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Chronic endometritis is a pathology often associated with reproductive failure, but there are still no clear recommendations on whether its inclusion in the initial study of infertile couples is necessary. In this discussion paper, based on a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis, the different aspects of the repercussions of chronic endometritis in fertility are evaluated. To avoid possible subjectivity in the analysis and results of this study, the researchers followed the Oxford criteria for the evaluation of evidence. The results from the evaluation of the reviewed literature seem to indicate that, pending new evidence, it would be advisable not to include chronic endometritis in the initial baseline study before assisted reproduction in order not to delay other assisted reproduction treatments. However, it would be advisable in cases of repetitive implantation failure and pregnancy loss after having undergone IVF with viable embryos and before continuing with costly reproductive processes, since results could be improved. The development of randomized studies assessing the impact of antibiotic treatment as a possible therapeutic option in infertile women with chronic endometritis, as well as the possible impact on endometrial microbiota and receptivity/implantation, would allow for the establishment of more precise clinical guidelines in this regard.

Study question Is insulin-like growth factor-I (IGF-I) a mediator of the effect of transdermal testosterone (TT) in poor responder (PR) patients? Summary answer IGF-I might be a mediator of the effect of TT in PR patients who undergo an IVF cycle What is known already Many strategies have been tried to improve the results in PR patients. Androgen supplementation with TT is the only that has significantly increased live birth rate in these patients. The mechanism by which TT might influence on the better results remains unclear but it is likely mediated or facilitated by IGF-I. Testosterone increases the number of primordial follicles, increase IGF-I by threefold and increase IGF-I receptor mRNA by fivehold in primordial follicles in primates. Some studies have suggested that IGF-I could be a parameter that reflects the endocrinological environment of mature follicles, which is correlated with oocyte and embryonic quality Study design, size, duration This prospective cohort study of 93 women PR according Bologna criteria treated with TT and IVF/ICSI was conducted between May 2015 and December 2016 Participants/materials, setting, methods Exogenous andogenization with TT for 5 days prior to ovarian stimulation was carried out. Hormonal parameters were evaluated: basal FSH, LH and Estradiol, AMH, IGF–1 pre and post TT. Ultrasound parameterswere also analysed: antral follicle count (AFC) and number of pre-ovulatory follicles the day of HCGr. We compared these parameters according to the ovarian response: adequate (> 4 oocytes) or insufficient ( Main results and the role of chance Baseline characteristics of the patients were: 36.9 years, FSH 11.8, AMH 0.86 and RFA 5.3. In 83% of the patients the oocyte retrieval was carried out, obtaining an average of 3.8 MII oocytes and 2.9 embryos of 2pn with a clinical pregnancy rate per transfer of 33.3%. The FORT Test (AFC/pre-ovulatory follicles x100) was 70%, higher than that observed in other studies with patients with PR without TT (55%). In cases in which an insufficient response was obtained ( Evaluating the hormonal and ultrasound parameters depending on whether or not pregnancy was achieved, a significant increase in IGF1 pre and post-TT was observed in the cases of pregnancy (31.5%) compared to those cases where there was no pregnancy (10.9%) (p = 0’01). There were no differences in the rest of the parameters. A significant correlation was found between AMH, AFC and increase in IGF-I levels (p Limitations, reasons for caution This a prospective cohort study with limited number of patients included. Wider implications of the findings: The significant increase in serum levels of IGF–1 in pregnant patients would indicate the existence of a more favorable clinical setting for the administration of testosterone, probably related to a more favorable ovarian reserve as demonstrated by its correlation with serum levels of AMH and with the AF. Trial registration number Not applicable

Objective Pregnancy after an embryo transfer depends largely on embryo quality, endometrial receptivity, and the technique used in the embryo transfer. Embryo transfers have been reported as inevitably traumatic and difficult for 5-7% of patients in assisted reproduction treatment. In these cases, transmyometrial embryo transfer should be considered as a suitable method to overcome difficult embryo transfers. The aim of this study was to report our experience with this technique and analyze its causes, results and complications. Methods Since 1993, 39 women (40 cycles of assisted reproductive technology treatment) were submitted to transmyometrial embryo transfers in our center. The procedures were carried out as described by the Towako group. Results The enrolled female patients had a mean age of 34 years and a mean baseline FSH level of 6.89 IU/mL. The median number of retrieved oocytes was 7.50 and a mean of 2.63 embryos were transferred. Implantation rate was 9.5%. With respect to clinical results, pregnancy and miscarriage rates were 25% and 30%, respectively. Since there were two twin pregnancies, the live birth rate was 22.5% (9/40). No major complications were reported. Conclusion Transmyometrial embryo transfer can and should be an option in cases of difficult/impossible transcervical embryo transfer.

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.

Background The aim of this report was to describe a case of pregnancy after drug-free in vitro activation (IVA) of follicles and fresh tissue autotransplantation in primary ovarian insufficiency (POI) patient and to review the pertinent literature. Methods We present a case in wich a 32 - years old patient with POI became pregnant after IVA without tissue culture and with ovarian tissue transplantation. We also reviewed the literature using Pubmed database. Case presentation Pretreatment with estradiol/progesterone stopped the day before surgery. The removal of the ovarian cortex and autotransplantation were performed by laparoscopy in the same surgical act. Ovarian fragments were transplanted in contralateral ovary and peritoneal pocket near to the ovary. Immediately after surgery GnRH agonist together HMG injections started, leading the growth of 3 preovulatory follicles and the retrieval of two mature eggs. After IVF two embryos were transferred and singleton pregnancy was established and currently she is 25 weeks pregnant. Results A total of 51 patients with POI in whom an in vitro activation of ovarian tissue was performed, were collected from the revieew of the literature. In 29.4% of them, follicular development was obtained and in 4 of them a pregnancy. In all of them, a combined technique (fragmentation and activation) was performed in two laparoscopies. No case has been reported successfully after drug-free in vitro activation. Conclusions This is the first report about a case with pregnancy after drug-free in vitro activation of follicles and fresh tissue autotransplantation in POI patient.

STUDY QUESTION Is the length of the anogenital distance (AGD) a biomarker of ovarian reserve and response to controlled ovarian stimulation (COS)? SUMMARY ANSWER Shorter AGD is associated with presence of poor ovarian response. WHAT IS KNOWN ALREADY Organ development during prenatal life is influenced by the prevailing intrauterine environment, and it has been suggested that nutritional, environmental and toxic factors could affect ovarian reserve set prenatally. AGD is a biomarker of prenatal-hormonal environment and observational studies have shown an association between its length and reproductive parameters in both sexes. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study of 437 women treated with IVF/ICSI conducted in a tertiary-care university hospital between January and December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS All women underwent their first COS for IVF/ICSI and reached criteria for oocyte retrieval. Based on the number of oocytes obtained, patients were divided into three groups: poor responders (≤3 oocytes) (n = 50), normoresponders (4-15 oocytes) (n = 332) and high responders (>15 oocytes) (n = 55). Before retrieval, the following patient data were recorded: age, body mass index (BMI), ovarian reserve markers (anti-Mullerian hormone [AMH], antral follicle count [AFC] and follicular stimulation hormone [FSH]), cause of infertility, total doses of gonadotropins used and ovarian sensitivity index (OSI). Patients with previous pregnancies, polycystic ovary syndrome (PCOS), endometriosis and previous ovarian or genital surgery were excluded. Anthropometric biomarkers of AGDAC (anus-clitoris) and AGDAF (anus-fourchette) were measured in all patients under sedation on the day of retrieval and before proceeding to oocyte pick-up. Multiple linear regression analyses were used to examine the association between both AGD and ovarian reserve markers, the total units of gonadotropins used, the number of oocytes obtained and the OSI. Logistic regression was used to predict poor response in COS for IVF/ICSI, while accounting for confounders such as age and BMI. MAIN RESULTS AND THE ROLE OF CHANCE Baseline FSH, AMH, AFC and age were significantly different among the three groups of ovarian response, as were the units of gonadotropin used, and the ovarian sensitivity index (OSI) (P < 0.001). Both AGDAC and AGDAF measurements were positively correlated with AMH levels (r = 0.38 and r = 0.21; P < 0.05), AFC (r = 0.41 and r = 0.20; P < 0.05), the OSI (r = 0.24 and r = 0.19; P < 0.05) and the number of oocytes retrieved (r = 0.29 and r = 0.28, respectively; P < 0.05). Conversely, there was a negative correlation between both AGD measurements and the doses of gonadotropins used (r= -0.19 and r= -0.15; P < 0.05). The area under the curve (AUC) for prediction of poor response of AGDAC was 0.70 (95% CI 0.66, 0.75), which was comparable to the classic ovarian reserve markers, such as AFC and AMH. AGDAF showed a significantly worse predictive capacity for poor ovarian response (AUC 0.60 [95% CI 0.55, 0.60]) than AMH and AFC. LIMITATIONS, REASONS FOR CAUTION The population used for the study was a highly selected group of infertile women who underwent COS for IVF, so the findings of this research may not be applicable for general population. Besides, measurement or selection biases might have been possible and must be considered. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study suggest that in utero exposure to certain hormonal environments could affect the ovarian reserve set prenatally. STUDY FUNDING/COMPETING INTEREST(S) None. The authors have no competing interests to declare.

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.

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.

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.

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).

The role of LH in the natural menstrual cycle is not disputed. However, there are a variety of opinions regarding the potential role of exogenous LH in ovulation induction and whether it is actually needed. Recent years have seen renewed interest in this issue for several reasons. First, ovulation-inducing drugs are increasingly being administered to normally ovulating women. Second, recombinant human FSH products completely devoid of LH activity are now available. Third, gonadotrophin-releasing hormone (GnRH) analogues (agonists and antagonists) prevent the untimely LH surge but also suppress endogenous LH activity during the follicular phase. This review analyses whether or not all patients need LH for follicular growth stimulation and new opportunities for improved treatment as a result of the availability of recombinant human LH both in patients with ovulatory disorders (World Health Organization (WHO) groups I and II anovulatory patients) and those undergoing multiple follicular development for assisted reproduction.

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.

Halving the standard daily dose of triptorelin at the start of ovarian stimulation in down-regulated women stimulated with recombinant FSH is enough for pituitary suppression and was associated with higher LH serum concentrations in the follicular phase. However, this did not translate into higher serum concentrations of androstenedione and E2 and had no significant effect on ovarian response and the outcome of IVF/intracytoplasmic sperm injection.

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.

Objective To determine the prevalence of markers of thrombophilia in patients with severe ovarian hyperstimulation syndrome (OHSS) and to evaluate the cost-effectiveness of screening for factor V Leiden and prothrombin G20210A mutations in women entering an IVF program. Design Case–control study and cost-effectiveness analysis. Setting University teaching hospital. Patient(s) Women undergoing controlled ovarian hyperstimulation for IVF complicated by severe OHSS (group 1, n=20), women undergoing controlled ovarian hyperstimulation for IVF without development of severe OHSS (group 2, n=40), and healthy control subjects (group 3, n=100). Intervention(s) Investigation of markers of thrombophilia. Estimate of number of IVF patients needed to detect a case of severe OHSS and thrombosis associated with thrombophilia genetic mutation was calculated from the available data. Main outcome measure(s) Blood samples were analyzed for inherited (resistance to activated protein C due to the factor V Leiden mutation; prothrombin G20210A mutation; deficiencies in antithrombin, protein C, and protein S) and acquired (presence of circulating lupus anticoagulants and/or anticardiolipin antibodies; deficiencies of antithrombin and protein S; acquired protein C resistance) markers of thrombophilia. The cost of preventing one thrombotic event in a patient developing severe OHSS after IVF and having factor V Leiden or prothrombin G20210A mutations was calculated. Result(s) None of the OHSS patients or controls had antithrombin, protein C, or free protein S deficiencies. All of them tested negative for antiphospholipid antibodies. No patient in group 1 had the factor V Leiden or prothrombin G20210A mutations. The prothrombin G20210A mutation was detected in 1 out of 40 patients (2.5%) in group 2. Both factor V Leiden and prothrombin G20210A mutations were detected in two of the control subjects (2%) (group 3). The estimated cost of preventing one thrombotic event arising as a consequence of screening for factor V Leiden and prothrombin G20210A mutation is a minimum of $418,970 and $2,430,000, respectively. Conclusion(s) The prevalence of thrombophilia is not increased in women with severe OHSS. Screening for V Leiden and prothrombin G20210A mutation in an IVF general population is not cost-effective.

The most commonly used biomarker tests of ovarian reserve are basal hormone measurements during the early follicular phase, including mainly FSH but also oestradiol, FSH:LH ratio, and inhibin B. This study was designed to assess prospectively the intra- and inter-cycle variability of serum values of those hormone biomarkers in the early follicular phase of consecutive cycles in a group of women candidates for assisted reproduction. Fifty eumenorrhoeic women underwent blood sampling for hormone measurement on cycle day 3 for three consecutive cycles, and during the first study cycle, daily samples were obtained on cycle days 2, 3, 4 and 5. No significant difference was detected among FSH concentrations and FSH:LH ratios during cycle days 2–5; in contrast, oestradiol and inhibin B were not constant through the early follicular phase. No difference in FSH or inhibin B serum concentrations and FSH:LH ratio on cycle day 3 during three consecutive cycles was noted; however, significant inter-cycle variability for oestradiol serum concentration on cycle day 3 was detected. FSH and inhibin serum concentrations, and FSH:LH ratio varied significantly less than oestradiol on cycle day 3, but inter-cycle variability was similar for the first three hormonal biomarkers of ovarian reserve. There was significantly less intra-cycle variability of FSH serum concentration and FSH:LH ratio than oestradiol and inhibin B serum concentrations. Basal FSH serum concentrations (or FSH:LH ratio) during the early follicular phase showed neither significant inter-cycle nor intra-cycle variability when measured during 3 consecutive months in an assisted reproduction patient population, thus offering greater flexibility of pretreatment sampling.

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

Elevated LH concentrations are frequently encountered in patients with polycystic ovary syndrome (PCOS) and increased LH (either endogenous or superimposed through the use of HMG) may have detrimental effects on reproductive function. In spite of this, FSH-only products and HMG have been used indiscriminately for ovulation induction - on the basis that the administration of HMG to patients with PCOS, who are not receiving GnRH agonists, does not result in significant increases in serum LH concentrations as judged by daily single blood samples. However, both endogenous and exogenous LH have a relatively short terminal half-life and studies have reported normal serum LH, but abnormal urinary LH and emphasized that early morning urinary measurements are more informative than those in serum because they reflect nocturnal LH secretion. Therefore, the present study was undertaken to perform a pharmacokinetic and endocrine comparison of recombinant human FSH and HMG in PCOS patients including LH measurements in the urine. Five PCOS patients receiving s.c. recombinant human FSH (rhFSH) and five PCOS patients receiving i.m. HMG for ovulation induction according to a chronic low-dose step-up regimen underwent blood and urine sampling at the following study points: Point 0 was the day of HCG injection; Points 1 to 5 corresponded to days HCG -1 to -2; -3 to -4; -5 to -6; -7 to -8; and -9 to -10; respectively. Serum hormone measurements included oestradiol, FSH, LH, progesterone, inhibin A, androstenedione, testosterone, and free testosterone index. FSH and LH were also measured daily in 8-h urine samples reflecting overnight renal urine secretion. Hormone concentrations calculated as the area under the curve showed that both FSH and LH concentrations in urine were significantly higher in HMG group than in group rhFSH. It is concluded that both LH and FSH concentrations significantly accumulate in the urine of PCOS patients receiving HMG for ovulation induction in a chronic low-dose protocol as compared with rhFSH treatment.

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.

The role of luteinizing hormone in the natural menstrual cycle is not disputed. There are, however, a variety of opinions regarding the potential role of exogenous luteinizing hormone in ovulation induction and whether it is actually needed. The recent introduction into clinical practice of recombinant gonadotropins has been paralleled by recent advances in the knowledge of the endocrine and paracrine mechanisms that regulate human folliculogenesis. On this basis, this review analyses whether or not all patients need luteinizing hormone for follicular growth stimulation. In addition, new opportunities for improved treatment are considered as a result of the availability of recombinant human luteinizing hormone both in patients with ovulatory disorders and those undergoing multiple follicular development for assisted reproduction.

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 (

Background Recent studies have indicated that the corpus luteum is a major source of circulating inhibin-A and serum concentrations of inhibin-A may reflect the human luteal function. The present prospective study was undertaken to determine the usefulness of mid-luteal serum concentrations of inhibin-A as markers of endometrial receptivity (as assessed by histological dating and alphavbeta3 integrin expression) and whether they are better predictors of endometrial function than serum progesterone. Methods Consecutive infertile women (experimental group, n = 50) with regular menstrual cycles, and fertile women who were requesting contraception and had regular menstrual patterns and normal secretory endometria (control group, n = 10) were included. In all women basal body temperature, luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A, and endometrial biopsies were used in the same cycle to assess luteal function. Results Out-of-phase mid-secretory endometria were detected in 17 of the 50 infertile women. Lack of alphavbeta3 integrin expression was detected in 27 of the 50 mid-luteal endometrial biopsies. Thus, hormonal concentrations were compared in the mid-luteal phase between the following eight groups of women: group 1 (n = 10), control fertile women; group 2 (n = 50), infertile women (all); subdivided into group 3 (n = 33), with in-phase biopsies; group 4 (n = 17), with out-of-phase endometria; group 5 (n = 23), expressing alphavbeta3 integrin in endometria; group 6 (n = 27), whose endometria did not express alphavbeta3 integrin; group 7 (n = 18), with both in-phase endometrial biopsy and alphavbeta3 integrin expression; and finally group 8 (n = 12), whose endometria were out-of-phase and did not express alphavbeta3 integrin. Mid-luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A of the seven infertile groups were similar to those of the control group of fertile women. No statistically significant difference between the infertile groups was observed for any hormonal parameter considered. Conclusion Mid-luteal serum inhibin-A determination does not accurately reflect endometrial function/maturation and it is not a better indicator of endometrial luteal phase dysfunction than mid-luteal serum progesterone.

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 ...

Marked granulosa cell proliferation along with important changes in the vascular bed of the ovary characterize IVF cycles associated with multiple follicular growth and maturation. The present report investigated follicular fluid (FF) and circulating concentrations of adrenomedullin, vascular endothelial growth factor (VEGF) and nitric oxide (NO) in 70 IVF patients (14 of whom became pregnant); these three vasoactive substances may be implicated in extensive ovarian tissue remodelling. Serum and FF concentrations of oestradiol and progesterone were also measured in the 70 IVF cycles studied. Follicular fluid concentrations of VEGF and adrenomedullin but not nitrite/nitrate (the two stable oxidation products of NO metabolism) were significantly higher (P < 0.0001) than the corresponding circulating concentrations. Follicular fluid concentrations of oestradiol and progesterone were not correlated with those of adrenomedullin, VEGF or nitrite/nitrate. No relationship existed between circulating concentrations of adrenomedullin, VEGF or nitrite/nitrate on the day of oocyte aspiration and parameters of ovarian response to gonadotrophin stimulation. In contrast, FF adrenomedullin concentration showed a direct relationship with day 3 FSH serum concentration (r = 0.53, P < 0.01) and the number of ampoules of gonadotrophin administered (r = 0.36, P < 0.005), but an inverse correlation with the total number of oocytes retrieved (r = -0.29, P < 0.01) and the number of mature oocytes (r = -0.25, P < 0. 05). A positive correlation was found for FF VEGF concentration and chronological age (r = 0.29, P < 0.05) and ampoules of gonadotrophins administered (r = 0.30, P < 0.05). There was no relationship between nitrite/nitrate FF concentrations and parameters of ovarian response. Neither serum concentrations nor FF concentrations of adrenomedullin, VEGF or nitrite/nitrate were correlated with IVF outcome. This study suggested for the first time that increased FF concentrations of adrenomedullin can be a marker of decreased ovarian response in IVF. Our results also provide further evidence favouring an association between FF VEGF and patient's age, while on the basis of our findings NO measurements are not a useful marker of ovarian response.

Purpose: The main goal in the present study was to comparefollicular development and estradiol levels after ovarianstimulation in pituitary suppressed normally ovulatingwomen undergoing IVF, using highly purified urinary folliclestimulating hormone (FSH) (u-FSH-HP) and recombinantFSH (rec-FSH). A secondary variable in our study wasembryo implantation potential, which is closely related toappropriate follicular development and oocyte competence.

Purpose: Our purpose was to determine prospectively, usingreceiver-operating characteristic (ROC) analysis, whetherthe ovarian reserve test with hMG could improve thepredictive value of a woman's age and basal levels of folliclestimulating hormone (FSH), E2, and inhibin or anycombination of them regarding ovarian response and pregnancy ratein IVF treatment following pituitary desensitization. Methods: The hMG test was performed within 3 months ofIVF treatment in 80 women undergoing the first cycle ofIVF and consisted of 2 ampoules of hMG daily for 5 daysstarting on cycle days 2 to 3. Hormone and ultrasoundevaluation was performed on cycle days 2 to 3 and 7 to 8. Results: The mean age and basal FSH levels weresignificantly higher in the canceled (n = 28) than in the control(n = 52) group, whereas the basal inhibin level wassignificantly higher in the latter. Regarding ovarian response, thecombination FSH plus inhibin had the better diagnosticaccuracy (predictive value of 70%) among basal variables.When post-hMG parameters (alone or in combination) wereanalyzed, E2 alone, with a 77% diagnostic accuracy,emerged as the best predictive variable of cancellation inIVF cycles. When ROC analysis was used, the area underthe ROC curve for E2 post-hMG (diagnostic accuracy of84.5%) was significantly higher than that for the estimatesbased on the combination of basal FSH and inhibin(diagnostic accuracy of 71.3%). However, woman's age was theonly variable independently associated with pregnancy rate. Conclusions: The predictive power of the hMG test ofovarian reserve is better than that of age and basal hormonevalues (FSH and inhibin) and it is based mainly on the E2response to hMG treatment. However, given that age is theonly predictor of pregnancy and considering the cost anddiscomfort of the hMG test, the usefulness, if any, of the testin predicting IVF performance in the daily clinical settingremains to be established.

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 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.