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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., (Copyright © 2016. Published by Elsevier Ltd.)

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., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

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

Osteopontin and its receptor alpha(v)beta(3) integrin have recently been proposed as a major complex to promote embryo attachment, and thus they would be useful as markers of endometrial receptivity. In the current study alpha(v)beta(3) integrin and osteopontin expression and co-expression in in-phase and out-of-phase endometrial biopsies from normal healthy women (n = 12) and infertile patients (n = 107) were investigated. Two endometrial biopsies (post-ovulatory day +6 to +8, and 4 days later) were performed during a single menstrual cycle in each subject. Oestradiol and progesterone serum concentrations were quantified on the same days as endometrial sampling. No statistically significant difference regarding alpha(v)beta(3) integrin and osteopontin expression and their coexpression was found between fertile controls and infertile patients irrespective of endometria being in-phase or out-of-phase, infertility factors detected or whether patients became spontaneously pregnant or not. Although a co-ordinate high concentration of both glycoproteins on post-ovulatory day 8 onwards was observed, there was an evident lack of temporal co-expression of these markers during the implantation window. It is concluded that the functional significance of the osteopontin:alpha(v)beta(3) integrin complex as a marker of endometrial receptivity and implantation potential in women seems to be untenable.

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.

Over the past 15 years, there has been a marked increase in the use of ovulation induction and intrauterine insemination (IUI) for the treatment of unexplained infertility. However, although ovulation induction and IUI have rapidly gained popularity, clinical use is based largely on practical experience rather than on well-designed scientific studies. This article summarizes the evidence in this area. Despite clinical heterogeneity and different methodological qualities of the trials, it can be concluded that ovulation induction significantly improves the probability of conception in couples with unexplained infertility, particularly when associated with IUI. It is remarkable, though, that there has been only one large-scale, randomized trial of ovulation induction plus IUI in the treatment of unexplained infertility in which one of the study arms is an untreated control group. For couples requiring treatment, the complication rate must be minimized, particularly the occurrence of high-order multiple pregnancy. Evaluation of the effectiveness and safety of low-dose gonadotrophin administration in patients with unexplained infertility is limited and further studies are warranted.

This single centre randomized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and low-dose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome (PCOS). Seventy-six infertile patients with PCOS were randomized to receive clomiphene citrate (50-150 mg/day for 5 days) (clomiphene citrate group, n = 38) or recombinant human FSH (FSH group, n = 38) in a chronic, low-dose, step-up protocol (daily starting dose 75 IU) for up to three consecutive cycles. Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin (HCG) was given to trigger ovulation in all cycles with appropriate follicular development. The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles. Secondary outcomes were cycle cancellation rate, ovulation rate per cycle, cumulative ovulation rate, pregnancy rate per cycle, incidence of OHSS, cumulative live birth rate, and multiple birth rate. One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable. The relative risk and its 95% confidence interval were 1.17 (0.97-1.46) for HCG cycles with ovulation, 1.78 (0.92-3.54) for the pregnancy rate per woman, and 1.83 (0.79-4.40) for live births per woman in favour of FSH. The cumulative pregnancy rate after three treatment cycles was 43% with FSH and 24% with clomiphene citrate (P = 0.06). By logistic regression analysis, the factors predicting ovulation included female age, serum androstenedione and use of FSH. Predictors of pregnancy were duration of infertility and use of FSH. This randomized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients. Thus, further studies, possibly multi-centre, in order to avoid problems with patient recruitment, are warranted to confirm these results.

Recent advances in manufacturing procedures for r-hFSH have resulted in a preparation (follitropin alfa) that is highly consistent in both isoform profile and glycan species distribution. As a result, follitropin alfa can be reliably quantified and vials can be filled by mass. This study compared the clinical results in a well-established assisted reproduction programme during the crossover from standard follitropin alfa filled-by-bioassay (FSH-bio) to follitropin alfa filled-by-mass (FSH-mass). The study included the last 125 patients treated with FSH-bio and the first 125 patients receiving FSH-mass for ovarian stimulation in their first assisted reproduction treatment cycle. Patient baseline characteristics were almost identical in the two groups. The duration of ovarian stimulation was significantly shorter in the FSH-mass group. The number of patients receiving the HCG injection and undergoing oocyte retrieval, follicular development and the serum concentration of oestradiol on the day of HCG injection were similar for the two treatment groups. The oocyte yield and the fertilization rates were similar in both groups of patients. However, embryo quality and implantation rates were significantly higher in the FSH-mass group. Accordingly, in spite of the mean number of embryos transferred being significantly lower in the FSH-mass group, there was a trend for higher clinical pregnancy rates in this group of patients. It is concluded that the new formulation of FSH-mass is more effective than the standard FSH-bio in terms of embryo quality, implantation rates, and number of days of stimulation.

The effect of subtle rises of progesterone in the late follicular phase of cycles of ovarian stimulation with gonadotrophin-releasing hormone (GnRH) agonists on pregnancy outcome is controversial. This study used receiver-operating characteristic (ROC) analysis to gain further insight into the predictive value of serum progesterone concentrations on the day of human chorionic gonadotrophin (HCG) injection in normally responding patients receiving the long protocol of GnRH agonist (group L; n = 218) and in low responders receiving the short ('flare-up') protocol (group S; n = 159). ROC analysis showed that serum progesterone concentration on the HCG day was not indicative of conception and non-conception cycles in the whole population studied, in group L or in group S. To further assess the potential impact of 'high' concentrations of circulating progesterone on the day of HCG administration on pregnancy rates and outcome, the threshold value (<0.9 ng/ml) to discriminate between women with 'high' (group H; n = 197) and 'normal' (group N; n = 180) progesterone was applied. No significant differences were found with respect to pregnancy and miscarriage rates between these two groups. Serum progesterone concentrations on the day of HCG administration therefore cannot predict pregnancy in assisted reproduction cycles using GnRH agonists and gonadotrophins.

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.

At present, there is considerable debate about the utility of supplemental LH in assisted reproduction treatment. In order to explore this, the present authors used a depot gonadotrophin-releasing hormone agonist (GnRHa) protocol combined with recombinant human FSH (rhFSH) or human menopausal gonadotrophin (HMG) in patients undergoing intracytoplasmic sperm injection (ICSI). The response to either rhFSH (75 IU FSH/ampoule; group rhFSH, 25 patients) or HMG (75 IU FSH and 75 IU LH/ampoule; group HMG, 25 patients) was compared in normo-ovulatory women suppressed with a depot triptorelin injection and candidates for ICSI. A fixed regimen of 150 IU rhFSH or HMG was administered in the first 14 days of treatment. Treatment was monitored with transvaginal pelvic ultrasonographic scans and serum measurement of FSH, LH, oestradiol, androstenedione, testosterone, progesterone, inhibin A, inhibin B and human chorionic gonadotrophin (HCG) at 2-day intervals. Although oestradiol serum concentrations on the day of HCG injection were similar, both the duration of treatment and the per cycle gonadotrophin dose were lower in group HMG. In the initial 16 days of gonadotrophin treatment, the area under the curve (AUC) of LH, oestradiol, androstenedione and inhibin B were higher in group HMG; no differences were seen for the remaining hormones measured, including the inhibin B:inhibin A ratio. The dynamics of ovarian follicle development during gonadotrophin treatment were similar in both study groups, but there were more leading follicles (>17 mm in diameter) on the day of HCG injection in the rhFSH group. The number of oocytes, mature oocytes and good quality zygotes and embryos obtained were significantly increased in the rhFSH group. It is concluded that in IVF patients undergoing pituitary desensitization with a depot agonist preparation, supplemental LH may be required in terms of treatment duration and gonadotrophin consumption. However, both oocyte, embryo yield and quality were significantly higher with the use of rhFSH.

Traditionally, the roles of LH in folliculogenesis have been considered to be limited to stimulating theca cells androgen production, triggering ovulation and supporting the corpus luteum. However, in the late stages of follicle development, granulosa cells become receptive to LH stimulation and LH becomes capable of exerting its actions on both theca cells and granulosa cells. Thus, it has been postulated that once an appropriate (i.e. LH-responsive) stage of follicular development has been achieved in response to treatment with FSH, there are theoretical grounds for reducing or completely withdrawing FSH and maintaining tonic stimulation of the dominant follicle with exogenous LH. This hypothesis was tested in a woman with long-standing hypogonadotrophic hypogonadism, which is the best and only true model to investigate correctly any LH hypothesis. Ovulation induction treatment was carried out with daily s.c. injections of 150 IU recombinant human FSH (rhFSH) (increased to 225 IU daily on stimulation day 15) and 375 IU recombinant human LH (rhLH). When a 14-mm follicle was identified on stimulation day 26, rhFSH was discontinued and from treatment days 26 to 29 the patient was given only rhLH at the above-mentioned dose of 375 IU/day. On treatment day 30, the single dominant follicle measured 22 mm in diameter and oestradiol serum concentration was 148 pg/ml. Thus, an injection of 10,000 IU i.m. human chorionic gonadotrophin was given and sexual intercourse was advised. The patient conceived and a viable singleton intrauterine pregnancy was obtained.