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Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. Most pregnancies were achieved after orthotopic transplantation of tissue (in the peritoneum or the remaining ovary); however, treatment of the transplantation site during surgery is controversial. In this observational case-series study, we include four patients who underwent ovarian tissue transplantation between 2012 and 2016 by laparoscopy. Previously ovarian tissue was cryopreserved with slow freezing protocol prior to chemo- and/or radiotherapy. After cancer remission, the cryopreserved ovarian tissues were orthotopically re-transplanted in the ovarian medulla by laparoscopy, using N-hexyl-2-cyanoacrylate as an absorbable adhesion barrier. All patients regained ovarian function between 8 and 24 weeks after transplantation, as shown by follicle development and estrogen production. In patients 1 and 2 the ovarian function ended one year after transplantation. Patient 3 has regular menstrual cycles 2 years after the transplant and patient 4 currently has an ongoing spontaneous pregnancy. The use of N-hexyl-2 cyanoacrylate can facilitate the placement of ovarian pieces in orthotopic transplantation by laparoscopy without affecting the restoration and duration of ovarian activity.

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— 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.

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.

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.

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.

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 Anti-Mullerian hormone (AMH) has been recently proposed as a marker for ovarian ageing and poor ovarian response to controlled ovarian hyperstimulation in assisted reproduction cycles. The present study was undertaken to investigate the usefulness of baseline cycle day 3 AMH levels and AMH serum concentrations obtained on the fifth day of gonadotropin therapy in predicting ovarian response and pregnancy in women undergoing ovarian stimulation with FSH under pituitary desensitization for assisted reproduction. Methods A total of 80 women undergoing their first cycle of IVF/intracytoplasmic sperm injection (ICSI) treatment were studied. Twenty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, 60 women were randomly selected from our assisted reproduction programme matching by race, age, body mass index, basal FSH and indication for IVF/ICSI to those in the cancelled group. For each cancelled patient, three IVF/ICSI women who met the matching criteria were included. Results Basal and day 5 AMH serum concentrations were significantly lower in the cancelled than in the control group. Receiver-operating characteristic (ROC) analysis showed that the capacity of day 5 AMH in predicting the likelihood of cancellation in an assisted reproduction treatment programme was significantly higher than that for basal AMH measurement. However, the predictive capacity of day 5 AMH was not better than that provided by day 5 estradiol. In addition, neither basal nor day 5 AMH or estradiol measurements were useful in the prediction of pregnancy after assisted reproductive treatment. Conclusions AMH concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproduction are better predictors of ovarian response than basal AMH measurements. However, AMH is not useful in the prediction of pregnancy. Definite clinical applicability of AMH determination as a marker of IVF outcome remains to be established.

Background There is scanty information analysing the predictive value of a poor response, in terms of cancellation of the IVF cycle because of poor follicular development, as a predictor of ovarian response in a subsequent treatment cycle. This study, where logistic regression analysis was used, was undertaken to investigate the relative power of the woman's age, basal FSH, and previous cycle cancellation both as single and combined predictors of ovarian response in an IVF program where pituitary desensitization is routinely used. Methods One hundred and twenty-nine consecutive patients having their first cycle of IVF/ICSI treatment cancelled because of poor follicular response and undergoing a second attempt within 6 months after the failed treatment cycle were initially selected (group 1). Group 2 comprised 129 patients undergoing the first cycle of IVF/ICSI treatment and who were randomly selected from our assisted reproductive treatment program matching by BMI and indication for IVF/ICSI to those in group 1. Results Cancellation rate was significantly higher but ovarian response significantly lower in group 1 as compared with group 2. As indicated by the AUC(ROC) determined with ROC analysis, such a poor outcome in patients having a previous IVF/ICSI cycle cancelled due to poor response was observed whatever the level of basal FSH. In a logistic regression analysis and according to the odds ratio values, the predictive capacity of a previous poor response was 9 and 7.6 times higher than the predictive capacity of age and basal FSH, respectively. Any two or all three variables studied did not improve the predictive value of previous cycle cancellation alone. Conclusions The history of an IVF/ICSI cancelled cycle due to poor follicular response in a standard stimulation protocol is a better predictor of cancellation in subsequent treatment cycles than age or FSH. The poor ovarian response associated with previous cycle cancellation occurs whatever the level of basal FSH.

Problem: The majority of women with recurrent miscarriage have no discernible cause but it has been postulated that immunologic aberrations may be the cause in most of such cases. Also, it has been stressed that deliberate modification of the maternal host defense system can improve the chances of success. We tested the hypothesis that it is possible to potentiate maternal immune functions so as to improve reproductive performance by replacing several embryos into the uterus, thus favoring the recognition of fetal antigens. Method of study: A total of 57 couples with three or more (mean 5.52; range 3–12) consecutive first-trimester spontaneous clinical abortions of unknown etiology were treated with in vitro fertilization (IVF) and embryo transfer for a total of 84 cycles. Patients underwent IVF after combined gonadotropin-releasing hormone agonist/gonadotropin treatment for ovarian stimulation, and up to four embryos were replaced into the uterus. Results: There were 32 pregnancies (three of them after frozen–thawed embryo transfers) and 26 (81%) of them were viable gestations. Overall, patients had a previous obstetric history of 315 pregnancy losses and 15 live-born babies. Thus, the probability of having a live baby before treatment was 4.54% (95% CI, 2.78–7.36) a figure significantly lower (P

Objective To investigate the predictive value of ultrasonographic parameters as prognostic indicators of implantation after IVF when measured on the day of embryo transfer. Design Comparative, observational study. Setting University teaching hospital. Patient(s) Two hundred eighty patients undergoing IVF. Intervention(s) Ovarian stimulation, IVF. Main outcome measure(s) Variables related to patients' clinical characteristics, treatment characteristics, ovarian response, ovum retrieval, outcome of IVF and ICSI, embryo transfer, ultrasonographic and Doppler endometrial measurements, and uterine blood flow that have been proposed as potential predictive factors of implantation. All transvaginal ultrasonographic assessments were performed on the day of embryo transfer. Result(s) Among 240 patients finally evaluable, 67 (group 1) became pregnant after IVF, and 173 (group 2) failed to conceive. The 111 nonpregnant patients who had the same embryo score per replacement (group 3) as did patients in group 1 were selected for comparison purposes. The only significant differences between groups 1 and 3 were the type A endometrium and the absence of a protodiastolic notch in the uterine arteries, both of which were more frequently found in group 1. However, a considerable overlap existed between conception and nonconception cycles regarding both variables. Conclusion(s) Ultrasonographic parameters as predictors of implantation in assisted reproduction have a limited value in the clinical setting.

BACKGROUND: There is scanty and contradictory information regarding the comparison of traditional histological dating criteria of the endometrium with the expression of the new markers of endometrial receptivity such as αvβ3 integrin and pinopods. Also, definite data with respect to the potential correlation existing between these different new markers in defining the putative window of implantation are lacking. METHODS: The temporal relationship between αvβ3 integrin expression and pinopod formation in normal and out-of-phase endometrial biopsies from normal healthy women (n 12) and infertile patients (n 36) was investigated. Two endometrial biopsies (postovulatory day 7t o8 and 4 days later) were performed during a single menstrual cycle in each subject. Estradiol and progesterone serum concentrations were quantified on the same days as endometrial sampling. RESULTS: No statistically significant difference regarding αvβ3 integrin expression, pinopod formation, and hormone concentrations was found between fertile controls and infertile patients irrespective of endometria being in-phase or out-of-phase. Although a coordinate high level of expression of αvβ3 integrin and pinopod on postovulatory days 7–8 was observed, there was an evident lack of temporal co-expression of these markers over the luteal phase in the endometrial samples investigated. CONCLUSIONS: There is a clear dissociation in the temporal expression of the most cited markers postulated to frame the window of implantation. The functional significance (if any) of these new markers remains to be established.

BACKGROUND It has been recently suggested that gonadotrophin-releasing hormone agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis and IVF and pregnancy outcome. The aims of this study, where receiver-operating characteristic (ROC) analysis was used, were: (i) to assess the usefulness of serum LH measurement on stimulation day 7 (S7) as a predictor of ovarian response, IVF outcome, implantation, and the outcome of pregnancy in patients treated with recombinant FSH under pituitary suppression; and (ii) to define the best threshold value, if any, to discriminate between women with 'low' or 'normal' LH concentrations. METHODS A total of 144 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment were included. Seventy-two consecutive patients having a positive pregnancy test (including 58 ongoing pregnancies and 14 early pregnancy losses) were initially selected. As a control non-pregnant group, the next non-conception IVF/ICSI cycle after each conceptual cycle in our assisted reproduction programme was used. RESULTS The median and range of LH values in non-conception cycles, conception cycles, ongoing pregnancies, and early pregnancy losses, clearly overlapped. ROC analysis showed that serum LH concentration on S7 was unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.52; 95% CI: 0.44 to 0.61) or ongoing pregnancy versus early pregnancy loss groups (AUC(ROC) = 0.59; 95% CI: 0.46 to 0.70). To assess further the potential impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of IVF/ICSI treatment, the three threshold values of mid-follicular serum LH proposed in the literature (

Recent reports investigating the value of basal inhibin B determination as a predictor of ovarian reserve and assisted reproduction treatment have led to discordant results. This study was undertaken to further assess the relative power of day 3 inhibin B and follicle stimulating hormone (FSH) (defined before treatment) and the woman's age both as single and combined predictors of ovarian response and pregnancy in an in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme. A total of 120 women undergoing their first cycle of IVF or ICSI was included. Forty consecutive cycles cancelled because of poor follicular response were initially selected. As a control group, the nearest completed IVF/ICSI cycles before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) were used. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group (P: < 0.01 and P: < 0.001 respectively), whereas basal inhibin B was significantly higher in the latter (P: < 0.05). The association of basal FSH (with an accuracy or predictive value of ovarian response of 79%) with cancellation rate was significant, independent of, and stronger than the effects of age and inhibin B (P: < 0.05). Any two or all three of these variables studied did not improve the predictive value of FSH alone. Woman's age was the only variable independently associated with pregnancy rate. It is concluded that the stronger predictors of success in patients undergoing their first IVF/ICSI treatment cycle are age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate.

Background. 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. Methods. 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 (E 2 ), progesterone and β-hCG were measured on days 13-14 after ET and one week later. Results. 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 E 2 and progesterone values. Nitrite/nitrate serum concentrations were similar for singleton and multiple pregnancies at both study points. In viable ...

Purpose: The aim was to compare the follicular response to 37.5 and 50 IU of recombinant follicle-stimulating hormone (FSH) as starting doses for ovulation induction in patients with polycystic ovary syndrome (PCOS). Methods: Prospective, randomized, crossover study including 15 women with clomiphene citrate-resistant chronic anovulatory infertility. Patients were treated with subcutaneous recombinant FSH at starting doses of 37.5 IU and 50 IU, respectively, according to a low-dose step-up protocol. Each woman received both treatments, in a randomized order, with an interval of ≥1 month between treatments. Results: All treatment cycles were ovulatory after an appropriate follicular response and hormone levels were similar with both treatments, although the total quantity of FSH required and the mean daily dose required to induce identical follicular development were significantly lower with a starting dose of 37.5 IU FSH. The mean duration of treatment to achieve ovulation was approximately 13 days with both treatments but treatment periods ≥20 days were required in some patients. Conclusions: In women with PCOS, a starting dose of 37.5 IU recombinant FSH may be adequate to induce follicular growth. However, the use of low starting doses may result in some cases in increased treatment periods and need for monitoring.

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.

OBJECTIVE: Severe ovarian hyperstimulation syndrome is an uncommon cause of ascites that is being increasingly recognized because of the high number of women undergoing assisted reproductive techniques, mainly in vitro fertilization. This prospective study investigates the clinical and biochemical characteristics of a large series of patients with this syndrome and ascites, including renal and electrolyte abnormalities, activity of neurohormonal systems participating in the regulation of extracellular fluid volume, and liver function tests. METHODS: This was a prospective longitudinal study including 50 consecutive patients with ascites due to severe ovarian hyperstimulation syndrome. Renal function, serum electrolytes, body weight, mean arterial pressure, pulse rate, plasma renin activity, plasma concentration of aldosterone, norepinephrine, antidiuretic hormone and atrial natriuretic peptide, and standard liver function tests were measured during the syndrome and 4–5 wk after recovery. A sample of ascitic fluid was obtained from eight patients for protein measurement and cell count. RESULTS: At diagnosis, patients had ascites associated with low urinary sodium excretion, oliguria, and hyponatremia. They had also markedly low arterial pressure and increased pulse rate in association with marked activation of vasoconstrictor and antinatriuretic factors. The ascitic fluid was characterized by a high protein concentration, low leukocyte count, and relatively high number of red blood cells. Fifteen (30%) patients had abnormal liver tests characterized by mild to moderate increases in AST (mean 103 ± 17.1 IU/L) and ALT (76 ± 8.3 IU/L), which were associated in some cases with increases in γ-glutamyl transpeptidase or alkaline phosphatase. All abnormalities reverted to normal after the resolution of the syndrome. CONCLUSIONS: With the increasing use of assisted reproductive techniques, physicians should be aware of severe ovarian hyperstimulation syndrome as a cause of ascites. The syndrome is associated with sodium retention, hyponatremia, arterial hypotension, and marked activation of vasoconstrictor and antinatriuretic systems. In one third of patients, liver tests abnormalities are present.

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.

Previous studies have shown that severe ovarian hyperstimulation syndrome (OHSS) is secondary to circulatory dysfunction due to the simultaneous occurrence of increased vascular permeability and marked arteriolar vasodilation which lead to an intense homeostatic stimulation of the renin-aldosterone and sympathetic nervous systems and antidiuretic hormone (ADH). In the present report, we have investigated the correlation between changes in haematocrit concentration, and white blood cell (WBC) and platelet counts and the severity of OHSS, as assessed by these markers of effective intra-arterial blood volume, in a series of 50 patients. In comparison with recovery values (4-5 weeks after hospital discharge), OHSS patients showed arterial hypotension, tachycardia, oliguria, very high plasma concentrations of renin, aldosterone, norepinephrine and ADH, and increased mean haematocrit values and WBC and platelet counts. The haematocrit concentration values were directly related to the plasma concentrations of vasoactive substances (plasma renin activity, aldosterone, norepinephrine and ADH) during OHSS (P < 0.001). In contrast, no correlation was evident between WBC or platelet counts and neurohormonal measurements during the syndrome. It is concluded that haematocrit, but not WBC or platelet counts, can act as a biological marker of the severity of OHSS as indicated by plasma measurement of volume-dependent endogenous vasoactive substances.

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.

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 act...

Purpose:Our purpose was to compare ovarian performance and hormonal levels, after ovulation induction, in both normal ovulatory women undergoing intrauterine insemination (group 1) and World Health Organization (WHO) group II anovulatory infertile patients (group 2), using two different gonadotropin drugs.

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.

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.

The present prospective clinical study was undertaken to determine the usefulness of midluteal phase serum immunoreactive alpha-inhibin concentrations as markers of luteal phase deficiency and whether they are better indicators of biopsy confirmed luteal phase defect than serum progesterone. Consecutive patients (n = 138) with regular menstrual cycles attending our Infertility Clinic (experimental group) and 15 fertile women who were requesting contraception and had regular menstrual patterns (control group) were included. In all women (patients and controls), basal body temperature, midluteal serum concentrations of oestradiol, prolactin, progesterone and immunoreactive alpha-inhibin, and premenstrual endometrial biopsy were used in the same cycle to assess luteal function. Out-of-phase secretory endometria were detected in 15 of the 138 patients. Thus, hormonal concentrations were compared between the following three groups of women: group 1 (n = 15), infertile patients with defective secretory endometria; group 2 (n = 123), infertile patients with normal secretory endometria; and controls (n = 15), fertile women with normal secretory endometria. Midluteal serum concentrations of progesterone, immunoreactive alpha-inhibin, oestradiol, and prolactin of the two groups studied were similar to those of the control group of fertile women. Our results indicate that midluteal serum inhibin determination does not accurately reflect histological maturation of the endometrium and it is not a better indicator of endometrial luteal phase deficiency than midluteal serum progesterone concentration.

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 aged < 45 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.

To determine the effectiveness of in-vitro fertilization (IVF) and embryo transfer for patients with unexplained habitual abortion, we carried out a prospective observational study using a historical comparison group. A total of 12 couples with three or more (mean 4. 91, range 3-10 miscarriages) first trimester spontaneous abortions of unknown aetiology were treated with IVF and embryo transfer (group 1). Patients underwent IVF after combined gonadotrophin-releasing hormone agonist/gonadotrophin treatment for ovarian stimulation, and three to four embryos were replaced into the uterus in all women. Eight of the 12 women (66.6%) in group 1 became pregnant (one patient after a frozen-thawed embryo transfer), and all of them had viable pregnancies. A patient with 10 previous abortions became pregnant and carried to term after IVF and embryo transfer, and subsequently miscarried two new spontaneous gestations. A historical comparison group (group 2) included the last eight women with unexplained recurrent abortion (mean 4, range 3-8 miscarriages) who underwent the same investigations for the condition and received identical early supportive care in their next spontaneous pregnancy as patients in group 1. Three of the eight pregnancies in group 2 ended in an abortion. Our results suggest that IVF and embryo transfer may be a new therapeutic approach for unexplained recurrent miscarriage.

Objective To determine the effectiveness of immunotherapy with high-dose IV immunoglobulin preceding IVF-ET for patients with repeated failure of ET. Design Prospective, observational. Setting Assisted Reproduction Unit of the Hospital Clinic i Provincial in Barcelona, a tertiary care setting. Patients Twelve consecutive tubal infertility patients experiencing repeated unexplained IVF-ET failure including at least three ETs replacing three to four fresh embryos each. Two women shared three or more human leukocyte antigens (HLA) with the husband. Intervention During the subsequent new IVF-ET cycle, each patient received 400 mg/kg IV immunoglobulin daily for 5 days during ovarian stimulation, that is, 5 to 7 days before ET. Main Outcome Measures Clinical pregnancies. Results No implantation occurred. There were no side effects. Conclusions High-dose IV immunoglobulin is not a useful tool for IVF-ET failure.

Objective To analyze natural cycle IVF (NC-IVF) results according to patient age, ovarian reserve status following the Bologna criteria, cause of infertility, and modification of the cycle with the use of GnRH antagonist. Design Retrospective cohort study. Setting Tertiary-care university hospital. Patient(s) Nine hundred forty-seven natural cycles carried out in 320 patients. Intervention(s) Analysis of 947 NC-IVF outcomes performed in one single center between January 2010 and December 2014. Main Outcome Measure(s) Pregnancy rates per cycle started, per ET, and per patient, as well as ongoing pregnancy rate at a minimum of 12 weeks of gestation. Result(s) Among the three age groups analyzed (≤35 years, 36–39 years, and ≥40 years), pregnancy rates per cycle were significantly lower in the older group of patients (11.4% vs. 11.6% vs. 5.9%). In addition, miscarriage rate (7.7% vs. 34.4% vs. 50%) and ongoing pregnancy rate (10.6% vs. 7.6%vs. 3.0%) were negatively affected by patient age. However, no differences were observed according to patient ovarian reserve status, cause of infertility, or modification of the cycle with GnRH antagonist. The multivariate logistic regression confirmed that patient age was the only variable that could predict pregnancy in NC-IVF cycles (odds ratio, 0.93; 95% confidence interval, 0.88–0.98). Conclusion(s) NC-IVF is a feasible and "patient-friendly" option to be offered to young patients, independent of their ovarian reserve status.

Background : Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. Methods : Sixty consecutive patients with ≥ 3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. Results : No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. Conclusions: In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation.

Study question Is there any effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage? Summary answer There was no significant difference in the chromosome abnormality rate between sporadic and recurrent miscarriage but the chromosome abnormality rate increased significantly with maternal age. What is known already About 50-70% of non-recurrent miscarriages occur because of a chromosomal anomaly, but no agreement about the effect of either maternal age or the number of previous miscarriages on the chromosomal anomaly rate has been reached. Study design, size, duration A retrospective cohort of 353 miscarriages successfully karyotyped in the same center between 2002 and 2011, grouped according to the number of miscarriages and maternal age. Participants/materials, setting, methods Among the 353 women, 153 were below 35 years (73 with sporadic, 48 with two and 32 with recurrent miscarriage) and 200 were 35 years or more (81 with sporadic, 55 with two and 64 with recurrent miscarriage). The chromosomal anomaly rate and the anomaly spectrum were compared between sporadic and recurrent miscarriage, within the two maternal age groups, using the chi-square test and the Bonferroni correction for all the P-values. Risk of chromosomal anomaly was estimated for maternal age, number of miscarriages and previous live births by multivariate binary logistic regression analysis. Main results and the role of chance Sporadic and recurrent miscarriage did not show significantly different chromosomal anomaly rates (68 versus 60%) and maternal age was the only statistically significant predictor of the chromosomal anomaly risk we identified. Some trends were observed in the chromosomal anomaly spectrum when sporadic was compared with recurrent miscarriage: recurrent miscarriage exhibited a decrease in viable trisomies (37 versus 11%) and an increase in non-viable trisomies (38 versus 57%) in women >35 years, together with an increase in unbalanced structural anomalies (4.9 versus 29%) in younger women. Limitation, reasons for caution The mixed origin of our study population, and the limited number of recurrent miscarriages, particularly in the younger group, limits statistical power to detect differences. Wider implications of the findings The most commonly observed chromosomal anomaly type in recurrent miscarriage depends on maternal age: non-viable autosomal trisomies in older women and unbalanced structural anomalies in younger women. When a chromosomal anomaly is identified as the cause of miscarriage, additional maternal evaluation may be avoided. Study funding/competing interests No competing interests declared.

At present, there is general agreement that ovarian stimulation improves pregnancy rates after intra-uterine insemination (IUI). Also, ovulation induction with gonadotrophins is associated with higher success rates than clomiphene citrate in IUI cycles. However, the drawbacks to the use of gonadotrophin stimulation before IUI include the risks of ovarian hyperstimulation and multiple gestation, and the relative cost of a treatment cycle in a view of the medication costs and the need for increased monitoring by hormone assays and ultrasonographic measurements. In the present prospective randomized trial, the efficacy and safety of ovarian stimulation with clomiphene citrate (50 mg/day for 5 days) and IUI (clomiphene/IUI group) were compared with those of late low-dose pure follicle stimulating hormone (FSH, 75 IU/day from day cycle 7 until the leading follicle reached > 17 mm in diameter) and IUI (FSH/IUI group) in ovulatory women who were infertile because of unexplained infertility (n = 40) or male subfertility (n = 60). The mean length of treatment in the FSH group was 6.4 +/- 2.5 days. Multiple follicular development was seen in 25% of clomiphene-stimulated cycles but only in 8% of those treated with FSH. Pregnancy rate per cycle in clomiphene/IUI and FSH/IUI groups was 4% (4/98) and 13% (12/94) respectively (P = 0.02). All pregnancies obtained were singleton. There were two and one clinical abortions in the clomiphene/IUI (50%) and FSH/IUI (8%) groups respectively. No patient developed ovarian hyperstimulation syndrome. Use of our therapeutic scheme, which proved to be efficacious, safe and economic for ovarian stimulation in IUI cycles, is advocated before the institution of in-vitro fertilization (IVF) or gamete intra-Fallopian transfer (GIFT) therapy in infertile patients with patient Fallopian tubes. This late low-dose technique of administering pure FSH is suitable for use in offices without immediate access to oestradiol results.

Cervical pregnancy is rare but one of the most dangerous of all pregnancy complications. The aetiology of cervical implantation is unclear and because of the fear of profuse haemorrhage abdominal hysterectomy has been historically considered the standard therapy. We report here an unusual case of an infertile woman with cervical ectopic pregnancy after ovulation induction with gonadotrophins and intrauterine insemination. The patient was successfully treated with parenteral methotrexate without significant morbidity. It is concluded that chemotherapy should be initially considered in most cervical pregnancies either as the sole form of treatment or to improve the chances of success in alternative conservative measures.

background: Recurrent implantation failure (RIF) following embryo transfer (ET) is a major continuing problem in IVF. Women with haemostatic defects may be at increased risk of miscarriage and preclinical pregnancy loss. The fibrinolytic system is considered, at present, the key to new thrombotic pathogenic mechanisms. Patients with unexplained recurrent miscarriage have an impairment of fibrinolysis, as demonstrated by prolonged clot lysis time (CLT) in association with increased plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI). In this study, we investigated fibrinolytic potential in patients with RIF. methods: Three groups of patients were studied: 30 women with RIF (RIF group), 60 patients undergoing a first successful IVF –ET cycle (IVF group) and 60 healthy fertile women (FER group). Plasma CLT was measured using a global fibrinolysis assay. TAFI antigen plasma levels and polymorphisms in the TAFI gene (+505A/G and +1542C/G) were analysed using enzyme-linked immunosorbent assay and allele-specific PCR, respectively. results: CLT was significantly longer (P , 0.0001 and P , 0.0009, respectively) and TAFI antigen levels were significantly higher (both P , 0.0001) in the RIF versus the IVF and FER groups. A direct relationship between CLT and TAFI antigen levels (r ¼ 0.40; P ¼ 0.001) was detected in the whole study population. There were no differences in distribution of TAFI polymorphisms between groups. conclusions: Patients with RIF have reduced plasma fibrinolytic potential, as shown by a prolonged CLT, and this may be explained, at least in part, by increased TAFI antigen levels.

Antiphospholipid syndrome patients with recurrent miscarriage have an impairment in fibrinolysis demonstrated by prolonged clot lysis time (CLT) that cannot be attributed to differences in thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels. Patients with unexplained recurrent miscarriage have an impairment in fibrinolysis demonstrated by increased CLT, that can be at least partly explained by higher TAFI antigen levels.

Recurrent early pregnancy loss but not infertility or implantation failure after in vitro fertilization and embryo transfer is now considered a treatable clinical condition associated with antiphospholipid antibodies (aPL). Treatment options rely on antiplatelet/anticoagulation therapy (with aspirin and heparin) because of lack of understanding of the pathogenesis of the process. However, because of the wide clinical diversity of the population with aPL, it appears illogical to treat all women the same. While in patients with a history of thrombotic events or an early pregnancy loss despite aspirin therapy the addition of heparin seems clearly indicated, based on the evidence to date, heparin cannot be recommended to all women with aPL and a history of previous recurrent early pregnancy loss. In the same way, aspirin alone may be insufficient for a number of patients even in the absence of thrombotic events. Therefore, further studies are needed to define better the respective indications for aspirin and heparin alone or in combination.

BACKGROUND Studies in macaques have indicated that androgens have some synergistic effects with FSH on folliculogenesis. This study investigated the usefulness of pretreatment with transdermal testosterone in low-responder IVF patients. METHODS Randomized clinical trial including 62 infertile women who had a background of the first IVF treatment cycle cancelled because of poor follicular response. Patients were randomized in two treatment groups in their second IVF attempt. In patients in Group 1 (n = 31), transdermal application of testosterone preceding standard gonadotrophin ovarian stimulation under pituitary suppression was used. In Group 2 (n = 31 patients), ovarian stimulation was carried out with high-dose gonadotrophin in association with a minidose GnRH agonist protocol. The primary end-point was the incidence of low-responder patients. The main secondary outcome was the incidence of patients reaching ovum retrieval. RESULTS The percentage of cycles with low response was significantly lower in Group 1 than in Group 2 (32.2 versus 71% 95% confidence interval for the difference, 15.7-61.6; P < 0.05). The number of patients with ovum retrieval tended to be higher in Group 1 than in Group 2 (80.6 versus 58.1% P = 0.09), the difference reaching statistical significance (81.2 versus 41.1%; P < 0.05) when only patients having normal basal FSH levels (16 and 17 patients in Groups 1 and 2, respectively) were considered. CONCLUSIONS Pretreatment with transdermal testosterone may improve the ovarian sensitivity to FSH and follicular response to gonadotrophin treatment in previous low-responder IVF patients. This approach leads to an increased follicular response compared with a high-dose gonadotrophin and minidose GnRH agonist protocol.

BACKGROUND: Surgical treatment has modest efficacy for the treatment of infertility associated with early-stage endometriosis. Immunomodulation with pentoxifylline is considered as a new strategy potentially useful in treating endometriosis. Thus, this study investigated the usefulness of combined laparoscopic surgery and pentoxifylline therapy in the treatment of infertility associated with minimal to mild endometriosis. METHODS: A prospective, randomized, controlled blind trial was conducted. Patients entered the study immediately after laparoscopic surgery and were randomly assigned to the treatment with either oral pentoxifylline (800 mg/day) (pentoxifylline group, n 5 51) or an oral placebo (placebo group, n 5 53). Patients were then observed for pregnancy for 6 months. RESULTS: Among 98 patients finally considered in the evaluation of the results, the 6 month overall pregnancy rates were 28 and 14% in the pentoxifylline and placebo groups, respectively. Thus, an absolute difference of 14% (95% CI 22 to 30) (Chi-squared test, P 5 0.1) in the cumulative probability of pregnancy in 6 months after laparoscopic surgery in patients receiving pentoxifylline versus placebo post-operatively was observed. CONCLUSION: Our findings provide preliminary clinical evidence to suggest the new experimental treatment approaches, toward endometriosis, that are based on immunomodulation deserve further attention. Well-designed multicenter trials are warranted to confirm or refute our results. The ClinicalTrials.gov Identifier is NCT00632697.

Submitted April 9, 2003; accepted October 23, 2003 Purpose : To investigate the relative power of HCG, estradiol, and progesterone determinations in the prediction of pregnancy outcome after IVF. These prognostic hormonal factors were studied as single and combined predictors. Methods : Serum concentrations of fl-HCG, progesterone, and estradiol were measured 12‐ 13 days after embryo transfer (study point 1) and 7 days later (study point 2) in a series of 20 consecutive infertile patients having a first-trimester spontaneous clinical abortion after an IVF-embryo transfer cycle. As a control group (nD 60), the next three IVF-embryo transfer cycles resulting in an ongoing pregnancy after each miscarried IVF cycle in our assisted reproduction program was used. The discrimination attained between the two study groups (ongoing pregnancies and miscarriages) was evaluated by logistic regression and receiver operating characteristic (ROC) curve analysis. Results : Mean hormone concentrations at study points 1 and 2 were higher in the ongoing pregnancy than in the abortion group. Regarding pregnancy outcome the percentage increment of HCG serum levels (‚1321%), with an accuracy (predictive value of pregnancy outcome) of 81.2% (sensitivity 98%, specificity 50%), had the best prognostic reliability but no significant differences were found when this parameter was compared with the predictive value of HCG concentration (‚72 IU/l) at study point 1 (diagnostic accuracy 80.5%; sensitivity 70%; specificity 80%). When ROC analysis was used, the best predictor of ongoing pregnancy according to the AUC ROC was HCG concentration at study point 2 but again no significant differences were found when this parameter was compared with the predictive value of HCG serum levels at study point 1. A multiple marker strategy did not help distinguish viable from nonviable pregnancies. Conclusion : A single, early (days 12‐13 after embryo transfer) HCG quantitative serum measurement in IVF cycles not only is diagnostic but also has good predictive value for pregnancy outcome.

Purpose: To investigate endometrial receptivity in terms of pinopode formation and αvβ3 integrin expression in infertile women with endometriosis during natural cycles. Methods: We investigated the expression of αvβ3 integrin and pinopode formation in the endometrium of 12 infertile patients with stage I or II endometriosis as the only cause of infertility, 12 infertile patients having unexplained infertility, and 12 fertile women who were undergoing tubal sterilization. Two endometrial biopsies (postovulatory day +7 to +8 and 4 days later) were performed during a single menstrual cycle in each subject. Results: No statistically significant difference regarding αvβ3 integrin expression and pinopode formation was found between infertile patients with endometriosis and the two control groups. Conclusion: αvβ3 integrin expression and pinopode formation are not reduced during the window of implantation in patients with stage I–II endometriosis. Whether these results imply normal endometrial receptivity in such patients or add to the increasing uncertainty about the clinical value of assessing the endometrium with those markers of implantation, warrants further studies.

BACKGROUND: There has been much debate about the effect of ‘residual’ LH levels in normogonadotrophic women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH ovarian stimulation. The aim of this prospective study, where receiver-operating characteristic (ROC) analysis was used, was to assess further the usefulness of serum LH levels as predictors of ovarian response, assisted reproduction treatment outcome, and the outcome of pregnancy when measured throughout the ovarian stimulation period in a large cohort of such assisted reproduction treatment women. METHODS: A total of 246 consecutive women undergoing their first cycle of IVF or ICSI treatment were included in this study. Blood samples for hormone analyses were obtained on day S0 (the day when pituitary suppression was evidenced) and every other day from stimulation day 5 (S5) until the day of hCG injection. RESULTS: LH serum levels throughout ovarian stimulation treatment were similar for cancelled (n =32) versus non-cancelled (n = 214) cycles, non-conception (n = 132) versus conception (n = 82) cycles, and ongoing pregnancy (n = 66) versus early pregnancy loss (n = 16) groups. There was no correlation between LH serum levels in non-cancelled cycles and parameters of ovarian response and assisted reproduction treatment outcome. ROC analysis showed that serum LH concentration during ovarian stimulation was unable to discriminate between cancelled and non-cancelled cycles, conception versus non-conception cycles, or early pregnancy loss versus ongoing pregnancy groups. CONCLUSIONS: Serum LH measurements during ovarian stimulation with recombinant FSH under pituitary suppression in normogonadotrophic women undergoing assisted reproduction treatment cannot predict ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy. Thus, there is little underlying physiological support for the addition of LH in stimulation protocols if daily doses of an appropriate GnRH agonist (leuprolide or triptorelin having lower potency than buserelin) and a step-down regimen of recombinant FSH administration are used.

alpha v beta 3 integrin expression and pinopod formation have been proposed as a means of distinguishing receptive endometrium from nonreceptive in clinical practice. However, one of the most intriguing facts in infertility is whether one cyclic event may be representative of all patients' cycles, and no study has evaluated the cycle-to-cycle variability of the expression of any of these new proposed markers in human endometrium. We investigated histological dating, alpha v beta 3 integrin expression, and pinopod formation in 45 endometrial biopsy specimens obtained in 15 primary infertility patients. All patients underwent three endometrial biopsies in consecutive spontaneous cycles, regardless of the previous histological findings. All endometrial samples were obtained on postovulatory d 7 as determined by ultrasonography. Agreement between the repeated observations (first vs. second, and first vs. third biopsies) with regard to histological dating and the presence or absence of alpha v beta 3 integrin and pinopods in the endometrium was analyzed using the 2 x 2 frequency tables and Cohen's kappa coefficient. The kappa values ranged from a low of -0.39 (level of agreement, poor) for alpha v beta 3 integrin expression to a high of 0.32 (level of agreement, fair) for biopsy dating by anticipated window of implantation. Overall, these results demonstrate that all endometrial variables investigated had poor reproducibility and high variability cycle to cycle.

BACKGROUND Integrin expression and pinopode formation have been proposed as a means of distinguishing receptive endometrium from non-receptive 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. The aim of the present study was to investigate the effect of ovulation induction, oral contraception, treatment with dehydrogesterone, and different regimens of hormone replacement therapy on endometrial alphavbeta3 integrin expression and pinopode formation using a prospective, controlled study design. METHODS Histological dating, alphavbeta3 integrin expression and pinopode formation were evaluated in control and treated cycles in six groups of women including eight subjects per group and who received clomiphene citrate, ovarian stimulation for IVF, oral contraception, dehydrogesterone for endometrial luteal phase defect, or two different regimens of hormone replacement therapy. Twelve healthy fertile women served as a general control group. RESULTS Alphavbeta3 integrin expression and pinopode formation in the human endometrium were closely related to endometrial maturation as defined by histological dating and this was irrespective of endometria being in-phase or out-of-phase and the hormonal treatment received. Only for clomiphene citrate did a direct effect with reduction in pinopode formation in the midluteal phase seem to exist. CONCLUSION Alphavbeta3 integrin expression and pinopode formation in the human endometrium are processes closely related to endometrial maturation and this is irrespective of endometria being in-phase or out-of-phase and the hormonal treatment received. The potential usefulness of those two so-called endometrial markers of implantation as targets for contraceptive approaches or fertility-promoting strategies seems unlikely.

It has been recently proposed that the immunohistochemical evaluation of alphavbeta3 integrin in combination with histologic dating in midluteal endometrial biopsy specimens should be performed to evaluate the endometrial receptivity in the infertile patient. However, no studies have attempted to correlate these findings with subsequent fecundity. In 100 consecutive infertile patients (mean age 31.9+/-3.4 years) undergoing a routine work-up, two endometrial biopsies were performed during a single menstrual cycle: a midluteal biopsy on postovulatory days 6 to 8 and another biopsy 4 days later. Histological dating and immunohistochemical evaluation of alphavbeta3 integrin expression were done in all endometrial biopsy specimens. All patients were followed without treatment during 18 to 24 months (mean 23.5+/-1.4, range 18 to 24). Twenty-five midluteal biopsies showed out-of-phase endometria, whereas all but one late-luteal biopsy specimens were in-phase. Glandular alphavbeta3 integrin expression was observed in 50% of midluteal specimens with this expression being significantly more frequent among in-phase (63%) than among out-of-phase (12%) specimens (p

Publisher Summary This chapter presents various management plans for reproductive failure in the antiphospholipid syndrome (APS). Despite the enormous amount of work on the APS, there are still various controversies regarding management of reproductive failure potentially associated with antiphospholipid antibodies (aPL). These controversies relate to decisions on treatment or no treatment in the patients with APS; selection of patients with aPL to be treated; management of patients presenting with infertility or repeated implantation failure after in vitro fertilization and having the LA and/or anticardiolipin antibodies (aCL); and management of recurrent pregnancy loss associated with aPL other than LA and aCL. There have been some claims supporting the view that the presence of aCL in women with recurrent miscarriage may result in a modest increase in the risk of fetal losses, and thus, the chance of a successful pregnancy even without anticoagulant treatment is still favorable. However, as the correlation between aPL and disease is rather imperfect, the treatment of the subjects presenting with definite clinical criteria for APS but having low levels of aCL remains controversial in daily clinical practice. As women with IgM only or low levels of IgG aCL comprise a population at less risk for aPL related disorders, such patients should not be treated with potentially dangerous medications such as prednisone and heparin, which are alleged to be efficacious for APS, since the balance between risk and benefit does not justifies therapy. Many clinicians recommend low-dose aspirin in women with low-titer aPL and the addition of heparin if levels increase once pregnancy is confirmed.