) cases. No cases of chromosomal anomalies were detected. CONCLUSION: Mild TR is a benign finding of a temporal nature in early pregnancy.

Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching.

The development of the chorionic villous tree into a complex and organized ramified tubular network can be termed branching morphogenesis. Studying the molecular mechanisms involved in this process may contribute to the understanding of pregnancy complications such as preeclampsia. Sprouty (Spry) proteins are important regulators of branching morphogenesis and growth factor signaling. We analyzed the expression of Spry genes in human placenta. RT-PCR and immunohistochemistry were employed to detect placental Spry expression. Quantitative RT-PCR was used to assess the effect of FGF and reduced oxygen fraction on Spry gene expression. Spry 1, 2 and 3 expression was observed in placental tissue from all three trimesters. Our results reveal for the first time that Spry proteins are localized in the stroma of the chorionic villi, adjacent to cytotrophoblasts in areas of villous sprouting. Immunofluorescent double staining with anti-Spry and anti-CD68 confirmed that placental macrophages (Hofbauer cells) express Spry. Reduced oxygen fraction, FGF-4 and FGF-10 stimulated Spry-2 expression. Hofbauer cells also expressed c-Cbl, a protein that interacts with Spry. Placental expression of Spry and c-Cbl implies an important role for Hofbauer cells in placental development, possibly through a mesenchymal-epithelial interaction with trophoblasts. Regulation of Spry-2 expression by FGF-4 and FGF-10 suggests an orchestrated regulatory system that modulates villous branching.

Eph and ephrin expression in normal placental development and preeclampsia.

Eph receptors and their ephrin ligands play a fundamental role in embryogenesis. Their functions include cell targeting and angiogenesis. In placental development, trophoblasts migrate and invade maternal tissue and spiral arteries, where they play a role in both anchoring the placenta to the uterus and increasing blood flow to the developing fetus (interstitial and endovascular invasions). We investigated the cellular distribution and expression patterns of representative Eph and ephrin RNA and protein in an effort to identify the molecules involved in trophoblast migration during normal placental development and placental pathologies. We found ephrin-A1 expressed exclusively in the invasive extravillous trophoblast (EVT) cell lineage. We therefore proceeded to investigate ephrin-A1 in placental pathologies with defects in EVT invasion. In preeclampsia, where trophoblast invasion is shallow, we observed ephrin-A1 expression similar to normal placenta. Furthermore, in initial experiments on the deeply invading trophoblasts of placenta accreta, which lacks decidua, ephrin-A1 is found to be expressed highly in extravillous trophoblasts that have invaded the myometrium. In addition, we found the prototype ephrin-A1 receptor, EphA2, localized in several placental cell types. EphB4 and ephrin-B2 molecules, which have specific expression patterns during artery and vein development, respectively, were also expressed in the placenta. The cell specific distribution of ephrin-A1 suggests that it may play a role in targeting and migration of trophoblasts, and in the vascular remodeling induced by the invading extravillous trophoblasts. Failure of ephrin-A1 expression is unlikely to be the primary cause in defective migration of trophoblasts observed in preeclampsia. Specific roles for other Eph and ephrin proteins remain to be investigated.

Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9.

Trophoblast invasion, accompanied by degradation of extracellular matrix, is crucial to normal pregnancy development, whereas shallow placental invasion and implantation likely plays a role in the subsequent development of pre-eclampsia. The growth factors vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and fibroblast growth factor (FGF) are placental growth factors that activate degradation of extracellular matrix. We determined the effect of VEGF, EGF, FGF-2, FGF-4 and FGF-10 on the plasminogen activator system of first trimester cytotrophoblasts cultured in vitro. We studied the activity of urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor-1 (PAI-1), and 92 kDa gelatinase-B (matrix metalloproteinase-9, MMP-9), using protein gel and reversed gel zymography. The expression pattern of FGF-4 and FGF-10 in human placental sections was determined by immunohistochemistry. FGF-4 was expressed in first trimester villi stroma, primarily in endothelial cells. FGF-10 expression was localized to first trimester extravillous trophoblasts. VEGF, EGF, FGF-4 and FGF-10, but not FGF-2, stimulate the activity of trophoblast uPA, PAI-1 and MMP-9. These results support the hypothesis that specific growth factors modulate the invasive potential of trophoblasts, and therefore may play an important role in early placental development. Our findings may contribute to the understanding of the pathophysiology of diseases associated with shallow placentation, such as pre-eclampsia.

Fetal supraventricular tachycardia diagnosed and treated at 13 weeks of gestation: a case report.

Supraventricular tachycardia (SVT) is the most commonly encountered clinically significant tachycardia in the fetus. When SVT is sustained, congestive heart failure and fetal hydrops may ensue, due to both systolic and diastolic dysfunction. Sonographic diagnosis is usually incidental during the second or third trimester. Treatment goals are cardioversion to sinus rhythm and reversal of cardiac dysfunction. We describe a case of fetal SVT diagnosed at 13 weeks of gestation. Treatment with digoxin and flecainide was successful; the heart rate returned to sinus rhythm within one day, and fetal hydrops resolved within 8 days of treatment. We suspect that as more first-trimester examinations are performed, more cases with SVT will be diagnosed. We discuss the treatment protocol, and suggest that co-administration of two drugs that act synergistically may be more efficient than monotherapy, which is currently used as the first line of treatment. In addition, we discuss the potentially deleterious effect of heart failure encountered at an early developmental stage on the central nervous system. More data need to be collected in order to substantiate a clear recommendation regarding optimal management.

Prenatal ultrasonographic diagnosis of atypical Nonne-Milroy lymphedema.

Nonne-Milroy lymphedema is a relatively rare disorder characterized by firm edema of the lower extremities either on the whole leg or limited to the feet or toes. We report a case of atypical Nonne-Milroy syndrome that presented prenatally with bilateral leg edema, bilateral hydrothorax and lung hypoplasia at 22 weeks' gestation. The differential diagnoses are discussed.