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Objective Fetuses conceived by assisted reproductive technology (ART) and those that are small-for-gestational age (SGA) show cardiovascular remodeling in utero; however, these two conditions are often associated. We aimed to evaluate the differential effect of ART and SGA on fetal cardiac remodeling. Methods This was a prospective cohort study of term singleton pregnancies seen at our department between April 2011 and September 2013. The cohort was divided according to fetal growth and mode of conception into the following four groups: 102 appropriate-for-gestational-age (AGA) fetuses conceived spontaneously (controls), 72 AGA fetuses conceived by ART (ART-AGA), 31 SGA fetuses conceived by ART (ART-SGA) and 28 SGA fetuses conceived naturally (Spont-SGA). SGA was defined as birth weight

Introduction: Recent reports consider endometriosis to be an immunological disorder, thus suggesting potential efficacy of immunomodulators for its treatment. The aim of this study was to assess the effects of oral administration of pentoxifylline on endometriosis-like lesions in a heterologous mice model. Study Design: Human endometrial tissue obtained from women (n = 5) undergoing surgery for benign conditions was implanted in nude female mice (n = 30). The animals were distributed into 3 experimental groups receiving: saline 0.1 mL/d (control, group I); pentoxifylline 100 mg/kg/d (group 2), and pentoxifylline 200 mg/kg/d (group 3). After 28 days, the number of implants and the total volume of surgically extracted tissue were recorded. Immunohistochemical analysis was performed to assess the area of endometriosis and vascularization of endometriosis-like lesions. Cytokine levels in peritoneal fluid samples were measured. Results: Macroscopic quantification showed a trend to dose-dependent reduction in the number of the endometriosis-like lesions after 28 days. The volume was significantly reduced in group 3 versus group 2 and controls (399.10 ± 120.68 mm3 vs 276.75 ±94.30 mm3 and 145.33 ± 38.20 mm3, respectively; P = .04). Similarly, the mean area of endometriosis was significantly lower in group 3 (0.12 ± 0.08 mm2) versus group 2 (1.35 ± 0.43 mm2) and control (2.84 ± 0.60 mm2; P = .001). Vascularization and cytokine levels were also reduced posttreatment. Conclusion: Our results suggest that the oral administration of pentoxifylline may be an alternative to current therapies for endometriosis. Nonetheless, further studies are required.

Objective The purpose of the study was to develop an easily applicable predictive model to predict deep infiltrating endometriosis in patients with ovarian endometrioma. Study design We performed a retrospective analysis of 178 consecutive women with ovarian endometrioma who underwent surgery, with histological confirmation and complete removal of endometriosis in the Hospital Clinic of Barcelona. Several markers were prospectively obtained and compared between the group of patients presenting deep infiltrating endometriosis associated with ovarian endometrioma and women with only ovarian endometrioma. Multiple logistic regression analysis was performed to create a model to predict the presence of deep infiltrating endometriosis and internal validation was later performed. Results Of the 178 patients studied, 80 (45%) were classified in the ovarian endometrioma group and 98 (55%) in the group of patients presenting deep infiltrating endometriosis associated with ovarian endometrioma. The independent variables to predict deep infiltrating endometriosis were: at least one previous pregnancy, a past history of surgery for endometriosis and the mean endometriosis-associated pelvic pain score. The area under the ROC curve was 0.91 (95% confidence interval: 0.86–0.94), with an optimal cut-off of the predicted probability of 0.54. The sensitivity of the model was 80% and the specificity 84%. Conclusions This model predicts the development of deep infiltrating endometriosis in patients with ovarian endometriomas allowing prioritization of women for referral to specialized centers.

Cell-derived microparticles (cMPs) are small membrane vesicles that are released from many different cell types in response to cellular activation or apoptosis. Elevated cMP counts have been found in almost all thrombotic diseases and pregnancy wastage, such as recurrent spontaneous abortion and in a number of conditions associated with inflammation, cellular activation and angiogenesis. cMP count was investigated in patients experiencing unexplained recurrent implantation failure (RIF). The study group was composed of 30 women diagnosed with RIF (RIF group). The first control group (IVF group) (n = 30) comprised patients undergoing a first successful IVF cycle. The second control group (FER group) included 30 healthy women who had at least one child born at term and no history of infertility or obstetric complications. cMP count was significantly higher in the RIF group compared with the IVF and FER groups (P < 0.05 and P < 0.01, respectively) (RIF group: 15.8 ± 6.2 nM phosphatidylserine equivalent [PS eq]; IVF group: 10.9 ± 5.3 nM PS eq; FER group: 9.6 ± 4.0 nM PS eq). No statistical difference was found in cMP count between the IVF and FER groups. Increased cMP count is, therefore, associated with RIF after IVF and embryo transfer.

STUDY QUESTION Are the levels of circulating cell-derived microparticles (cMPs) in patients with recurrent miscarriage (RM) associated with the antiphospholipid syndrome (APS)? SUMMARY ANSWER cMPs in women with RM are not associated with antiphospholipid antibodies (aPLs). WHAT IS KNOWN ALREADY Previous studies have focused on cMP levels in RM patients. Most studies have shown higher levels of cMPs in RM patients whereas others have reported lower levels. Data regarding cMPs in patients with the APS are scanty in the literature. STUDY DESIGN, SIZE, DURATION A case-control study including three groups of patients. A total of 154 women were prospectively recruited from September 2009 to October 2013. Four patients refused to participate. The APS group consisted of 50 women that had been previously diagnosed with primary APS and had had ≥3 consecutive first trimester miscarriages. The uRM group included 52 couples with ≥3 consecutive first trimester miscarriages of unknown etiology. The fertile control (FER) group was composed of 52 healthy fertile women with no history of pregnancy losses. Miscarriage was defined as intrauterine pregnancy loss at

Background Back and knee pain (BP; KP), which often accompanies osteoporosis, is a prevalent health problem affecting quality of life (QoL) in middle-aged women. Aim To compare the effects of calcium carbonate (CC) and ossein–hydroxyapatite complex (OHC) on BP and KP and QoL in perimenopausal osteopenic women. Subjects 74 perimenopausal women were randomized to receive 1200 mg/day of CC (n = 38) or 1660 mg/day of OHC (n = 36) for 6 months. Methods This was a randomized, open-label, parallel-group, controlled, prospective study. Back and knee basal pain was recorded using a visual analogue scale (VAS) at each control and exercise-induced pain was recorded using a visual rating system (VRS). Changes in QoL were evaluated using the SF-36 questionnaire. Results In patients treated with OHC, mean VAS and VRS pain scores decreased significantly after 5 and 6 months of treatment, indicating a significant analgesic effect. In the CC group, however, changes were minor and non-significant. Two-way analysis of variance using treatment group and time as independent variables revealed a significantly greater effect of OHC over CC on VAS and VRS scores. SF-36 showed significant improvement for OHC on the physical component summary score and no changes for CC. Responses to items assessing emotional and social aspects of QoL showed only a significant improvement in vitality for OHC and no significant changes for CC in any of the four dominions constituting the SF-36 mental component. Conclusion OHC has a significant analgesic effect and improves the physical component of QoL to a greater extent than CC.

We performed an individual patient meta-analysis to determine whether aspirin has a significant protective effect on the risk of first thrombosis among patients with antiphospholipid antibodies (aPL). Five international cohort studies with available individual patient-level data, reporting on primary prophylaxis with continuous treatment with low-dose aspirin in patients with aPL were included. The main outcome was the occurrence of a first thrombotic in patients with aPL treated with low-dose aspirin compared to those not treated with low-dose aspirin. Pooled Hazard Ratios (HRs) and 95%CIs were calculated using frailty models. We pooled data from 497 subjects and 79 first thrombotic events (3469 patient-years of follow-up). After adjustment on cardiovascular risk factors, aPL profiles, and treatment with hydroxychloroquine, the HR for the risk of a first thrombosis of any type in aPL carriers treated with low-dose aspirin versus those not treated with aspirin was 0.43 (95%CI 0.25-0.75). Subgroup analysis showed a protective effect of aspirin against arterial (HR: 0.43 [95%CI: 0.20-0.93]) but not venous (HR: 0.49 [95%CI: 0.22-1.11]) thrombosis. Subgroup analysis according to underlying disease revealed a protective effect of aspirin against arterial thrombosis for systemic lupus erythematosus (SLE) (HR: 0.43 [95%CI: 0.20-0.94]) and asymptomatic aPL carriers (HR: 0.43 [95%CI 0.20-0.93]). We found no independent protective effect of hydroxychloroquine. This individual patient data meta-analysis shows that the risk of first thrombotic event as well of first arterial thrombotic event is significantly decreased among SLE patients and asymptomatic aPL individuals treated by low-dose aspirin.

OBJECTIVE: To assess the postnatal persistence of fetal cardiovascular remodelling associated with assisted reproductive technologies (ART) in children at 3 years of age. DESIGN: A cohort study of children conceived by ART. SETTING: Maternal-Fetal Medicine Unit, Hospital Clinic Barcelona, Spain. POPULATION SAMPLE: Eighty singleton pregnancies conceived by ART and 80 spontaneously conceived (controls) followed from fetal life up to childhood. METHODS: Cardiovascular evaluation was performed at 3 years of corrected age, including echocardiography, carotid intima-media (cIMT) by ultrasound, and blood pressure. MAIN OUTCOME MEASURES: Postnatal persistence of cardiovascular changes in children conceived by ART. RESULTS: Compared with controls, children conceived by ART showed larger atria (right atrial area: control 4.9 cm(2) (0.9) versus ART 5.5 cm(2) (0.9), P < 0.001), more globular ventricles (right ventricular sphericity index: control mean 1.8 (SD 0.5) versus ART 1.6 (0.2), P < 0.001), and signs of systolic (tricuspid annular plane systolic excursion: control 18 mm (2) versus ART 16 mm (3), P < 0.001) and diastolic dysfunction (isovolumic relaxation time: control 68 ms (12) versus ART 79 ms (12), P < 0.001). ART children also presented increased systolic blood pressure (control 90 mmHg (6) versus ART 94 mmHg (5), P < 0.003) and cIMT (control 0.52 µm (0.14) versus ART 0.60 µm (0.16), P < 0.001) as compared with those spontaneously conceived. CONCLUSIONS: Cardiovascular changes previously reported in ART fetuses persist postnatally at 3 years of age. These results underscore the importance of future studies for assessing the long-term cardiovascular health associated with ART. TWEETABLE ABSTRACT: Cardiovascular changes described in fetuses conceived by ART, persist in children at 3 years of age.

OBJECTIVE: Recent data suggest that singleton fetuses conceived by assisted reproductive technology (ART) present cardiovascular remodeling that may persist postnatally. Twin pregnancies are more frequent in the ART population and are associated with increased adverse perinatal outcomes, such as hypertensive disorders, gestational diabetes and preterm birth. However, it is unknown whether cardiac remodeling is also present in twin pregnancies conceived by ART. Our aim was to assess the presence of fetal cardiac remodeling and dysfunction in twin pregnancies conceived by ART as compared with those conceived spontaneously (SC). METHODS: This was a prospective cohort study including 50 dichorionic twin fetuses conceived by ART and 50 SC twin fetuses. The study protocol included collection of baseline/perinatal data and a fetal ultrasound examination at 28-30 weeks' gestation, including assessment of estimated fetal weight, fetoplacental Doppler and fetal echocardiography. Measurements of atrial area, atrial/heart ratio, ventricular sphericity index, free wall thickness, mitral and tricuspid annular plane systolic excursions, and systolic and early diastolic peak velocities were assessed. Multilevel analyses were used to compare perinatal and ultrasonographic parameters. Comparisons of echocardiographic variables were adjusted for parental age, paternal body mass index and incidence of pre-eclampsia. RESULTS: Compared with SC twins, ART twin fetuses showed significant cardiac changes, predominantly affecting the right heart, such as dilated atria (right atrial/heart area: 15.7 ± 3.1 vs 18.4 ± 3.2, P < 0.001), more globular ventricles (right ventricular sphericity index: 1.57 ± 0.25 vs 1.41 ± 0.23, P = 0.001) and thicker myocardial walls (septal wall thickness: 2.57 ± 0.45 mm vs 2.84 ± 0.41 mm, P = 0.034) together with reduced longitudinal motion (tricuspid annular plane systolic excursion: 6.36 ± 0.89 mm vs 5.18 ± 0.93 mm, P < 0.001). CONCLUSIONS: ART twin fetuses present signs of cardiac remodeling and dysfunction. These changes are similar to those observed in ART singletons and reinforce the concept of fetal cardiac programing in ART. These results open opportunities for early detection and intervention in infants conceived by ART. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

We performed a meta-analysis to determine whether aspirin has a significant protective effect on risk of first thrombosis among patients with antiphospholipid antibodies (aPL+). Observational and interventional studies identified from the Medline, Embase and Cochrane databases were selected if they assessed the incidence of first thrombosis in aPL+ patients treated with aspirin versus those without. Pooled effect estimates were obtained using a random-effects model. Of 1211 citation retrieved, 11 primary studies (10 observational and 1 interventional) met inclusion criteria, including a total of 1208 patients and 139 thrombotic events. The pooled odds ratio (OR) for the risk of first thrombosis in patients treated with aspirin (n=601) was 0.50 (95%CI: 0.27 to 0.93) compared to those without aspirin (n=607), with significant heterogeneity across studies (I(2)=46%, p=0.05). Subgroup analysis showed a protective effect of aspirin against arterial (OR: 0.48 [95%CI: 0.28-0.82]) but not venous (OR: 0.58 [95% CI: 0.32-1.06]) thrombosis, as well as in retrospective (OR: 0.23 [0.13-0.42]) but not prospective studies (OR: 0.91 [0.52-1.59]). Subgroup analysis according to underlying disease revealed a significant protective effect of aspirin for asymptomatic aPL+ individuals (OR: 0.50 [0.25-0.99]), for systemic lupus erythematosus (SLE) (OR: 0.55 [0.31-0.98]) and obstetrical antiphospholipid syndrome (APS) (OR: 0.25 [0.10-0.62]). This meta-analysis shows that the risk of first thrombotic event is significantly decreased by low dose aspirin among asymptomatic aPL individuals, patients with SLE or obstetrical APS. Importantly, no significant risk reduction was observed when considering only prospective studies or those with the best methodological quality.

Normal pregnancy is associated with extensive changes in hemostasis such that the procoagulant effect becomes dominant. The evolutionary advantage of this hypercoagulability may be to counteract the inherent instability associated with hemochorial placentation, which is unique to human beings. However, overall, there is a four- to 10-fold increased thrombotic risk throughout gestation and the postpartum period. Certain inherited or acquired thrombophilic factors may predispose to arterial and/or venous thrombosis and have a possible association with pregnancy complications, including recurrent miscarriage (RM), which affects up to 5% of couples with childbearing desire. A subgroup of women with RM has been demonstrated to be in a prothombotic state before and after pregnancy. The long-term health implications of this hypercoagulability may imply an increased risk of ischemic heart disease. Moreover, the presence of antiphospholipid antibodies rather than thrombophilic genetic defects (i.e., factor V Leiden or prothrombin G202010A mutation) in patients with RM is a determinant of thrombotic events later in life, especially among those patients having also cardiovascular risk factors. This article highlights the thromboembolic risk in nonpregnant RM patients in different thrombophilic settings and the need for thromboprophylaxis among these patients.

Background— Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies. Methods and Results— This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1–7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1–6.1]; P 2 [interquartile range, 1.2–1.5 cm 2 ]; atrial area in ART, 1.6 cm 2 [interquartile range, 1.3–1.8 cm 2 ]; P P P Conclusions— Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated.

Purpose Several environmental toxicants (ETs), including dioxins and dioxin-like compounds (DLCs), perfluorochemicals, organochlorine pesticides, phthalates, and heavy metals (especially cadmium with its estrogen-like properties in animal models) have been investigated as possibly being related to endometriosis. Methods Systematic review of pertinent literature. Results DLCs have been the most investigated ETs. DLCs are persistent organic pollutants with highly toxic potential and include three types of compounds: polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) or furans, and polychlorinated biphenyls (PCBs). The most toxic is 2, 3, 7, 8- tetrachlorodibenzo-p-dioxin (TCDD). The connection mechanism between dioxins and endometriosis is still unclear. However, dioxins and DLCs are endocrine-disrupting compounds that can affect the pathobiology of endometriosis at multiple levels. Part of the dioxin and DLCs toxic effects can be accounted for by their interaction with the aryl hydrocarbon receptor (AhR). It has been proposed that dioxin can initiate or promote endometriosis by means of interaction with estrogen receptors or by suppressing the expression of progesterone receptors. Furthermore, TCDD alters the expression of cytokines and growth factors, remodeling enzymes and cytochrome P450 expression and activity. Conclusions Studies in rhesus models have revealed a correlation between dioxin exposure and endometriosis. However, evidence from epidemiologic studies is inconclusive.

Clinical results were compared in a well-established, assisted reproduction program during the cross-over from highly purified (HP)-human menopausal gonadotropin (hMG) to rhFSH/rhLH. We included the last 33 patients treated with HP-hMG and the first 33 patients receiving rhFSH/rhLH for ovarian stimulation in their first intracytoplasmic sperm injection cycle. Patient baseline characteristics were almost identical in the two groups. Ovarian stimulation characteristics (days of stimulation, total amount of FSH administered using a modest initial loading dose of 150 IU/d, patients with oocyte retrieval) were similar for the two groups. However, the number of total and leading follicles and E2 serum levels on the human chorionic gonadotropin injection day were significantly higher in the rhFSH/rhLH group. The oocyte yield was significantly higher in the rhFSH/rhLH group as well as the number of metaphase II oocytes, difference almost reaching the statistical significance. The number of oocytes fertilized was also higher in patients receiving rhFSH/rhLH treatment. Implantation and clinical pregnancy rates were similar in both the study groups. It is concluded that in women undergoing controlled ovarian hyperstimulation under pituitary suppression for ART, the recombinant combined product containing FSH and LH in a fixed 2:1 ratio is more effective than HP-hMG in terms of follicle development, oocyte yield and quality, and fertilization rates.

STUDY QUESTION Are the levels of total circulating cell-derived microparticles (cMPs) and circulating tissue factor-containing microparticles (cMP-TF) increased in patients with endometriosis? SUMMARY ANSWER The levels of total cMP, but not cMP-TF, were higher in patients with endometriosis, and these were attributed to higher levels in patients with deep infiltrating endometriosis (DIE). WHAT IS KNOWN ALREADY Previous studies have reported elevated levels of total cMP in inflammatory conditions as well as higher levels of other inflammatory biomarkers in endometriosis. Increased expression of tissue factor (a transmembrane receptor for Factor VII/VIIa) in eutopic and ectopic endometrium from patients with endometriosis has been described. There is no previous data regarding total cMP and cMP-TF levels in patients with endometriosis. STUDY DESIGN, SIZE, DURATION A prospective case-control study including two groups of patients was carried out. The E group included 65 patients with surgically confirmed endometriosis (37 with DIE lesions) and the C group comprises 33 women without surgical findings of any form of endometriosis. Patients and controls were recruited during the same 10-month period. Controls were the next patient without endometriosis undergoing surgery, after including two patients with endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS Venous blood samples for total cMP and cMP-TF determinations were obtained at the time of surgery, before anesthesia at a tertiary care center. To assess total cMP, an ELISA functional assay was used and cMP-TF activity in plasma was measured using an ELISA kit. MAIN RESULTS AND THE ROLE OF CHANCE Total cMP levels in plasma were higher in the E group compared with the C group (P < 0.0001). The subanalysis of endometriosis patients with DIE or with ovarian endometriomas without DIE showed that total cMP levels were higher in the DIE group (P = 0.001). There were no statistically significant differences in cMP-TF levels among the groups analyzed. LIMITATIONS, REASONS FOR CAUTION This is a preliminary study in which the sample size was arbitrarily decided, albeit in keeping with previous studies analyzing cMP in other inflammatory diseases and other biomarkers in endometriosis. The control group included patients with other pathologies as well as healthy controls, and blood samples were taken at different phases of the cycle. WIDER IMPLICATIONS OF THE FINDINGS Elevated total cMP levels in DIE patients may reflect an inflammatory and/or procoagulant systemic status in these patients. Further studies are warranted to confirm our findings and to assess the role of cMP levels in the pathophysiology of DIE. STUDY FUNDING/COMPETING INTERESTS This study was supported in part by a grant from FIS-PI11/01560 and FIS-PI11/00977 within the 'Plan Nacional de I + D + I' and co-funded by the 'ISCIII-Subdireccion General de Evaluacion' and 'Fondo Europeo de Desarrollo Regional (FEDER)' and by the grant 'Premi Fi de Residencia Emili Letang 2015' from the Hospital Clinic of Barcelona. The authors have no competing interests to disclose.

To evaluate the long-term safety, satisfaction and tolerability of flutamide therapy for female hyperandrogenism.A 20-year surveillance study.Setting: Gynecology Department in a teaching hospital.Hyperandrogenic women complaining for hirsutism treatment were followed between February 1995 and April 2015.Women received flutamide 125 or 250 mg/day alone (n = 55) or combined with oral contraceptives (n = 65).Adverse events, safety, tolerability satisfaction and efficacy were assessed every 6 months during all the follow-up. Lab tests including liver and lipid profiles were also recorded in each control.Patients under flutamide therapy showed significant improvements in hirsutism scores after 6 months of treatment with a maximum effect at 12 months that was maintained during all the therapy time. Satisfaction reported by patients with the efficacy of the drug in a visual scale was also high. A total of 54.2 % women presented one or more adverse effects during the follow-up; 33.3% showed at least one adverse effect possibly related with the study drug; and 24.1% withdrew from the study because of adverse effects. During the follow-up, as many as 89.9 % of patients abandoned flutamide. Reasons include: questions linked to medical problems (50%), attempt pregnancy (4%) and significant improvement in the symptomatology (35.8%).Flutamide is very effective for hirsutism treatment; however, adverse effects are very frequent and affect compliance.

Background: The identification of presurgical clinical markers may be helpful to allow the staging of endometriosis severity. It has been suggested that pain characteristics orientate the gynecologist about the anatomical involvement of endometriosis. The study was performed to analyze the correlation between pain symptoms and the anatomical location of endometriosis. Methods: One hundred fifty-five consecutive patients with a complete removal of deep infiltrating endometriosis (DIE) were included. Prior to surgery, data on patient and disease characteristics were obtained. The intensity of the pain symptoms was registered using a Visual Analogue Scale. The endometriotic lesions were categorized according to the Enzian morphological classification. Correlation and multivariate analysis were performed to assess the potential associations between pain characteristics (dysmenorrhea, pelvic pain, dyschezia, dyspareunia or dysuria) and the location of endometriosis or other disease-related characteristics (hematuria, rectal bleeding or adenomyosis). Results: Pelvic pain was significantly associated with the presence of adenomyosis. Dyschezia was correlated with rectal bleeding and dysuria with the presence of hematuria. No relationship was found between other kinds of pain and the morphological location of endometriosis or other disease-related characteristics. Conclusion: Our data suggest that pelvic pain is correlated with the presence of adenomyosis in women with DIE. Further studies are required.

OBJECTIVES: To assess the impact of Turners syndrome (TS) and other congenital hypogonadisms (OCH) on the sense of smell and taste. DESIGN: An analytical study of three independent cohorts was designed: patients affected by TS OCH and a control group of healthy women taking contraception. SETTING: Gynaecological Endocrinology Unit and Smell Clinic in Rhinology Unit of Hospital Clinic of Barcelona. PARTICIPANTS: Thirty TS patients between 20 and 50 years of age receiving hormone replacement treatment (HT) were included as the exposed cohort; fourteen age-matched women with OCH taking HT were recruited; forty-three age-matched healthy controls receiving hormone contraception treatment were selected as the control group. This group was matched with an historical cohort of forty healthy women without contraception used to validate BAST-24 in Hospital Clinic of Barcelona. INTERVENTIONS: Clinical history presence of nasal symptoms general physical examination nasal endoscopy and Barcelona Smell Test-24 (BAST-24) and gustometry were carried out on all patients. MAIN MEASURES: TS physical dysmorphology features intensity of nasal symptoms and signs of nasal obstruction were collected. BAST-24 test included 24 odours to assess both sensory (detection memory and forced choice) and sensitivity (intensity irritability freshness and pleasantness) odour characteristics as well as 4 tastes to evaluate taste domains (detection and forced choice). RESULTS: Healthy women taking hormone contraception felt odours with more intensity (p=0.002) and less irritability (p

Cytokines, and specifically interleukin 6 (IL-6) and interleukin 8 (IL-8), have been associated with the pathogenesis of endometriosis. We studied serum concentrations of IL-6 and IL-8 in patients with deep infiltrating endometriosis (DIE) or ovarian endometriomas (OE), but no other forms of associated endometriosis disease type. We carried out a case-control study including 19 patients with OE alone (OE group), 14 patients with DIE alone (DIE group) and 24 healthy patients without endometriosis (C group). Serum concentrations of IL-6 and IL-8 were measured in the three groups of patients. Serum levels of both IL-6 and IL-8 were significantly higher in the OE group. A high positive correlation was found between serum IL-6 and IL-8 levels in the OE group but not in the DIE and C groups. Serum IL-8 alone achieved the highest predictive value of the presence of OE (adjusted OR: 1.44; sensitivity: 78.2%; specificity: 76.2%). The combination of IL-6 and IL-8 levels did not significantly improve the discrimination between subjects with OE and those with DIE over that of IL-8. OE but not DIE are associated with increased serum levels of IL-6 and IL-8, and thus these may become useful tools for discriminating OE alone from DIE.

Recent evidence has confirmed two independent pathways in the development of vaginal squamous cell carcinoma (VaSCC): one related to and the other independent of human papillomavirus (HPV). The aim of our study was to evaluate whether HPV status has prognostic significance in this neoplasm.All confirmed primary VaSCCs diagnosed and treated from 1995 to 2009 in two institutions were retrospectively evaluated (n=57). HPV infection was detected by PCR using SPF-10 primers and typed with the INNO-LIPA HPV assay and p16(INK4a) expression by immunohistochemistry. Disease-free and overall survival (DFS and OS) were analyzed by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model.HR-HPV DNA was detected in 70.2% patients. HPV16 was the most prevalent genotype (67.5% of cases). p16(INK4a) was positive in 97.5% HPV-positive and 17.6% HPV-negative tumors (p.001). FIGO stage was associated with DFS (p=.042) and OS (p=.008). HPV-positive tumors showed better DFS (p=.042) and OS (p=.035) than HPV-negative tumors. Multivariate analysis confirmed better DFS and OS of HPV-positive patients independent of age and stage. This reduced risk of progression and mortality in HPV-positive patients was limited to women with FIGO stages I and II tumors (HR=0.26; 95% CI 0.10-0.69; p=0.006).HPV-positive early stage (FIGO I and II) VaSCCs have a better prognosis than early HPV-negative tumors. HPV detection and/or p16(INK4a) immunostaining can be easily implemented in routine pathology and should be considered as valuable prognostic biomarkers in the study of patients with VaSCC.

Recent evidence supports a specific and broad role of androgen produced by theca cells in reproductive physiology. This pilot study evaluated the usefulness of hCG theca stimulation test in predicting ovarian response and pregnancy.Prospective cohort study including 80 infertile women treated with IVF/ICSI. On Day 3 of the menstrual cycle preceding, the first IVF/ICSI cycle a blood sample was drawn to evaluate baseline FSH, estradiol (E(2)), 17-hydroxy-progesterone, androstenedione and testosterone levels. All women then received 250 µg recombinant hCG s.c. and underwent a second blood sampling 24 h after hCG injection to measurement steroid serum levels.Percentage increment of E(2) but not its precursors was significantly higher in normo-responders and pregnancy cycles than in poor responders and non-pregnancy cycles (P = 0.03 and P = 0.02, respectively) diagnostic accuracy being 67 and 75%, respectively. The percentage increase in E(2) thus still fails in as many as 33 and 25% of patients in predicting ovarian response and pregnancy, respectively. In addition, E(2) concentrations are poorly reproducible and a wide range of variation in all serum steroids investigated-including E(2)-after hCG injection was observed.The predictive power of the hCG test is based on E(2) but not androgen response to hCG injection. This test cannot be recommended in routine clinical practice because it is too laborious for screening purposes, shows great variability in the response obtained and its overall accuracy is not better than that reported for other available markers of ovarian reserve. The use of the currently available markers, antral follicle count and anti-Müllerian hormone, is therefore recommended.

OBJECTIVE To estimate why the live birth rate per implanted embryo is higher in twin than in singleton pregnancies. METHODS Data from 1,159 singleton and 523 dichorionic twin pregnancies, obtained after assisted conception, were included. To account for the higher live birth rate observed in twin pregnancies, two possibilities were considered: embryo collaboration and assistance. To test these hypotheses, we compared the observed values for each possible outcome in twin pregnancies (double birth, single birth, double loss) with the expected values regarding as the null hypothesis that the survival of either embryo is independent from the presence of the other. The effect of maternal age was also examined. RESULTS Live birth rate, per implanted embryo, was higher in twin than in singleton pregnancies: 83% compared with 76% (odds ratio 1.53, 95% confidence interval 1.24-1.88; P

ObjectiveTo investigate whether patients having antiphospholipid syndrome (APS) as the only aetiological factor for recurrent spontaneous abortion (RSA) are at increased risk of thrombosis later in life.MethodsA case–control study at a tertiary university referral centre. The study group consisted of 57 primary APS and RSA women (APS–RSA group). Control groups included: 86 patients with RSA of unknown aetiology (uRSA group), 42 patients with RSA and thrombophilic genetic defects as the only aetiologic factor for RSA (tRSA group) and 30 antiphospholipid antibody (aPL) positive but otherwise healthy women (aPL group). The main measurement was the thrombosis rate after long-term follow-up.ResultsAPS–RSA patients had a significantly higher 12-year cumulative thrombotic incidence rate compared with the three comparator groups (19.3% vs 4.8%, 0.0% and 0.0%, respectively (log rank), pConclusionsOur data indicate that a history of RSA associated with aPL is a risk factor for subsequent thrombosis in the long term.

Two independent pathways in the development of vulvar squamous cell carcinoma (VSCC) have been described, one related to and the other independent of high-risk human papillomavirus (HR-HPV). The aim of our study was to evaluate whether the HPV status has a prognostic significance or can predict response to radiotherapy.All VSCC diagnosed from 1995 to 2009 were retrospectively evaluated (n=98). HPV infection was detected by amplification of HPV DNA by PCR using SPF-10 primers and typed by the INNO-LIPA HPV research assay. p16(INK4a) expression was determined by immunohistochemistry. Disease-free and overall survival (DFS and OS) were estimated by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model.HR-HPV DNA was detected in 19.4% of patients. HPV16 was the most prevalent genotype (73.7% of cases). p16(INK4a) stained 100% HPV-positive and 1.3% HPV-negative tumors (p.001). No differences were found between HPV-positive and -negative tumors in terms of either DFS (39.8% vs. 49.8% at 5 years; p=.831), or OS (67.2% vs. 71.4% at 5 years; p=.791). No differences in survival were observed between HPV-positive and -negative patients requiring radiotherapy (hazard ratio [HR] 1.04, 95% confidence interval [CI] .45 to 2.41). FIGO stages III-IV (p=.002), lymph node metastasis (p=.030), size ≥ 20 mm (p=.023), invasion depth (p=.020) and ulceration (p=.032) were associated with increased mortality but in multivariated only lymph node metastasis retained the association (HR 13.28, 95% CI 1.19 to 148.61).HPV-positive and -negative VSCCs have a similar prognosis. Radiotherapy does not increase survival in HPV-positive women.

Objectives To evaluate the effects of mid-follicular recombinant human luteinizing hormone (rhLH) supplementation in down-regulated women of advanced reproductive age undergoing in vitro fertilization (IVF). Study design This was a prospective, randomized parallel-group study (allocation 1:1) including 187 normogonadotrophic infertile patients aged ≥35 years. Subcutaneous triptorelin was used for pituitary desensitization, and ovarian stimulation was achieved with recombinant human follicle-stimulating hormone (rhFSH) either alone (Group 1) or in combination with rhLH in one of two daily doses: 37.5IU (Group 2) or 75IU (Group 3). Ovarian stimulation characteristics and IVF outcome were evaluated. The main outcome was pregnancy rate. Results A total of 62, 62 and 63 patients were randomized to groups 1, 2 and 3 respectively, and 56, 54 and 55 patients respectively were available for final analysis of the results. Follicular development and oocyte yield were significantly higher in group 1 patients compared with patients in groups 2 and 3. Oocyte maturity and number of oocytes fertilized were also higher in group 1 patients; this difference almost reached statistical significance. No significant difference in implantation and clinical pregnancy rates was found among the three treatment groups. Conclusions rhLH supplementation is not a useful tool for patients of advanced reproductive age in ovarian stimulation protocols using an appropriate gonadotrophin-releasing hormone agonist and a step-down regimen of rhFSH.

Objective To investigate the effect of two laparoscopic techniques for treatment of ovarian endometriomas on recurrence rate. Design Prospective randomized clinical trial. Setting University teaching hospital. Patient(s) Ninety women with ovarian endometriomas. Intervention(s) Patients were randomly selected to undergo either laparoscopic cystectomy (group 1) or laser vaporization (group 2) of ovarian endometrioma. Main Outcome Measure(s) Recurrence, evaluated by ultrasound scan examination, was assessed at 12 and 60 months of follow-up. Result(s) Endometrioma recurrence rate was higher, though not significantly different, in group 2 at 60 months of follow-up. Nevertheless, at 12 months of follow-up recurrences were statistically higher in group 2. Conclusion(s) The comparison between laparoscopic laser ablation and laparoscopic cystectomy for ovarian endometriomas after long-term follow-up showed earlier recurrences and a higher recurrence rate in the laser group, although at 5 years of follow-up there were no statistically significant differences.

background: At a psychological level, having to undergo IVF in order to be a mother may be appraised differently by women who start this treatment. These different forms of assessment can affect the pregnancy rates. The objective of this study was to determine whether psychological variables such as primary appraisal and coping typologies were associated with positive results in b-hCG pregnancy test after IVF. methods: We performed a cross-sectional clinical study in a private infertility centre. We recruited women undergoing IVF treatment in the Assisted Reproduction Unit of the Hospital Clinic prior to treatment commencement. Women were asked to complete the Spanish adaptation of the Coping Responses Inventory-Adult Form, and coping typologies analysed in relation to pregnancy outcome of that round of treatment. results: Women who face infertility and IVF with optimistic appraisal had a considerably increased likelihood of pregnancy compared with those with a pessimistic appraisal (odds ratio ¼ 4.37; 95% confidence interval ¼ 1.76 –10.83). On the other hand, the pregnancy rate was significantly higher than the non-pregnancy rate among women who have a coping typology characterized by high use of approach strategies and with low use of avoidance strategies (Z-test ¼ 4.34, P , 0.001). conclusions: Psychological variables such as positive appraisal and coping typologies were associated with increased pregnancy rates after IVF. The main limitations of this study were the size of the sample and in particular its cross-sectional design which only allows predictive associations to be made.

The osteopontin: alphavbeta3 integrin complex has been proposed as a means of distinguishing receptive from non-receptive endometrium in clinical practice, thus offering new directions for the development of contraceptive approaches targeted to the endometrium as well as a better understanding of occult causes of infertility in women. Histological dating and immunohistochemical study were performed in control and study cycles in seven groups of women including 10 subjects per group and who received clomiphene citrate, ovarian stimulation for IVF, oral contraception, dehydrogesterone for endometrial luteal phase defect, two different regimens of hormone replacement therapy, or no treatment. Ten healthy fertile women served as a general control group. Osteopontin and alphavbeta3 integrin expression in the human endometrium was closely related to endometrial maturation and this was irrespective of the endometrium being in-phase or out-of-phase and the hormonal treatment (or no treatment) received. In conclusion, immunohistochemical assessment of the endometrium indicates that the use of osteopontin and alphavbeta3 integrin or the osteopontin: alphavbeta3 integrin complex as targets for the development of contraceptive approaches or the understanding of the pathogenesis of female infertility offer little benefit compared with simple histological dating.

To explore the role of cabergoline, a dopamine agonist, in the progression of meningiomas.Case report.Teaching hospital in Barcelona, Spain (Gynecology, Obstetrics and Neonatology Clinical Institute, Hospital Clínic).Women with a history of meningioma underwent surgery via right pterional craniotomy. During the follow-up, at 18 months after the operation the patient developed a progressive hyperprolactinemia with amenorrhea and galactorrhea. An MR examination revealed a recurrence of the neoplasm.Cabergoline treatment.Progression of meningioma.Long-standing cabergoline treatment in this patient with meningioma relapse early after surgery and subsequent hyperprolactinemia resulted in absence of progression of the neoplasm many years after the dopamine agonist initiation.These data suggest that cabergoline, a dopamine agonist, had an antiproliferative effect on the growth of meningiomas. Thus, one can hypothesise that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists such cabergoline may have a potential role in the medical treatment of patients with meningiomas.

Problem Antiphospholipid syndrome (APS) pregnancies are associated with thrombotic obstetric complications, despite treatment. This study evaluated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) levels, TAFI gene polymorphisms and Clot Lysis Time (CLT) in pregnant patients with APS in relation to pregnancy outcome and thrombosis. Method of study Group 1 consisted of 67 pregnant patients with APS. Group 2 included 66 pregnant patients with uneventful term pregnancies and delivery. Patients were sampled during each trimester and at baseline. TAFI antigen and CLT and two polymorphisms of the TAFI gene, Ala147Thr and +1542C/G, were determined. Results Significantly prolonged CLT was found at baseline in Group 1. Allele distribution of the TAFI gene polymorphisms was similar in both groups. Basal TAFI and CLT in patients with APS having an adverse or a good obstetrical outcome were similar. Comparison of TAFI and CLT baseline levels in patients with APS with or without previous thrombosis showed no statistical differences. Conclusion Patients with APS have impairment in fibrinolysis evidenced by prolonged CLT at baseline. TAFI and CLT do not seem to be useful as markers of obstetric outcome or risk of thrombosis in patients with APS.

Objetivo: Describir una nueva tecnica de entrada abdominal con un solo trocar (single port access [SPA]) para la cirugia ginecologica laparoscopica, que combina las ventajas de la cirugia a traves de orificios naturales permitiendo, sin embargo, la utilizacion de instrumentos estandar y evitando la apertura de visceras huecas. Paciente y metodos: Se describe nuestra experiencia en un caso de anexectomia bilateral realizada con tecnica de SPA. Resultados: La anexectomia bilateral con tecnica de SPA fue factible y se realizo con instrumental laparoscopico estandar. El tiempo operatorio fue de 87 min. No hubo complicaciones destacables. Diferentes problemas tecnicos, como la falta de triangulacion o el conflicto de espacio entre el cirujano y el ayudante, entre otros, se asociaron al procedimiento. Conclusiones: La anexectomia laparoscopica con tecnica de SPA es factible y segura en manos expertas. El desarrollo de nuevos instrumentos especificamente disenados para este tipo de cirugia contribuira a acortar el tiempo quirurgico y los problemas tecnicos actuales.

The relationship between autoimmunity and reproduction has long been recognized. This relationship is bidirectional and includes many diverse issues, but in this review article, we focus on which autoimmune disturbances are the basic cause of recurrent pregnancy losses in patients with autoimmune diseases. The antiphospholipid antibodies seem to be clearly associated with recurrent miscarriage. Although there is no agreement on the mechanisms of recurrent pregnancy losses in patients with these antibodies, vasculopathy of the terminal spiral arteries may be implicated and there is a general consensus to routinely screen for antiphospholipid antibodies in patients with recurrent miscarriage. Well-designed diagnostic studies are needed to estimate the true association between other specific autoantibodies and recurrent miscarriage.

Objective To assess the effect of surgeon's increasing experience in conservative laparoscopic surgery of women with rectovaginal endometriosis on the surgical outcome of these patients recurrence rate. Design Prospective cohort study. Setting University teaching hospital. Patient(s) The first 60 consecutive patients undergoing laparoscopic conservative surgery for symptomatic rectovaginal endometriosis at our institution during a 4- year period. Intervention(s) Cases were classified into two groups according to the date of the patient's operation: the first 30 cases were defined as the early cases and the subsequent 30 cases as the late cases. Main Outcome Measure(s) Operating time, perioperative complications, and surgical outcome. Univariate and multivariate analyses for risk factors with recurrence of disease. Result(s) The two groups were similar in patient characteristics. There was a reduction in the rate of laparoconversion, operating time, estimated amount of blood loss, cases with incomplete removal, and recurrence rate with increasing surgeon's experience. Surgical completeness was significantly associated with recurrence of disease. Conclusion(s) A learning curve is demonstrated in the conservative laparoscopic management of patients with rectovaginal endometriosis. After gaining experience in performing 30 cases, the recurrence rate is significantly reduced.

We compared the efficiency and safety of a newly developed reusable morcellator (Olympus VarioCarve) with that of a disposable morcellator (GyneCare Morcellex) for gynecologic laparoscopic surgery. In group 1 (n = 15 patients; 11 myomectomies and 4 supracervical hysterectomies), the laparoscopic disposable morcellator was used, and in group 2 (n = 14; 11 myomectomies and 3 supracervical hysterectomies), the reusable morcellator was used. There were no statistical differences in total tissue weight. Morcellating time was significantly shorter in group 2, and the rate of morcellation was significantly greater in group 2. Significantly fewer and longer pieces of tissue were removed with the reusable morcellator. No iatrogenic organ damage was observed.

Hirsutism in young women is not uncommon. Several drugs have been investigated as treatment and have been largely ineffective or inconsistent although cosmetic measures have been achieved in some patients. Previous studies have suggested that flutamide and other nonestrogenic antiandrogen agents may be effective in patients with hirsutism. However, severe adverse effects such as liver toxicity limit their clinical usefulness. Reports addressing this issue have been either short-term studies (6-12 months) or had a small sample size. This prospective study assessed the safety and tolerability of long-term flutamide treatment in hirsute women. The participants were 93 women with moderate to severe hirsutism. Women who fulfilled inclusion criteria (n = 83) received either flutamide 250 mg/d alone (n = 27) or combined with a fixed dose of an oral contraceptive containing 0.020 mg of ethinyl estradiol and 0.15 mg of desogestrel (n = 56) for 84 months. Baseline and treatment data for both groups was very similar and were pooled in the final analysis. Each patient was evaluated for efficacy, safety and tolerability at 6 and 12 months follow-up, and at yearly intervals until the end of the study. Self-perception of therapeutic effect was rated by the patients using a visual analog scale. Tolerability and patient satisfaction were determined by use of questionnaires. Compared with basal values, treatment with flutamide produced a significant progressive decrease in hirsutism after 6 months of treatment (P < 0.001). Improvement in hirsutism scores was maximal at 12 months and maintained at this level throughout the 84-month study period. At follow-up, 34 patients (40.96%, 34/83) had one or more adverse events and 28 (33.73%, 28/83) presented with at least one adverse effect possibly related to flutamide treatment. Twenty patients (24.09%, 20/83) left the study due to intolerance or adverse effects requiring discontinuation of the drug. In total, 39 women (47%, 39/83) withdrew from the study during follow-up. Among those remaining in the study, self-perception of therapeutic efficacy and satisfaction with effects of therapy was high at both 6 and 84 months and none reported dissatisfaction of any type. These findings showing the long-term effectiveness of flutamide for hirsutism are consistent with data from short-term studies but further demonstrate the high incidence of adverse effects and poor treatment compliance.

Luteinized granulosa cells and macrophages actively secrete vascular endothelial growth factor (VEGF) and adrenomedullin in the human ovulatory follicle. LH/human chorionic gonadotrophin (HCG) directly stimulates VEGF synthesis by granulosa cells while adrenomedullin may play a role in the process of luteinization. The current study examines whether pure human LH and HCG directly stimulate VEGF and adrenomedullin production by follicular fluid macrophages and granulosa cells. Macrophages and granulosa cells were obtained from pooled follicular aspirates of five individual patients during oocyte retrieval for IVF treatment. The cells were cultured in medium alone (control) or in medium supplemented with 1 IU/ml recombinant HCG (rHCG) or 6 IU/ml recombinant LH (rLH) for up to 7 days. VEGF production by macrophages was about five- or six-fold enhanced after 5 and 7 days by culture in the presence of rHCG or rLH when compared with control cultures. This effect was less pronounced on granulosa cells. Conversely, treatment with rHCG or rLH had no effect on the production rate of adrenomedullin neither in macrophages nor in granulosa cells. The effects of rHCG and rLH on VEGF production by granulosa cells or macrophages in culture were similar. This study suggests for the first time that LH-like gonadotrophins may directly stimulate VEGF but not adrenomedullin synthesis by follicular fluid macrophages.

Objective To evaluate the effect of FSH levels in the development of human osteoporosis. Design Case-series study. Setting Gynecology department in a teaching hospital. Patient(s) A total of 8 women diagnosed with Kallman syndrome (KS) were compared with 11 with Turner syndrome and 11 with pure gonadal dysgenesia (GD, karyotype 46,XX). Intervention(s) We assessed the pituitary–gonadal axis, bone turnover markers, bone mass, and patient characteristics. Main Outcome Measure(s) Bone mineral density as assessed by dual-energy X-ray absorptiometry, plasma FSH, LH, E 2 , osteocalcin (BGP), and urinary type I collagen cross-linked N -telopeptide. Other biochemical markers included 25-hydroxyvitamin D, as well as parathyroid hormone and urine concentration of calcium and creatinine. Result(s) In girls with Turner syndrome and GD, FSH (64.03 ± 29.2 and 90.08 ± 22.41 mIU/mL, respectively) and LH (45.29 ± 11.90 and 48.83 ± 12.44 mIU/mL, respectively) levels were significantly higher compared with those observed in girls with KS (FSH: 1.87 ± 0.64 and LH: 1.02 ± 0.57), whereas no differences were detected in E 2 or bone marker levels. Bone mineral density correlated positively with FSH levels but not with E 2 ; however, after adjusting for previous growth-hormone therapy, these differences were not found. In addition, bone mineral density in spine and total hip was significantly lower in patients with KS. Conclusion(s) Follicle-stimulating hormone does not appear to have a major role in the development of bone loss in young women with primary amenorrhea.

Objective To quantify p27 messenger RNA (mRNA) levels in human arrested and normally developing embryos and nonfertilized oocytes to determine whether the p27 protein abundance, reported in cleavage-stage embryos exhibiting developmental arrest, is regulated at the mRNA expression level. Design Real-time reverse transcription quantitative polymerase chain reaction was used to quantify the expression of p27 in three samples: arrested embryos (group A, n=29), normally developing embryos (group D, n=34), and nonfertilized oocytes (group O, n=20). Setting Research laboratory working closely with a clinical IVF practice. Patient(s) Oocytes and embryos were obtained from patients undergoing assisted fertilization. Intervention(s) None. Main Outcome Measure(s) Quantification of mRNA transcripts. Result(s) The amount of p27 mRNA was statistically significantly higher in group A (mean ± SEM, 86,143 ± 42,496 relative units [RU]) compared with groups D (10,680 ± 3,850 RU) and O (3,555 ± 1,458 RU). Furthermore, in a group of 13 two- to four-cell arrested embryos, high levels of p27 mRNA (51,481 ± 31,120 RU) were found in comparison with the nonfertilized oocyte group (3,555 ± 1,458 RU). Conclusion(s) Cleavage-stage human embryos exhibiting developmental arrest show increased p27 mRNA expression. This probably is due to increased transcriptional activity.

Objectives To examine perinatal outcomes in pregnancies conceived by different methods: fertile women with spontaneous pregnancies, infertile women who achieved pregnancy without treatment, pregnancies achieved by ovulation induction (OI) and in vitro fertilization or intra-cytoplasmic sperm injection (IVF/ICSI). Methods Retrospective single-center cohort study including 200 fertile and 748 infertile women stratified according to infertility treatment. The outcome measurements were preterm delivery (PTD), small-for-gestational-age (SGA), gestational diabetes, placenta previa or preeclampsia. Results The overall rate of pregnancy complications was significantly increased in all infertility groups regardless of the infertility treatment (adjusted odds ratio (OR): infertile without treatment 2.3 versus OI 2.2 versus IVF/ICSI 3.4). While PTD was mainly associated to IVF/ICSI (adjusted OR: infertile without treatment 1.3 versus OI 1.6 versus IVF/ICSI 3.3), SGA was significantly associated to both OI and IVF/ICSI (adjusted OR: infertile without treatment 1.9 versus OI 2.7 versus IVF/ICSI 2.6). All these associations remained statistically significant after adjusting by maternal age and twin pregnancy. Conclusions This study confirms the higher prevalence of pregnancy complications in infertile women irrespectively of receiving infertility treatment or not, and further describes a preferential association of prematurity with IVF/ICSI, and SGA with treated infertility (OI and IVF/ICSI).

BACKGROUND: Recurrent pregnancy loss (RM) affects 0.5–1% of couples. The pathophysiology of RM is complex. The suggested causes include anatomical, genetic and molecular abnormalities, endocrine disorders, thrombophilias and anti-phospholipid syndrome. In 50% of the cases neither of the above can be identified. We aimed at examining the evidence on the role of progesterone in the pathophysiology of RM, and the clinical evidence on effectiveness of progestogen treatment. METHODS: We searched PubMed and the Cochrane database covering the period of 1968–2007. The search terms progestogens and recurrent miscarriage, NK cells and recurrent miscarriage as well as cytokines and recurrent miscarriage were used. RESULTS: Progesterone is indispensable for creating a suitable endometrial environment for implantation. RM may be due to subnormal progesterone secretion and retarded endometrial development in the peri-implantation period. Progesterone also acts on the immune system, mainly by affecting cytokine synthesis and the function of NK cells. A recent meta-analysis showed that though progesterone treatment did not affect pregnancy outcome in women with miscarriages in general, separate analysis of three small and dated studies including altogether 91 patients with RM revealed a small but significant effect. It is noteworthy that the design of these 40 years old studies does not meet modern requirements. CONCLUSION: Standardized laboratory protocols for identifying potential targets of progestogen treatment as well as implementation of well-designed randomized studies are needed to establish the usefulness of progesterone supplementation in the treatment of RM.

Resumen Introduccion La diferenciacion sexual no siempre viene determinada por el sexo cromosomico, asi en ocasiones se pueden encontrar varones portadores de cromosomas sexuales XX o mujeres XY, esta disociacion entre el sexo gonadal y el cromosomico se suele acompanar de problemas reproductivos, por lo que esta alteracion se presenta con mayor frecuencia en las consultas de esterilidad. Objetivo Valorar la incidencia de varones XX en la consulta de esterilidad, asi como sus posibles implicaciones clinicas. Material y metodos Se revisa a 4 varones XX de una poblacion de 4.560 varones que acudieron a la consulta de andrologia reproductiva por una esterilidad primaria. A todos ellos se les practico un estudio seminal, exploracion general y gonadal, determinaciones plasmaticas de gonadotropinas, testosterona, estradiol e inhibina B. En todos ellos se aplicaron tecnicas de FISH a fin de detectar la posible presencia del gen SRY. Resultados En todos los pacientes el seminograma mostro una azoospermia, que en 3 pacientes se asociaba a una hipospermia. Los 4 pacientes presentaban unos valores plasmaticos elevados de gonadotropinas y una inhibina B no detectable, y la testosterona y el estradiol estaban en rangos aceptables de normalidad. La exploracion clinica solo evidencio una atrofia testicular en todos ellos. En los 4 pacientes se observo la presencia del gen SRY, en 3 de ellos situado en el cromosoma X y en el cuarto en el cromosoma 1. Conclusiones La presencia de varones XX en nuestra consulta de esterilidad se ha dado con una frecuencia del 0,087% (4/4.560), lo que supone una incidencia casi 20 veces superior a la esperada en una poblacion general, que es del 0,005% (1/20.000). Todos estos pacientes presentan una esterilidad, consecuente a su azoospermia. A pesar de la disociacion entre sexo gonadal y el cromosomico a la exploracion clinica solo se evidencia una atrofia testicular, sin otra alteracion fenotipica.

Vascular endothelial growth factor (VEGF) has been investigated as a marker of ovarian response to controlled ovarian hyperstimulation and as a predictor of ovarian hyperstimulation syndrome (OHSS) in IVF cycles. In most studies, serum has been used for circulating VEGF concentration measurement, but it has been suggested that plasma is the preferred medium to measure VEGF levels because of the potential contribution of VEGF released from platelets during blood clotting. This study investigated VEGF concentrations in paired serum and plasma samples from patients undergoing controlled ovarian hyperstimulation for IVF.Serum and plasma VEGF levels, as well as the number of platelets, were measured in 30 IVF patients who comprised three study groups delineated according to the estradiol (E(2)) serum concentration reached on the day of HCG administration: 10 patients having low E(2) serum levels (1500 pg/ml, group L), 10 patients having intermediate E(2) serum levels (1500-3000 pg/ml, group I) and 10 patients having high E(2) serum levels (3000 pg/ml, group H).There was a statistically significant correlation between plasma and serum VEGF levels (rho = 0.61; P0.005) for the entire population studied, although serum values were higher by a factor of approximately 6-fold. No significant correlation was found between peripheral blood VEGF concentrations and serum E(2) or follicle number on HCG day or the number of oocytes collected. Similarly, paired serum and plasma VEGF measurements did not correlate with platelet count.Serum and plasma VEGF concentrations are strongly correlated in paired samples from infertile patients undergoing controlled ovarian hyperstimulation. However, neither serum nor plasma VEGF levels were correlated with parameters associated with ovarian follicular activity. Peripheral blood VEGF levels were not correlated with platelet count.

Problem Whether decidual leukocyte recruitment and/or increase is primarily hormonally regulated or induced mainly by blastocyst implantation is a matter of debate. Thus, this study investigated the number and distribution of leukocyte populations, with emphasis on natural killer (NK) cells of uterine and peripheral type, within decidual tissue from women with decidualized endometrium both related and unrelated to pregnancy and those with ectopic decidua associated with intrauterine pregnancy, as well as in tubal implantation sites. Method of study Immunohistochemical characterization of immune cells using antibodies to CD3, CD4, CD8, CD20, CD68, CD16, CD56, CD57, in formalin-fixed, paraffin-embedded tissue, and a quantitative analysis of these subpopulations was conducted in tissue blocks from four groups of patients: (i) 20 women with decidualized endometrium due to progestin therapy (i.e. not associated with gestation) (group Prog-D); (ii) 20 women with intrauterine pregnancy-associated ectopic decidua (seven in the Fallopian tube, five in the ovary, five in the uterine cervix, and three in the omentum) (group Ect-D); (iii) 20 women with spontaneous abortion who had an histologic sample of the decidua at the uterine implantation site (group Uter-D); and (iv) 20 consecutive patients who had had an ectopic tubal pregnancy (group Tub-Preg). Twenty gynecologic specimens with marked inflammatory reaction were used as controls (group Con). Results CD3+, CD4+, CD8+, CD68+ cells were detected in all tissue samples investigated. In contrast, CD20+ cells were detected in all samples in group Con, but only in 75%, 25%, 55% and 70% of groups Prog-D, Ect-D, Uter-D and Tub-Preg, respectively. In all tissue samples investigated, CD57+ and CD16+ cells were detected. Conversely, CD56+ cells were completely absent in 15 of 40 cases (37.5%) lacking decidual reaction (group Tub-Preg, 7/20; group Con, 8/20) but were present in all cases showing decidual reaction. In contrast with CD56+ cells, CD57+ NK cells were more abundant in group Con than in the four study groups. Conclusions CD56+ NK cells are closely related to decidua irrespective of its eutopic or ectopic location rather than to the implantation site. This suggests that the recruitment and/or increase of uterine NK cells into the uterus is not dependent on the physical presence of an implanting embryo but instead is controlled hormonally.

To evaluate the effects of recombinant human luteinizing hormone (rhLH) supplementation on ovarian stimulation and implantation rate in down-regulated women of advanced reproductive age.Prospective randomized study.University teaching hospital.A total of 120 consecutive normogonadotropic infertile womenor = 35 years old undergoing their first cycle of IVF or intracytoplasmic sperm injection (ICSI) treatment.Ovarian stimulation in a long agonist protocol with a combination of recombinant human follicle-stimulating hormone (rhFSH) and rhLH (group 1, n = 60) starting on day 6 of FSH stimulation until hCG at a daily fixed dose of 150 IU of rhLH, or with rhFSH alone (group 2, n = 60).Ovarian stimulation characteristics, ovum retrieval, and IVF/ICSI outcome.The mean number of intermediate (10-14 mm) and large (14-18 mm) but not leading (or = 18 mm) follicles was significantly lower in group 1 on the day of hCG injection. The oocyte yield and maturity as well as the number of oocytes fertilized were significantly higher in group 2 than in group 1. However, the number of patients having embryo transfer (n = 55 in both treatment groups), the number and quality of embryos replaced, the implantation rate (20.6% vs. 21.7%) and clinical pregnancy rates per embryo transfer (44% vs. 45%) were similar in groups 1 and 2.The rhLH supplementation does not increase ovarian response and implantation rates in patients of older reproductive age stimulated with rhFSH under pituitary suppression for assisted reproductive technologies (ARTs).

BACKGROUND: Recent evidence showed that ultrasound-guided embryo transfer significantly increases successful implantation compared to the clinical touch method. It has been postulated that new echodense catheters which are more readily detectable by ultrasound may refine transfer techniques even more, thus improving IVF outcome. METHODS: A prospective, randomized, controlled trial comparing IVF outcome for women undergoing embryo transfer under ultrasound guidance by a single healthcare provider with random assignment according to a computer-generated randomization table to either standard soft Wallace catheter (standard catheter group, n = 95) or the new echogenic soft Wallace catheter (echogenic catheter group, n = 98). RESULTS: The use of the echodense catheter facilitated catheter identification under ultrasound, and thus the duration of the embryo transfer procedure since the loaded catheter was handed to the physician and up to embryo discharge was significantly shorter in the echogenic catheter group as compared with the standard catheter group. There were 39 and 53 clinical pregnancies in the standard catheter (41%) and echogenic catheter (54.1%) groups, respectively. This was not statistically significant (P = 0.08) according to the OR (0.6) and CIs (0.33–1.04). However, twin pregnancy rate was significantly increased (P < 0.01) with the use of the new catheter which was the underlying source for obtaining significant increase in implantation rate in this group (37.1%) as compared with the standard catheter group (23.2%). CONCLUSION: This pilot study suggests that the use of the echogenic Wallace catheter simplifies ultrasound-guided embryo transfer but not definite benefit in terms of pregnancy rates was obtained. In contrast, the use of the new catheter was associated with a significant increase in the number of twin pregnancies.

Objective The objective of the study was to investigate the potential role of impaired factor XII–dependent activation of fibrinolysis in treated antiphospholipid syndrome gestations developing late-pregnancy complications. Study design This was a prospective study in a third-level teaching hospital, including 75 patients: 25 pregnant patients having the antiphospholipid syndrome and carrying their pregnancies until 26 weeks' gestation or later (group 1); 25 pregnant patients having normal term pregnancies and delivery and no previous miscarriage (group 2); and 25 pregnant patients being diagnosed as having severe pre-eclampsia and/or intrauterine growth restriction but testing negative for antiphospholipid antibodies (group 3). Hemostatic evaluation was carried out from patients in groups 1 and 2 between 6 and 10 weeks, between 18 and 22 weeks, and between 28 and 32 weeks' gestation. Patients in group 3 were sampled between 28 and 32 weeks. An additional blood sample was obtained 4 to 6 months after delivery (baseline). The Mann-Whitney U test, the Friedman test, and the χ 2 test were used. Results Patients in group 1 were characterized by increased factor VIIa levels, increased prothrombin fragment 1+2 levels, reduced factor XIIa levels, diminished functional urokinase-type plasminogen activator levels, and decreased levels of plasmin/alpha-2-plasmin inhibitor complexes. These abnormalities were more evident in patients in group 1 developing pre-eclampsia and/or intrauterine growth restriction. Conclusions Impaired factor XIIa–dependent activation of fibrinolysis seems to be a key mechanism related to late-pregnancy complications in patients with the antiphospholipid syndrome.