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Background Physicians of the Spanish Influenza Sentinel Surveillance System report and systematically swab patients attended to their practices for influenza-like illness (ILI). Within the surveillance system, some Spanish regions also participated in an observational study aiming at estimating influenza vaccine effectiveness (cycEVA study). During the season 2009-2010, we estimated pandemic influenza vaccine effectiveness using both the influenza surveillance data and the cycEVA study. Methods We conducted two case-control studies using the test-negative design, between weeks 48/2009 and 8/2010 of the pandemic season. The surveillance-based study included all swabbed patients in the sentinel surveillance system. The cycEVA study included swabbed patients from seven Spanish regions. Cases were laboratory-confirmed pandemic influenza A(H1N1)2009. Controls were ILI patients testing negative for any type of influenza. Variables collected in both studies included demographic data, vaccination status, laboratory results, chronic conditions, and pregnancy. Additionally, cycEVA questionnaire collected data on previous influenza vaccination, smoking, functional status, hospitalisations, visits to the general practitioners, and obesity. We used logistic regression to calculate adjusted odds ratios (OR), computing pandemic influenza vaccine effectiveness as (1-OR)*100. Results We included 331 cases and 995 controls in the surveillance-based study and 85 cases and 351 controls in the cycEVA study. We detected nine (2.7%) and two (2.4%) vaccine failures in the surveillance-based and cycEVA studies, respectively. Adjusting for variables collected in surveillance database and swabbing month, pandemic influenza vaccine effectiveness was 62% (95% confidence interval (CI): -5; 87). The cycEVA vaccine effectiveness was 64% (95%CI: -225; 96) when adjusting for common variables with the surveillance system and 75% (95%CI: -293; 98) adjusting for all variables collected. Conclusion Point estimates of the pandemic influenza vaccine effectiveness suggested a protective effect of the pandemic vaccine against laboratory-confirmed influenza A(H1N1)2009 in the season 2009-2010. Both studies were limited by the low vaccine coverage and the late start of the vaccination campaign. Routine influenza surveillance provides reliable estimates and could be used for influenza vaccine effectiveness studies in future seasons taken into account the surveillance system limitations.

SETTING Tuberculosis (TB) control requires accurate knowledge of TB incidence, but few studies have been published on TB incidence using individual data from drug prescriptions. OBJECTIVE To measure the estimated completeness of regional surveillance system data before and after adding data from anti-tuberculosis drug prescriptions. DESIGN We compiled data on all individuals who received specific anti-tuberculosis drugs from three sources-the passive surveillance system, the active surveillance system and the anti-tuberculosis drug prescription database-in the Balearic Islands, Spain, between 2010 and 2012. We applied the capture-recapture method to measure completeness of data reporting. Statistical significance was set at P < 0.05, and 95% confidence intervals (CIs) were calculated. RESULTS We detected 605 incident cases, compared with an estimated incidence of 719 cases (95%CI 646-793), representing 84.1% data completeness. We detected 480 of an estimated 559 pulmonary TB cases (95%CI 501-617; 85.9% data completeness) and 125 of an estimated 161 extra-pulmonary TB cases (95%CI 113-211; 77.6% data completeness). CONCLUSIONS By adding a new source, we increased detection with respect to a previous study by 10.4% for all forms of TB, 9.7% for pulmonary TB and 13% for extra-pulmonary TB.

Resumen Objetivo Evaluar la efectividad del Test Combinado (bioquimica y ecografia en el primer trimestre) para la deteccion prenatal del syndrome de Down en la poblacion general. Material y metodos Se determinaron los marcadores bioquimicos de primer trimester (proteina plasmatica A asociada al embarazo y fraccion β libre de la gonadotropina corionica) en suero materno a las 7-12 semanas. La translucencia nucal fetal y la edad gestacional se determinaron mediante ecografia a las 10-14 semanas. Se estimo el riesgo combinado el mismo dia de la ecografia y se ofrecio el diagnostico citogenetico mediante biopsia de corion si el riesgo era de 1:250 o superior. Resultados La edad gestacional media en la determinacion bioquimica fue de 9,5 semanas y de 12,1 para la ecografia. En las 4.447 gestaciones estudiadas con seguimiento completo, los indices de deteccion fueron del 91% (10/11) para la trisomia 21 y del 83% (5/6) para la trisomia 18 o 13, con una tasa de falsos positivos del 3,8% (167/4.423). Conclusion El Test Combinado, al determinar los valores de marcadores bioquimicos y de translucencia nucal en intervalos gestacionales optimos durante el primer trimestre, mostro una tasa de deteccion del 91% para la trisomia 21 con una reduccion en la tasa de falsos positivos al 3,8%.

The aim of this study was to evaluate the frequency of false-negative (FN) sentinel node procedures in patients with breast cancer and the subsequent clinical outcome in such patients.A total of 325 breast cancer patients underwent sentinel lymph node biopsy at our institution between June 1998 and May 2004. A 2-day protocol was used to localise the sentinel node with the injection of 99mTc-nanocolloid. There were two phases in the study: the learning phase (105 patients) and the application phase (220 patients). In the learning phase, a complete lymphadenectomy was always performed. In the application phase, sentinel nodes were studied intraoperatively and lymphadenectomy was performed when considered warranted by the pathological intraoperative results.The median follow-up duration in the 220 patients studied during the application phase was 21.2 months (range 4-45 months). In this phase a total of 427 sentinel nodes were obtained (range 1-5 per patient, median 1.99), with 66 positive sentinel nodes in 56 patients (26%). The lymphadenectomies performed were also positive in 25% of cases (14 patients). We observed a total of two false-negative sentinel lymph node results (3.45%). One of them was found during the surgical excision of non-sentinel nodes, and the other presented as an axillary recurrence 17 months postoperatively (1.72% clinical false-negative rate). The latter patient died 1 year after the first recurrence.After a median follow-up of 21.2 months we observed only one clinical recurrence among 220 patients. Our results indicate that adequate local control is achieved by application of the sentinel node protocol.

Nuchal translucency (NT) is defined as the accumulation of subcutaneous fluid in the nuchal region of the fetus at 11–14 weeks. Its measurement in order to modify the previous background risk has been proved to be able to detect around 70% of trisomy 21 pregnancies (for a 5% fixed positive rate). When affected fetuses dying before 20 weeks are excluded, detection rate may decrease to 60%. Given that appropriate training of sonographers and adherence to a standard technique for the measurement of NT is of paramount importance to reduce variability, the Fetal Medicine Foundation has established a certification process. Fetal nuchal edema displayed at 15–20 weeks was described as enlarged nuchal skinfold, and is a less sensitive but more specific marker than nuchal translucency. Webbing of the neck in infants with trisomy 21 may be envisaged as the remainder of nuchal distension.

Objective To evaluate the effectiveness of the addition of first-trimester biochemistry to fetal nuchal translucency (NT) measurement in the Combined Test when screening for trisomy 21 in twin pregnancies. Methods Maternal serum free β-hCG and PAPP-A were determined at 8 to 12 weeks and fetal NT was measured at 11 to 14 weeks. The individual risks were estimated for each of the fetuses using both NT screening alone and the Combined Test. An invasive diagnostic procedure was offered when the risk was 1:250 or over in either one of the fetuses. In the first period, only the results of NT screening were clinically applied. After previous analysis, the Combined Test was introduced into clinical practice. Results In the two-and-a-half-year study period, a complete follow-up was obtained in 100 twin pregnancies. Three fetuses (two pregnancies) with trisomy 21 were detected by both methods. The false-positive rate achieved by NT screening (14.3% of pregnancies and 8.6% of fetuses) was substantially reduced when first-trimester biochemistry was added in the Combined Test (5.1% of pregnancies and 3.6% of fetuses). Conclusion The Combined Test appears to maintain the detection rate achieved by NT screening for trisomy 21 in twin pregnancies, but false-positive rates and invasive diagnostic procedures are reduced. Copyright © 2005 John Wiley & Sons, Ltd.

Objective To construct normal ranges for umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI) and cerebroplacental ratio (CPR) in prolonged pregnancies according to strict methodological criteria using polynomial regression analysis. Methods This was a retrospective, cross-sectional observational study involving 140 women, 10 women for each gestational day between 287 and 300 days of gestation. Fetal Doppler parameters were assessed to construct normal reference ranges for UA PI and MCA PI. CPR was calculated as a ratio of MCA PI/UA PI. Results Mathematical modeling of the data demonstrated that the optimal fit was a linear polynomial one. Mean, 5th and 95th centiles were calculated for UA, MCA and CPR and centile curves from the regression analysis were constructed. Conclusions Reference ranges for UA PI, MCA PI and CPR in prolonged pregnancies have been constructed. MCA PI shows a wider range than previously reported in the literature. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.

Objectives To assess the value of middle cerebral artery Doppler indices obtained from different sampling sites in predicting umbilical cord gases at delivery in prolonged pregnancies. Methods This was a prospective study of consecutive pregnant women referred for prolonged-pregnancy surveillance. The predictive value of distal and proximal middle cerebral artery Doppler indices for cord blood gases was evaluated in women who delivered within 48 h of their last antenatal test using stepwise multiple regression. Results There was a significant linear correlation between proximal and distal middle cerebral artery pulsatility indices (R = 0.777; P < 0.0001), the mean values being 1.49 (SD, 0.45) and 1.56 (SD, 0.47), respectively. There was also a linear correlation between proximal and distal cerebroplacental ratios (R = 0.68; P < 0.0001), the mean values being 1.85 (SD, 1.96) and 1.92 (SD, 1.89), respectively. The stepwise multiple regression analysis for umbilical artery pH showed that once the distal middle cerebral artery pulsatility index was introduced into the model, the addition of any variable did not result in a significant improvement of the predictive capacity. The model showed a coefficient of determination (R2) of 0.079. There was a significant correlation between umbilical artery pO2 and both proximal middle cerebral artery pulsatility index (positive) and the occurrence of elective Cesarean section (negative). This model accounted for 21% of the variance (R2 = 0.21). No other variables added any significant prediction for pO2. Conclusions In post-term pregnancies the proximal middle cerebral artery pulsatility index significantly predicts umbilical artery pO2 at delivery but does not predict pH. There is a weak association between distal middle cerebral artery pulsatility index and pH but, as this only explains 8% of the variance, it is of little clinical value. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.

Objective To assess the effectiveness of the Combined Test in the prenatal detection of trisomy 21 in the general pregnant population using a new timing for the screening approach. Methods First-trimester maternal serum biochemical markers (pregnancy-associated plasma protein-A and free-β hCG) were determined in maternal serum at 7 to 12 weeks. Fetal nuchal translucency and gestational age were assessed at the 10- to 14-week ultrasound scan. A combined risk was estimated and delivered to the women the same day. When the risk was 1:250 or above, chorionic villus sampling was offered. Results Mean gestational age at biochemistry was 9.4 weeks, being 12.3 at ultrasound. In the 2780 studied pregnancies with a complete follow-up, observed detection rates were 88% (7/8) for trisomy 21 and 75% (3/4) for trisomy 18, with a 3.3% (92/2765) false-positive rate. Conclusion The Combined Test, assessing biochemistry and ultrasound at individually optimal ages in the first trimester, showed an 88% detection rate for trisomy 21 with a remarkably reduced false-positive rate (3.3%). Copyright © 2004 John Wiley & Sons, Ltd.

Resumen Objetivo Conocer la incidencia de polipos endometriales malignos en funcion del estado hormonal, la presencia o no de hemorragia uterina anormal (HUA), el uso de tamoxifeno (TMX) y de terapia hormonal sustitutiva (THS). Material y metodos Se analizan 1.822 polipectomias histeroscopicas. Tomaban THS 85 pacientes y TMX, 150. Resultados Los polipos de pacientes premenopausicas presentan mas HUA que los de las posmenopausicas. Se hallaron 16 polipos histologicamente malignos (0,87%). De estos, 14 se extirparon a pacientes posmenopausicas, 11 de ellas presentaban HUA. Entre pacientes premenopausicas se resecaron 2 polipos malignos, uno de ellos era asintomatico. No se detectaron polipos malignos entre pacientes con THS. Se encontraron 4 polipos malignos entre mujeres con tratamiento con TMX, 2 de ellos eran asintomaticos. Conclusion La reseccion sistematica de los polipos endometriales permite detectar todos los polipos malignos, incluso en los casos de pacientes asintomaticas y/o premenopausicas.

Resumen El embarazo implantado sobre la cicatriz de una cesarea anterior constituye la localizacion mas infrecuente de los embarazos ectopicos y, posiblemente, es una de las mas peligrosas por el riesgo de rotura uterina y hemorragia que comporta. Se trata de una entidad rara, con pocos casos publicados en la bibliografia mundial y en la que el diagnostico diferencial puede llegar a ser muy dificultoso. La incertidumbre en los criterios diagnosticos y en su pronostico hace que no exista hoy un consenso aceptado sobre cual es la mejor opcion terapeutica.

Resumen Objetivo Analizar los resultados anatomicofuncionales de la operacion de Vecchietti por laparoscopia para la creacion de una neovagina Material y metodos Estudio tipo caso-control: grupo caso formado por 6 pacientes con el sindrome de Rokitansky a las que se creo una neovagina segun la tecnica de Vecchietti por laparoscopia; grupo control formado por un historico de 5 pacientes intervenidas segun la tecnica de McIndoe. Se analizaron las variables: tiempo y complicaciones quirurgicas, tiempo de estancia hospitalaria, complicaciones posquirurgicas y longitud de vagina. Los resultados funcionales se analizaron mediante un cuestionario de sexualidad (FSFI) Resultados Ambos grupos presentaron resultados anatomicos similares. Se hallaron diferencias significativas en el tiempo de ingreso hospitalario y en las complicaciones posquirurgicas. Los resultados funcionales en las pacientes con relaciones sexuales activas fueron similares a la poblacion normal Conclusion Con la tecnica de Vecchietti por laparoscopia, se obtienen buenos resultados anatomicos y funcionales, se reducen el tiempo de ingreso hospitalario y las complicaciones posquirurgicas

Objective To compare Doppler evaluation of the ductus venosus and contraction stress test (CST) in the prediction of adverse perinatal outcome in growth-restricted fetuses with evidence of hemodynamic redistribution and a non-reactive non-stress test (NST). Methods Data were collected from all singleton pregnancies seen in our Fetal Surveillance Unit who underwent antenatal monitoring for fetal growth restriction, non-reactive NST and arterial redistribution beyond 26 weeks of pregnancy. Patients were divided into four groups based on their CST and ductus venosus waveform results. Perinatal outcome was evaluated by means of four variables: the need for admission to the neonatal intensive care unit (NICU), need for neonatal intubation, an umbilical artery pH < 7.10 and significant neonatal morbidity. Outcome was compared among fetuses delivered within 3 days of their antenatal test. Logistic regression analysis was used to analyze the relation between predictive and outcome variables. Results Sixty-eight women met the inclusion criteria for the study. The positive predictive value of the CST was 45% for admission to the NICU, 13% for significant neonatal morbidity, 26% for need of neonatal intubation and 29% for umbilical artery pH < 7.10. The positive predictive values of abnormal ductus venosus waveform (ADVW) were 81.5%, 26%, 48% and 55%. Groups with ADVW showed significantly poorer neonatal outcome. No significant differences were observed when CST results were compared. Logistic regression analysis showed that both gestational age at delivery and ADVW significantly predict the occurrence of adverse perinatal outcome. Conclusion In growth-restricted fetuses with hemodynamic redistribution and a non-reassuring NST, Doppler assessment of the ductus venosus correlates with adverse perinatal outcome. In this clinical situation there is no benefit of CST in terms of prediction. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd.

Adjusted early estimates of the 2013/14 influenza vaccine effectiveness (VE) in Spain for all age groups was 35% (95% CI: -9 to 62), 33% (95% CI: -33 to 67) and 28% (95% CI: -33 to 61) against any influenza virus type, A(H1N1)pdm09 and A(H3N2) viruses, respectively. For the population targeted for vaccination, the adjusted VE was 44% (95% CI: -11 to 72), 36% (95% CI: -64 to 75) and 42% (95% CI: -29 to 74), respectively. These preliminary results in Spain suggest a suboptimal protective effect of the vaccine against circulating influenza viruses. This work was supported from the Influenza A(H1N1)pdm09 Programme of the Carlos III Institute of Health (GR09/0017 and PS12/00087). The GR09/0017 received additional funding from the World Health Organization Regional Office for Europe (WHO/Europe)/United States CDC (Centers for Disease Control and Prevention) and Epiconcept. Sí

The aim of this study was to determine the prevalence of alterations and normal variable chromosome features in males from infertile couples. Karyotyping was performed to 84 men attending the infertility clinic at the Hospital Clinic i Provincial of Barcelona (Spain). Sex chromosome abnormalities were detected in 19 patients (26.62%): 14 (16.67%) aneuploidies 47,XXY and 47,XYY, 3 (3.57%) Y-chromosome long arm deletions; 1 (1.19%) mosaic 45,x/46,XY and 1 (1.19%) Robertsonian translocation (45.X-15-Y+t(15p: Yq). Chromosomal polymorphisms were observed in 29 patients. Yqh+ was the most frequent variant in sex chromosomes and increased length in heterochromatin and satellites were present in autosomal chromosomes. The high prevalence of chromosomal abnormalities observed in infertile men justify the use of karyotyping to evaluate males enrolled in new assisted reproductive technologies programs.

Resumen Objetivo Determinar la capacidad diagnostica de la ecografia, el Doppler-color y pulsado, y la determinacion serica de CA125 en el diagnostico diferencial de las tumoraciones anexiales. Material Y Metodos Un total de 126 pacientes con una tumoracion anexial fueron evaluadas mediante ecografia, Doppler-color y pulsado y determinacion serica de CA125 de forma previa a la cirugia. Se calcula la capacidad de cada parametro en terminos de sensibilidad, especificidad, valores predictivos positivo y negativo, precision global y razon de riesgo. Resultados Un total de 98 (77,7%) tumores fueron benignos y 28 (22,2%) malignos. Los tumores malignos presentaron, de forma significativa, mayor volumen, paredes y tabiques mas gruesos, mayor frecuencia de partes solidas y de ascitis, vascularizacion mas intensa, distribucion central de los vasos y valores superiores de CA125 que los tumores benignos. El tipo ecografico mas frecuentemente asociado a malignidad fue el quiste solido multilocular, siendo la presencia de partes solidas la variable con mayor potencia discriminatoria. Conclusiones La informacion que aporta el estudio ecografico convencional es superior a la que aporta el estudio de la vascularizacion del tumor y el marcador tumoral CA125.

Nitric oxide (NO) may play an important role in embryo implantation and early embryo development. This study investigated the potential role of circulating nitric oxide (NO) measurement to predict the outcome of implantation and pregnancy after IVF and ET.Two blood samples were collected from 237 IVF patients on days 13-14 and 20-21 after ET. Serum concentration of nitrite/nitrate (the two stable oxidation products of NO metabolism), estradiol (E2), progesterone and beta-hCG were measured on days 13-14 after ET and one week later.No significant differences were found with respect to nitrite/nitrate serum concentrations in conception versus non-conception cycles, viable versus abnormal pregnancies, and viable pregnancy group versus non-conception cycles, respectively, despite that significant differences were observed regarding E2 and progesterone values. Nitrite/nitrate serum concentrations were similar for singleton and multiple pregnancies at both study points. In viable pregnancies, no significant change was observed for nitrite/nitrate serum concentration from days 13-14 to 20-21 after ET. No correlation was found between nitrite/nitrate serum concentration and E2 or progesterone serum levels.Circulating levels of nitrite/nitrate are similar in successful and unsuccessful implantation after IVF and are unrelated to the outcome of pregnancy. This precludes the use of serum NO measurement as a marker of implantation and successful pregnancy in IVF.

Integrins have recently been proposed as having a major role in endometrial receptivity. Different patterns of integrin expression have been described during the normal endometrial cycle, and the co-expression of several integrins, mainly alpha1, alpha4 and beta3 has been considered as specific to the 'window of implantation'. In the present study 55 infertile patients underwent two endometrial biopsies during a single menstrual cycle. An early biopsy was done on postovulatory days 6-8, and a late biopsy was performed on postovulatory days 10 to 12. Histological dating as well as immunohistochemical evaluation of alpha1, alpha4, beta1, beta3, beta5, alpha(v)beta3 integrin expression and oestrogen and progesterone receptors were determined in all endometrial biopsies. Oestradiol and progesterone serum concentrations in serum were evaluated on the same days of the endometrial samplings. Nine out of the 55 midluteal biopsies (16.4%) showed out-of-phase endometria, but all biopsies were in phase in the late luteal phase. Differences in integrin expression between in- and out-of-phase biopsies were observed only for alpha(v)beta3 integrin glandular expression during the midluteal phase. Alpha(v)beta3 integrin glandular expression was found in all late luteal phase biopsies. Alpha(v)beta3 expression was closely correlated with histological maturation of the endometrium appearing suddenly at postovulatory day 6-7 and being expressed by all endometria dated as postovulatory day > or = 8, irrespective of midluteal endometrial biopsies being in phase or out of phase. No differences in integrin expression were detected between patients with or without endometriosis or between patients who became spontaneously pregnant and those who did not. In conclusion, further studies are necessary before patterns of integrin expression may offer an alternative to predict uterine receptivity and implantation potential.

Background: There is some evidence that hormone replacement therapy may produce significant improvements in fine wrinkling, while aging skin is more frequently found in smokers. However, studies of the combined effect of a protective factor, such as HRT, and a damaging factor, such as smoking, are rare. Objectives: To determine in postmenopausal women the relationship between smoking status and the average number of packets of cigarettes since the subject took up smoking (packs-years) on the one hand, and facial wrinkling on the other, and to evaluate the role of hormone replacement therapy in the prevention of wrinkles in smokers and non-smokers. Methods: All subjects were recruited from our menopause clinic at Hospital Clinic i Provincial in Barcelona and were placed into one of three groups according to their smoking status: 215 life-long non-smokers, 306 former smokers and 209 current smokers. Smoking status, pack-years and hormone replacement were assessed by direct questioning. Facial wrinkle scores were estimated by standardized visual assessment. Results: The relative risk of moderate–severe wrinkling for current smokers compared to that for life-long non-smokers was 2.57 (confidence interval: 1.83–3.06; P

Increased antiphospholipid antibody prevalence has been demonstrated by a number of recent studies in in-vitro fertilization (IVF) patients but the potential effects of antiphospholipid antibodies on the different components of the reproductive process and the consideration of whether to test IVF patients for antiphospholipid antibodies are controversial. The present study was undertaken to investigate the possible association between the presence of circulating antiphospholipid antibodies (namely the lupus anticoagulant and anticardiolipin antibodies), among a series of 21 consecutive IVF patients having a clinical spontaneous abortion after their first embryo transfer. As a control group (n = 42), the nearest IVF cycle resulting in an ongoing pregnancy before and after each miscarried IVF cycle (i.e. the closest cycles in temporal relationship to the index cycle) was used. One patient (4.8%) in the study group and two women (4.8%) among controls were seropositive for antiphospholipid antibodies. These low and similar seropositivity rates found in the two groups studied lead us to conclude that antiphospholipid antibodies testing in IVF patients should be considered only in those women having repeated failures of implantation/clinical abortion after embryo transfer but not in an infertile general population reaching an IVF programme.

At present, it is well accepted that maternal recognition of paternally derived fetal antigens occurs during normal pregnancy and may be beneficial for implantation and maintenance of gestation. Thus, we have investigated the compatibility of human leukocyte antigens (HLA) in couples with successive failed in-vitro fertilization (IVF) cycles. Study group 1 included 50 couples with prior primary infertility who had not achieved a pregnancy afteror = 3 (range 3-7, mean 3.7) IVF cycles where at least two embryos (mean 3.3, range 2-4) were transferred in each attempt. An infertile control group (group 2) included 50 infertile couples undergoing IVF with the same indications as couples in group 1, who achieved a viable pregnancy with their first IVF attempt. The results were compared with those found in a population sample including 100 men and 100 women from the local population (group 3). We found a statistically significant (P0.05) excess of HLA sharing (or = 2 antigens) between partners in group 1 as compared to groups 2. There was a trend toward increased HLA sharing in group 1 when groups 1 and 3 were compared. We conclude that some cases of implantation failure after IVF and embryo transfer might be caused by underlying close histocompatibility between partners.

Zygotes morphologically classified as tripronuclear (3PN) after intracytoplasmic sperm injection (ICSI), which are thought to be digynic in their origin, were studied by fluorescent in-situ hybridization (FISH). FISH results allowed us to assess the suspected ploidy after morphological evaluation of the zygote and to determine the origin of the third pronuclei. Our results show that, firstly, 36% of those zygotes classified as 3PN following their morphological evaluation were, in fact, diploid, and secondly, the main cause for triploidy after ICSI is the non-extrusion of the second polar body.

The present study is the first prospective randomized controlled trial of the effect of pentoxifylline on future fertility in infertile women with asymptomatic minimal or mild endometriosis. After completion of a basic infertility workup and laparoscopy, patients were entered into the study and randomly allocated to receive either a 12 month course of oral pentoxifylline (800 mg/day) (n = 30) or an oral placebo (n = 30). Those patients with other infertility factors were included in the study only if the factors were correctable and ultimately determined to be non-contributory. Life-table analysis was used to compare pregnancy rates between the two groups over a 12 month period that started immediately after laparoscopy. The 12 month actuarial overall pregnancy rates were 31 and 18.5% in the pentoxifylline and placebo groups respectively. However, this difference was not statistically significant by the chi(2)-test. Similarly, the Cox regression method showed no differences between the hazard of pregnancy in the two groups studied (odds ratio, 0.56; 95% confidence interval, 0.18-1.67). Therefore, there is no evidence from this study that immunomodulation with pentoxifylline aids fertility in those women with minimal or mild endometriosis. Further studies including more infertile patients with endometriosis are desirable in order to confirm our results.

The present study was undertaken to investigate the possible association between activated protein C resistance and first-trimester repeated abortion. Fifty-five consecutive patients with unexplained first-trimester repeated abortion and 50 healthy control women having at least one child but no previous abortion were included. Activated protein C resistance was measured in all subjects and factor V Leiden genotype testing was performed in those individuals with phenotypic activated protein C resistance. One patient with first-trimester repeated abortion and one control subject had phenotypic activated protein C resistance. Genotype analysis confirmed that both subjects were heterozygous for factor V Leiden. Our results indicate that first-trimester repeated abortion is not associated with activated protein C resistance. Factor V Leiden screening in first-trimester repeated abortion is not warranted.A case-control study failed to substantiate concerns that first-trimester repeated abortion is associated with activated protein C resistance. In its heterozygous form, activated protein C resistance creates a life-long hypercoagulable state and a 5- to 10-fold increased risk of venous thrombosis. Frozen blood samples from 55 consecutive patients with two or more (mean, 2.9; range, 2-7) consecutive first-trimester spontaneous abortions of unknown etiology were compared to those from 50 healthy blood donors with at least one child but no previous abortion. Mean activated protein C resistance ratio in the 55 cases was 3.2 in the direct test and 2.9 in the modified test. Only one case had phenotypic activated protein C resistance (ratio of 1.4 in the direct test and 1.5 after factor V depleted plasma dilution). Genotype analysis confirmed that this patient, who had two previous abortions at 10 and 8 weeks of gestation, was heterozygous for the factor V Leiden mutation. One woman in the control group had activated protein C resistance phenotype (ratios 1.9 and 1.8 in the direct and modified tests, respectively) that was confirmed as heterozygous for factor V Leiden mutation. The development of resistance to activated protein C is presumed to occur mainly after 14 weeks of gestation and is more evident at term. The findings of this study suggest that factor V Leiden screening in first-trimester repeated abortion is not warranted.

Previous studies conducted at our clinic suggested that the administration of hormone replacement therapy (HRT) in postmenopausal women could result in the inhibition of oestrogen-induced prolactin (PRL) release. The aim of this study was to determine how the pituitary function is affected by the sequential addition of medroxyprogesterone acetate (MPA) to oestrogen replacement therapy. Twenty-one postmenopausal women receiving no other medication were treated with a standard dose (0.625 mg/day) of conjugated equine oestrogens (CEE) for a period of 24 days, plus 5 mg/day MPA added sequentially during the last 12 days of the oestrogen therapy. Blood samples were collected before treatment, during oestrogen and oestrogen-progestogen administration and after cessation of treatment. Folliclestimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E2) and PRL levels were studied. During treatment gonadotrophin concentrations decreased significantly, while after cessation of HRT the levels of FSH and LH increased. These gonadotrophin fluctuations indicated a sharp rise in E2 levels during therapy and a significant decrease during the treatment-free period. PRL levels were found to be higher during CEE therapy, but they fell when patients received CEE in combination with MPA. These observations suggest that the role of progestogens in a variety of experimental and clinically relevant situations needs to be investigated not only as regards their direct action but also their modulation of the effect of oestrogen.

Objective To describe sequential changes in uterine artery waveform between the first and second trimesters of gestation and to analyze their association with the subsequent risk of hypertensive disorders and fetal growth restriction (IUGR). Methods Sequential uterine artery Doppler recordings were obtained in a final cohort of 870 singleton pregnancies over two gestational age intervals: 11–14 weeks and 19–22 weeks. The left and right uterine arteries were examined by color and pulsed Doppler and the mean pulsatility index (PI) as well as the presence of a bilateral protodiastolic notch were recorded during both intervals. Pregnancies were followed for occurrence of hypertensive disorders and IUGR. Results Mean uterine artery PI showed a significant linear decrease within each of the two intervals considered, while the prevalence of a bilateral notch showed decreasing values only throughout 11–14 weeks of gestation. Sixty-four (7.3%) pregnancies developed a hypertensive disorder and/or IUGR, including three (0.34%) cases of gestational hypertension, 24 cases of pre-eclampsia (2.75%) and 37 (4.25%) of IUGR. Compared with pregnancies with a normal outcome, complicated pregnancies showed a significantly higher prevalence of a bilateral notch and a higher mean PI in each of the two intervals studied. Compared with normal pregnancies, complicated pregnancies had a significantly higher persistence of a bilateral notch (30% vs. 8%), a higher proportion of women with an abnormal first-trimester uterine artery PI shifting to normal in the second trimester (14% vs. 4%) and a higher incidence of a normal first-trimester mean PI that shifted to abnormal in the second trimester (13% vs. 4%). Persistence of an abnormal mean PI from the first to the second trimester identified the group with the greatest risk for adverse perinatal outcome (OR, 10.7; 95% CI, 3.7–30.9). In addition, women in whom the uterine artery mean PI shifted from abnormal to normal between the two trimesters and women in whom the reverse shift occurred showed a similar intermediate risk (OR, 5; 95% CI, 2.1–10.6), comparable to that in women with persistence of a bilateral notch (OR, 5.6; 95% CI, 2.9–10.7). Conclusions The sequence of changes in uterine flow between the first and second trimesters correlates with the subsequent development of hypertensive disorders and IUGR. Women with a persistent abnormal mean PI represent the group with the greatest risk for adverse perinatal outcome. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.

We report the case of a 19-year-old pregnant woman who presented with a nipple tumor. The lesion consisted in a spindle-cell proliferation with histologic features similar to those of fibrous histiocytoma, with a highly vascularized stroma. Although it showed low mitotic activity, scattered marked atypical cells with prominent nucleoli were identified, thus raising concern about the benign nature of the tumor. Immunohistochemical evaluation revealed that the spindle cells were diffusely positive for vimentin, focally positive for CD68, and negative for all the other tested antibodies. The patient had a total excision of the lesion and she is free of disease after 30 months. To our knowledge this is the first reported case of a lesion of this type in the nipple after body-piercing.

The objective of this study was to determine the value of myometrial invasion by magnetic resonance imaging (MRI), histologic typing and grading by endometrial biopsy, and the intraoperative evaluation of both parameters by frozen section in the evaluation of endometrial cancer. The preoperative and intraoperative records of 180 patients with endometrial cancer were used to compare the preoperative endometrial biopsy, the myometrial invasion by MRI, and the intraoperative frozen sections, with the final histopathologic findings. The preoperative endometrial biopsy gave us the tumor histologic type and grade. MRI gave us the depth of myometrial invasion. The evaluation of intraoperative frozen sections gave us the tumor histologic type, the tumor grade, and also the myometrial invasion. Patients were classified as low risk (grade 1 and 2, and myometrial invasion50%) and high risk (grade 3 or myometrial invasion50%). Standard statistical calculations were used. Evaluation of the tumor grade by preoperative biopsy has a sensitivity and a specificity of 75% and 95%, respectively. Evaluation of the tumor grade by intraoperative biopsy has a sensitivity and a specificity of 40% and 98%, respectively. Evaluation of the depth of myometrial invasion with MRI has a sensitivity and a specificity of 79% and 82%, respectively. Evaluation of the depth of myometrial invasion with intraoperative frozen sections has a sensitivity and a specificity of 74% and 95%, respectively. Evaluation of all four of the parameters together has a sensitivity and a specificity of 80% and 82%, respectively with a kappa of 0.621. In our opinion, the combination of preoperative biopsy and intraoperative frozen section is the best way to decide whether a lymphadenectomy is necessary with a low rate of understaging patients. MRI would have a fringe benefit in these patients.

To establish reference values for the first-trimester uterine artery (UtA) pulsatility index (PI) and to investigate the role of UtA Doppler in the early prediction of hypertensive disorders and their associated complications in an unselected Mediterranean population.A prospective study including 1091 consecutive singleton pregnancies undergoing routine early ultrasound screening at 11-14 weeks of gestation was performed. The left and right UtA were examined by color and pulsed Doppler transvaginally. The mean PI and the presence of bilateral protodiastolic notching were cross-sectionally recorded. Reference ranges were calculated and the pregnancies were followed for occurrence of pre-eclampsia, gestational hypertension, intrauterine growth restriction, placental abruption and stillbirth. The sensitivity and predictive values of a mean UtA-PI95th percentile and the presence of bilateral notching in the prediction of these pregnancy complications were calculated.A total of 999 women were finally included. Both the mean UtA-PI and the prevalence of bilateral notches showed a significant linear decrease between 11 and 14 weeks' gestation. Sixty-seven (6.7%) pregnancies developed at least one of the formerly described complications, including 22 (2.2%) cases of pre-eclampsia and 37 (3.7%) cases with intrauterine growth restriction. Compared with women with a normal outcome, complicated pregnancies showed a significantly higher mean PI (2.04 vs. 1.75; P0.05, t-test) and a higher prevalence of bilateral notching (58% vs. 41%; P0.05, Chi-square test). Using the 95th percentile in mean UtA-PI as a cut-off, 23.9% (95% CI, 13.7-34.1) of complicated pregnancies and 30.8% (95% CI, 5.68-55.85) of severe cases were identified.Our results suggest that pregnancies with an increased risk of developing hypertensive disorders and related complications already have an abnormally increased UtA-PI in early pregnancy. However, the use of a single uterine Doppler measurement for screening purposes in unselected early pregnancy populations has limited clinical value. The use of UtA-PI combined with other screening tests needs to be determined by further investigation.

To construct normal ranges for umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI) and cerebroplacental ratio (CPR) in prolonged pregnancies according to strict methodological criteria using polynomial regression analysis.This was a retrospective, cross-sectional observational study involving 140 women, 10 women for each gestational day between 287 and 300 days of gestation. Fetal Doppler parameters were assessed to construct normal reference ranges for UA PI and MCA PI. CPR was calculated as a ratio of MCA PI/UA PI.Mathematical modeling of the data demonstrated that the optimal fit was a linear polynomial one. Mean, 5th and 95th centiles were calculated for UA, MCA and CPR and centile curves from the regression analysis were constructed.Reference ranges for UA PI, MCA PI and CPR in prolonged pregnancies have been constructed. MCA PI shows a wider range than previously reported in the literature.

To assess the value of middle cerebral artery Doppler indices obtained from different sampling sites in predicting umbilical cord gases at delivery in prolonged pregnancies.This was a prospective study of consecutive pregnant women referred for prolonged-pregnancy surveillance. The predictive value of distal and proximal middle cerebral artery Doppler indices for cord blood gases was evaluated in women who delivered within 48 h of their last antenatal test using stepwise multiple regression.There was a significant linear correlation between proximal and distal middle cerebral artery pulsatility indices (R = 0.777; P0.0001), the mean values being 1.49 (SD, 0.45) and 1.56 (SD, 0.47), respectively. There was also a linear correlation between proximal and distal cerebroplacental ratios (R = 0.68; P0.0001), the mean values being 1.85 (SD, 1.96) and 1.92 (SD, 1.89), respectively. The stepwise multiple regression analysis for umbilical artery pH showed that once the distal middle cerebral artery pulsatility index was introduced into the model, the addition of any variable did not result in a significant improvement of the predictive capacity. The model showed a coefficient of determination (R(2)) of 0.079. There was a significant correlation between umbilical artery pO(2) and both proximal middle cerebral artery pulsatility index (positive) and the occurrence of elective Cesarean section (negative). This model accounted for 21% of the variance (R(2) = 0.21). No other variables added any significant prediction for pO(2).In post-term pregnancies the proximal middle cerebral artery pulsatility index significantly predicts umbilical artery pO(2) at delivery but does not predict pH. There is a weak association between distal middle cerebral artery pulsatility index and pH but, as this only explains 8% of the variance, it is of little clinical value.

Background. Although studies have reported good results with laparoscopic-assisted vaginal hysterectomy (LAVH) to treat endometrial cancer, it has been associated with recurrent disease at trocar insertion sites. Long-term follow-up is necessary to detect possible adverse effects of this technique. Cases. We present two case reports of stage IIB endometrial cancer with port-site metastasis 39 and 48 months after initial surgery with LAVH. Conclusion. Although LAVH is a good technique to treat patients with endometrial cancer, port-site metastasis is a possible complication and should be taken into consideration until a randomized study shows the long-term benefits and risks of laparoscopic over standard treatment.

Raloxifene, a selective oestrogen receptor modulator, is effective in the treatment of osteoporosis without stimulating the breast and the endometrium. Although it is associated with a decrease of cardiovascular risk markers the effect of these changes on atherogenesis, is not clear. In this study, we aimed to investigate the effect of raloxifene on aorta atherogenesis. A total of 32 cholesterol-fed New Zealand white rabbits were studied for 4 months. Twenty-four rabbits underwent bilateral ovariectomy; of these eight received raloxifene (group OR), eight received oestradiol valerate (group OE) and eight received placebo after sterilisation (group OP). Finally, another eight were sham-operated (non-ovariectomised) and received placebo with a hypercholesterolaemic diet (group SP). After the diet, total levels of cholesterol increased in group SP from 111.25 +/- 34.8 mg/dl to 1112.25 +/- 364.2, in group OP from 122.62 +/- 27.7 mg/dl to 1367.37 +/- 348.4, in group OE from 65.25 +/- 17.01 to 1710.5 +/- 356.2 and in group OR from 108.88 +/- 15.54 mg/dl to 1407.86 +/- 397.7 (no significant differences). At 4 months, in both treated and untreated rabbits, the cholesterol-rich diet caused atherosclerotic lesions affecting 24.51 +/- 16.1% for group SP, 30.47 +/- 12.2% for group OP, 30.31 +/- 18.07% for group OR and 17.91 +/- 10.19 for group OE (P

Background: Different hormonal replacement regimens are used for treating climacteric complaints; however, not all of them have the same clinical profile. Cardiovascular disease (CVD) is a major health problem and tibolone, raloxifene, estradiol (alone or with cyproterone acetate) have been added to cholesterol-fed rabbits to study atherosclerosis. Methods: A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. Forty rabbits underwent bilateral ovariectomy and the other eight were sham operated (group S). The ovariectomized rabbits were allocated to five groups of eight animals each receiving tibolone (Group T, 6 mg/day), raloxifene (R, 35 mg/day), estradiol valerate (E, 3 mg/day), estradiol valerate plus cyproterone acetate (EC, 3+0.5 mg/day, respectively), and no treatment for the control group (C). The sham group received no treatment too. Results: After 4 months the percentage of the extent of atherosclerosis in the aorta was 30.4% in C group, 24.5% in S group, 10.2% in T group, 30.3% in R group, 17.9% in E group and 28.1% in EC group (P

To compare Doppler evaluation of the ductus venosus and contraction stress test (CST) in the prediction of adverse perinatal outcome in growth-restricted fetuses with evidence of hemodynamic redistribution and a non-reactive non-stress test (NST).Data were collected from all singleton pregnancies seen in our Fetal Surveillance Unit who underwent antenatal monitoring for fetal growth restriction, non-reactive NST and arterial redistribution beyond 26 weeks of pregnancy. Patients were divided into four groups based on their CST and ductus venosus waveform results. Perinatal outcome was evaluated by means of four variables: the need for admission to the neonatal intensive care unit (NICU), need for neonatal intubation, an umbilical artery pH7.10 and significant neonatal morbidity. Outcome was compared among fetuses delivered within 3 days of their antenatal test. Logistic regression analysis was used to analyze the relation between predictive and outcome variables.Sixty-eight women met the inclusion criteria for the study. The positive predictive value of the CST was 45% for admission to the NICU, 13% for significant neonatal morbidity, 26% for need of neonatal intubation and 29% for umbilical artery pH7.10. The positive predictive values of abnormal ductus venosus waveform (ADVW) were 81.5%, 26%, 48% and 55%. Groups with ADVW showed significantly poorer neonatal outcome. No significant differences were observed when CST results were compared. Logistic regression analysis showed that both gestational age at delivery and ADVW significantly predict the occurrence of adverse perinatal outcome.In growth-restricted fetuses with hemodynamic redistribution and a non-reassuring NST, Doppler assessment of the ductus venosus correlates with adverse perinatal outcome. In this clinical situation there is no benefit of CST in terms of prediction.

Objective : The aim of the present study was to determine whether assignment to continuous estrogen–progestin therapy is more effective in protecting against bone loss than assignment to a sequential regimen. Study Design : A total of 104 postmenopausal women were randomly assigned to one of two groups of treatment, Conjugated Equine Estrogens and Medroxyprogestin without interruption (continuous group) and Conjugated Equine Estrogens over 25 days with Medroxyprogestin beyond the 14th day (sequential group). Bone mineral density (BMD) was measured at inclusion, 12 and 24 months later by dual energy X-ray absorptiometry. Results : among women completing the 2-year treatment period, continuous and sequential regimens yielded results significantly different from baseline values, but not significantly different from each other at the 12-month (4.2 and 4%) or 24-month visits (6.6 and 6.3%). In the intention-to-treat analysis, the results with both regimens also differed from baseline values; additionally, the continuous group showed a greater increase in BMD than the sequential group at the 12-month (3.5 and 3%) and at the 24-month visits (5.5 versus 4.6%). Conclusion : assignment to continuous administration seems to be more effective in increasing bone density than the sequential regimen. Thus, combined continuous estrogen therapy would seem to be the most effective regimen for those women requiring long-term hormone replacement therapy.

Our purpose was to determine prospectively, using receiver-operating characteristic (ROC) analysis, whether the ovarian reserve test with hMG could improve the predictive value of a woman's age and basal levels of follicle stimulating hormone (FSH), E2, and inhibin or any combination of them regarding ovarian response and pregnancy rate in IVF treatment following pituitary desensitization.The hMG test was performed within 3 months of IVF treatment in 80 women undergoing the first cycle of IVF and consisted of 2 ampoules of hMG daily for 5 days starting on cycle days 2 to 3. Hormone and ultrasound evaluation was performed on cycle days 2 to 3 and 7 to 8.The mean age and basal FSH levels were significantly higher in the canceled (n = 28) than in the control (n = 52) group, whereas the basal inhibin level was significantly higher in the latter. Regarding ovarian response, the combination FSH plus inhibin had the better diagnostic accuracy (predictive value of 70%) among basal variables. When post-hMG parameters (alone or in combination) were analyzed, E2 alone, with a 77% diagnostic accuracy, emerged as the best predictive variable of cancellation in IVF cycles. When ROC analysis was used, the area under the ROC curve for E2 post-hMG (diagnostic accuracy of 84.5%) was significantly higher than that for the estimates based on the combination of basal FSH and inhibin (diagnostic accuracy of 71.3%). However, woman's age was the only variable independently associated with pregnancy rate.The predictive power of the hMG test of ovarian reserve is better than that of age and basal hormone values (FSH and inhibin) and it is based mainly on the E2 response to hMG treatment. However, given that age is the only predictor of pregnancy and considering the cost and discomfort of the hMG test, the usefulness, if any, of the test in predicting IVF performance in the daily clinical setting remains to be established.

Couples where the male partner is HIV-infected but the female partner is not often express a desire for children. Assisted reproduction techniques (ART) with sperm "wash" can reduce the risk of acquisition of infection for the woman. The information about the characteristics of such couples coming to these clinics for advice and support is scant.To describe the characteristics of a cohort of HIV-discordant couples seeking reproductive assistance in a referral clinic in Barcelona, Spain.Demographic, social and HIV related information were collected prospectively according to a standard protocol. Blood tests, a full evaluation for STDs and sperm analysis were performed.Between April 1994 and February 1999, 140 couples contacted the clinic for reproductive advice, 100 couples were fully assessed and were offered reproductive assistance. The vast majority were white, with a history of injecting drug use. Nearly half of the men had been diagnosed during their present relationship. STDs were uncommon and abnormalities among sperm analysis were frequent.An increasing number of HIIV infected individuals desire to have children. With the introduction of HAART and the safety of sperm wash in such cases, the need to have children is more frequently expressed. These couples are in general healthy and accept to be included in an ART program.

We report a case of a patient with polycystic ovary syndrome and primary infertility who was admitted to our in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme because of her partner's severe oligozoospermia and asthenozoospermia. Ovarian stimulation was accomplished in the three treatment cycles using gonadotrophin therapy after a dual approach with ovarian suppression using oral contraceptive pills followed by gonadotrophin-releasing hormone agonist therapy. Oocyte retrieval was unsuccessful in the first two treated cycles despite the fact that human chorionic gonadotrophin (HCG) from three different batches was used. In the third treatment cycle, recombinant HCG was used and five oocytes were retrieved. This is the first report of recurrent empty follicle syndrome despite the use of different batches of commercially available urinary HCG, and of its successful treatment using recombinant HCG.

There are conflicting data about the effects of oral contraceptives on bone mass in young women. Moreover, amenorrheic women may also be affected to varying degrees by osteopenia. Both conditions (oral contraceptive use and amenorrhea) are not infrequent in women during their reproductive years.To evaluate the safety for bone mass of two oral contraceptives, one containing cyproterone acetate and the other containing desogestrel.A total of 67 women between 19 and 29 years of age were studied. Of these women, 35 were selected to receive an oral contraceptive containing 35 mg ethinylestradiol and 2 mg cyproterone acetate. A second group of 32 women received an oral contraceptive containing 30 mg ethinylestradiol and 150 mg desogestrel for 2 years. Immediately before and after the 12th and 24th months of therapy, bone mineral density was assessed by dual X-ray absorptiometry, and hormonal profiles and Ferriman-Gallwey scores were evaluated.After the 2-year follow-up, all subjects showed regular cycles, no pregnancies, and no changes in bone mass density. In addition, hirsute subjects showed a decrease of almost 42% in hirsutism scores.Oral contraceptives containing cyproterone acetate or desogestrel in the studied doses have no deleterious effects on bone marrow.

Severe ovarian hyperstimulation syndrome (OHSS) is consistently associated with a circulatory dysfunction characterized by arterial hypotension, low peripheral vascular resistance, and increased activity of the renin-aldosterone system. To investigate whether circulatory dysfunction also occurs in asymptomatic patients undergoing controlled gonadotropin ovarian hyperstimulation under pituitary suppression for in vitro fertilization (IVF), 12 women without clinical manifestations of OHSS underwent sequential blood, urine, and hemodynamic measurements at five study points: the 7th day of the menstrual cycle preceding IVF (study point 1 or baseline), the day when pituitary suppression was shown (study point 2), the day of hCG ovulatory injection (study point 3), the day after hCG was injected (study point 4), and 7 days after hCG administration (study point 5). Mean arterial pressure, cardiac output, peripheral vascular resistance, plasma concentrations of estradiol (E2) and aldosterone, and plasma renin activity (PRA) were measured at each study point in all women. Serum levels of nitrite/nitrate, and plasma concentration of atrial natriuretic peptide, norepinephrine, adrenomedullin, and cyclic guanosine 3'5'-monophosphate were measured in samples obtained at study points 1 and 5. Multiple follicular development during ovarian stimulation associated with increased plasma E2 concentration (mean peak plasma E2 level, 2430 +/- 428 pg/mL, range 1630-3840 pg/mL) were observed in each woman. All patients developed a significant increase in cardiac output and decrease in arterial pressure and peripheral vascular resistance, and a marked elevation in PRA and aldosterone, all indicating the development of arteriolar vasodilation. Changes in circulatory measurements were temporarily related with the increase in E2 both being detected at study points 3-5. In contrast, there was a clear chronological dissociation between the increase in plasma E2 concentration and the stimulation of the renin-aldosterone system. PRA and aldosterone only reached abnormal levels at study point 5 in association with a significant increase in plasma norepinephrine concentration. Serum levels of nitrite/nitrate and plasma concentrations of atrial natriuretic peptide, adrenomedullin, and cyclic GMP were similar at study points 1 and 5. It is concluded that the circulatory dysfunction that characterizes severe OHSS is a universal event in patients undergoing controlled ovarian hyperstimulation for IVF. Although the increase in E2 levels during IVF cycles is associated with significant circulatory changes, the circulatory dysfunction that characterizes severe OHSS is clearly unrelated to the onset of hyperestrogenemia. Arteriolar vasodilation during IVF cycles was not associated with an increased activity of the vasodilator substances atrial natriuretic peptide, adrenomedullin, and nitric oxide.

Immunopathophysiological mechanisms in endometriosis-associated reproductive failure were studied in appropriate populations: infertile and fertile women with and without endometriosis. The incidence of sera positive for any of the autoantibodies tested among infertile women with endometriosis (n = 25) was similar to that observed in the three control groups [unexplained infertility patients (n = 25) and fertile women with (n = 10) and without (n = 25) endometriosis]. The mean volume of peritoneal fluid was significantly elevated in women with endometriosis (both fertile and infertile) as compared with patients without endometriosis (fertile or infertile). The concentration of peritoneal fluid leukocytes and the percentage of cells positive for macrophage markers were significantly increased and the percentage of T lymphocytes significantly decreased in infertile women with endometriosis but not in patients with unexplained infertility and fertile women with endometriosis, as compared with fertile controls without endometriosis. Macrophages from infertile patients with endometriosis had higher sperm phagocytosis than did those from infertile women without endometriosis or fertile subjects with or without endometriosis. Incidences of serum and peritoneal fluid samples embryotoxic to the in-vitro development of 2-cell mouse embryos were significantly higher in infertile patients with endometriosis than in unexplained infertility patients and fertile women with or without endometriosis. It is concluded that immunological mechanisms of endometriosis-associated infertility exist but that these peritoneal immunological factors in infertile women with endometriosis are related to their subfertility rather than to the presence of ectopic endometrial implants. This is supported by the lack of immunological abnormalities observed among fertile women with endometriosis. These immunological abnormalities are lacking in patients with unexplained infertility.

We report a case of pituitary-ovarian suppression obtained with sequential danazol/leuprolide acetate administration in a patient undergoing in vitro fertilization and unresponsive to leuprolide acetate alone and sequential oral contraceptive-leuprolide acetate therapy. Leuprolide acetate (1 mg daily subcutaneously) was administered after 5 weeks of danazol treatment (800 mg daily) while the latter was maintained for 1 additional week. Ovarian activity was assessed by transvaginal ultrasonography and serum estradiol determination. After 5 weeks of danazol therapy, ovarian arrest was obtained despite the fact that gonadotropin serum levels did not change relative to basal values. Leuprolide acetate injection for 14 days was associated with a decrease in serum concentrations of follicle-stimulating hormone and luteinizing hormone and a further decrease of the estradiol level. We conclude that sequential danazol/leuprolide acetate therapy is a useful alternative for obtaining ovarian arrest in patients unresponsive to leuprolide acetate alone.

Ten infertile women, 28 to 36 years of age, with regular menstrual cycles were treated with oral estradiol valerate and intravaginally administered micronized progesterone under pituitary suppression with leuprolide acetate. Patients underwent endometrial biopsies on cycle days 17 and 28 (luteal phase days 3 and 14) and blood sampling for plasma progesterone and estradiol determinations on cycle days 17, 21 and 26 (luteal phase days 3, 7 and 12). All ten endometrial biopsies on cycle day 17 were in-phase and only two out of ten (20%) were out-of-phase on cycle day 28. This produced an incidence of endometrial luteal phase deficiency that was not different from the 14% found among an infertile general population of 300 women. Midluteal estradiol plasma levels in the study group were similar to those found in a control group of fertile women, but progesterone levels were significantly lower on cycle day 21 in the treatment group. As much as 75% (six out of eight patients) of treated women having in-phase late luteal endometrial biopsies had low midluteal plasma progesterone levels, a situation that is found in only 3% of infertile patients (9/300) or 3.5% (9/258) of those infertile women with normal endometria (p = 0.03). Thus, the present study adds further evidence favoring the current postulate that vaginal micronized progesterone enhances hormone delivery to the uterus and this explains the marked discrepancy between the strong uterine effect and the relatively low plasma progesterone levels.

Routine screening for circulating antiphospholipid antibodies (aPL), namely the lupus anticoagulant (LA) and anticardiolipin antibodies (aCL), was carried out in a total of 1273 women aged45 years. Of them, 822 were experimental subjects and 451 were controls. The former comprised the following three study groups: 498 infertile patients (group 1), 284 spontaneous recurrent aborters (group 2), and 40 patients with repeated failure of embryo transfer (group 3). Controls included five groups of women: 125 normal healthy women who had never been pregnant (group 4), 125 normal healthy parous women with no previous abortion (group 5), 52 women in labour after normal pregnancies at term (group 6), 49 infertile patients achieving a livebirth with their first in-vitro fertilization (IVF) and embryo transfer (group 7), and 100 female patients with systemic lupus erythematosus (positive controls, group 8). aPL positivity in the eight groups studied was as follows: 24, 9.2, 10, 0.8, 0, 0, 0 and 42% respectively for groups 1 to 8. There were no differences within groups 1 and 3 regarding incidence of aPL when patients were grouped according to infertility aetiological factors and indications of IVF respectively. Twenty-six out of 284 recurrent aborters (9.2%) tested positive for aPL, and the LA and/or a CL were identified as the aetiological factor in 12% of patients (24/199) with supposedly unexplained recurrent abortion. Incidence of positive sera for aPL in group 1 was similar to that observed in control groups 4, 5 and 6. On the contrary, incidence of aPL positivity in groups 2 and 3 was significantly higher than in control groups 4, 5 and 6 and among infertile women (group 1). The difference between groups 3 and 7 almost reached statistical significance. Interestingly, there was no difference between groups 2 and 3, but groups 2 and 7 resulted probably different regarding incidence of aPL positive sera. As expected, the highest incidence of patients testing positive for aPL was found in group 8. Seven infertile patients having circulating aPL and becoming pregnant spontaneously or after specific infertility treatment, successfully carried to term in spite of the fact that they did not receive immunotherapy. Among recurrent aborters, the live-born baby rate was significantly higher after treatment with low-dose aspirin than prior therapy. It is concluded that the presence of circulating aPL may be associated with recurrent abortion but with infertility. In addition, our results favour a possible role of aPL in failure of implantation after IVF embryo transfer.

The luteal phase of in vitro fertilization-embryo transfer (IVF-ET) cycles has come under great scrutiny as the cause for the discrepancy between fertilization rates (> 70%) and pregnancy rates (around 20%) in most IVF programs is sought. The effects of the various stimulation protocols on the subsequent hormonal events of the luteal phase are both important and controversial but information regarding cycles where ovarian stimulation has been carried out with gonadotropins under pituitary suppression is scanty. The effect of high levels of estrogen in the late follicular phase and around the time of implantation is a matter of concern. As combined gonadotropin-releasing hormone analog (GnRH-a) gonadotropin treatment for superovulation is associated with supraphysiological ovarian steroid levels, both in the follicular and luteal phase of IVF cycles, we compared preovulatory (estradiol), midluteal (estradiol, progesterone and prolactin) and late luteal (estradiol and progesterone) hormone levels in on-going pregnancies, abortions and non-conception cycles in 222 patients accomplishing their first IVF-ET attempt who received such ovarian stimulation therapy. For both successful and unsuccessful implantation cycles, estradiol on the day of human chorionic gonadotropin (hCG) administration correlated positively with progesterone and estradiol levels and negatively with the progesterone/estradiol ratio in the midluteal phase. Mean peak follicular estradiol, midluteal estradiol and progesterone levels, mean mid- and late luteal progesterone/estradiol ratio, and mean midluteal prolactin concentration, were similar in the three groups studied. The mean late luteal estradiol and progesterone in the on-going pregnancy group were significantly higher than in non-conception cycles (p < 0.005 and p < 0.001, respectively) as a reflection of trophoblastic hCG production. Forty-eight patients (21.6%) had hyperprolactinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

On the basis that gonadotrophin-releasing hormone agonists (GnRHa) induce a significant but transient shrinkage of leiomyomas and that oral contraceptive use may be associated with a decreased risk of fibroids, we tested the hypothesis that sequential GnRHa/low-dose oral contraceptive treatment could be a therapeutic alternative in perimenopausal women with uterine fibroids. Six premenopausal women with leiomyomata uteri were treated with D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp-6-LHRH) depot (Decapeptyl 3.75) for 6 months and demonstrated a significant reduction in mean uterine volume. A low-dose oral contraceptive containing 30 micrograms of ethinyl oestradiol plus 150 micrograms of desogestrel was given during the ensuing 12 months. When GnRHa therapy was discontinued, there was a rapid regrowth of the uterine fibroids and the uterine volume had reached, or even exceeded, pretreatment values by the eighth to 12th month of contraceptive therapy. Sequential GnRHa/low-dose oral contraceptive treatment is not a useful tool for leiomyomata uteri.

Previous reports have suggested a predilection for right-sided ovulation and that epithelial ovarian cancer arises more commonly in the right ovary, thus establishing a possible causal relationship between ovulation and ovarian cancer. However, evaluation of ovulation patterns in consecutive cycles has produced contradictory results and there are no reports corroborating a higher incidence of right-sided ovarian cancers. We reviewed the records of 293 patients with epithelial ovarian cancer and found no significant difference between the frequency of tumors in the right and left ovaries. We also prospectively analyzed the side of ovulation in 41 unselected consecutive patients undergoing 156 in vitro fertilization cycles without ovarian stimulation. Follicular development was carefully monitored by daily ultrasonic scan and estradiol and LH plasma determinations. Eight-two ovulations (52%) were on the right (not statistically significant). Thus our results bring into question previous studies suggesting a link between the side of ovulation and epithelial ovarian cancer.

Malignant struma ovarii is a very rare tumour, with considerable controversy concerning the necessary histologic features for malignancy. Still more infrequent is the condition termed 'metastatic ovarian strumosis' or simply 'benign strumosis or strumatosis' and characterized by the presence of peritoneal implants of mature thyroid tissue occurring in struma ovarii. 'Strumosis' should not be confused with malignancy. Presented is a case of 'metastatic ovarian strumosis' in a 36-year-old woman with primary infertility who underwent three in-vitro fertilization (IVF) cycles with ovarian stimulation. She received hormonal treatment for 6 months after her last IVF because of 'persistent enlarged ovarian follicles' which were in fact 'thyroid follicles'.

Male sterility due to abnormal sperm morphology or motion has been widely reported, although relatively little has been published on the sperm nuclear protein abnormalities. We report the first cases worldwide of infertile patients having a complete selective absence of protamine P2 in the sperm nucleus. This provides a selective phenotype that will aid understanding of the mechanisms of synthesis, processing, or function of the P2 protamines. In addition, it is of marked immediate relevance to medicine as it allows the diagnosis of this type of human male sterility and the opportunity to understand the basis of this defect.