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Study Question: Does a single oral dose of nolasiban 900 mg administered 4 h before embryo transfer (ET) increase pregnancy rates in women undergoing IVF?Summary Answer: In an individual patient data (IPD) meta-analysis of three clinical trials, a single oral dose of nolasiban 900 mg was associated with an increased ongoing pregnancy rate of an absolute 5% (relative 15%).What Is Known Already: Several clinical studies have shown that blocking activation of oxytocin receptors by an oxytocin receptor (OTR) antagonist has the potential to decrease uterine contractions, increase endometrial perfusion and enhance endometrial decidualisation and other parameters of endometrial receptivity. It has been hypothesised that antagonism of oxytocin receptors could improve the likelihood of successful embryo implantation and thus increase pregnancy and live birth rates following ET.Study Design, Size, Duration: This is an analysis of three randomised, double-blind, placebo-controlled trials, which randomised 1836 subjects between 2015 and 2019. We describe the results of a meta-analysis of individual participant data (IPD) from all three trials and the pre-specified analyses of each individual trial.Participant/material, Setting, Methods: Participants were patients undergoing ET following IVF/ICSI in 60 fertility centres in 11 European countries. Study subjects were below 38 years old and had no more than one previously failed cycle. They were randomised to a single oral dose of nolasiban 900 mg (n = 846) or placebo (n = 864). In IMPLANT 1, additional participants were also randomised to nolasiban 100 mg (n = 62) or 300 mg (n = 60). Fresh ET of one good quality embryo (except in IMPLANT 1 where transfer of two embryos was allowed) was performed on Day 3 or Day 5 after oocyte retrieval, approximately 4 h after receiving the study treatment. Serum hCG levels were collected at 14 days post oocyte retrieval (Week 2) and for women with a positive hCG result, ultrasound was performed at Week 6 post-ET (clinical pregnancy) and at Week 10 post-ET (ongoing pregnancy). Pregnant patients were followed for maternal (adverse events), obstetric (live birth, gestational age at delivery, type of delivery, incidence of twins) and neonatal (sex, weight, height, head circumference, Apgar scores, congenital anomalies, breast feeding, admission to intensive care and specific morbidities e.g. jaundice, respiratory distress syndrome) outcomes.Main Results and the Role Of Chance: In an IPD meta-analysis of the clinical trials, a single oral dose of nolasiban 900 mg was associated with an absolute increase of 5.0% (95% CI 0.5, 9.6) in ongoing pregnancy rate and a corresponding increase of 4.4% (95% CI -0.10, 8.93) in live birth rate compared to placebo. Similar magnitude increases were observed for D3 or D5 transfers but were not significantly different from the placebo. Population pharmacokinetics (PK) demonstrated a correlation between higher exposures and pregnancy.Limitations, Reason For Caution: The meta-analysis was not a pre-specified analysis. While the individual trials did not show a consistent significant effect, they were not powered based on an absolute increase of 5% in ongoing pregnancy rate. Only a single dose of up to 900 mg nolasiban was administered in the clinical trials; higher doses or extended regimens have not been tested. Only fresh ET has been assessed in the clinical trials to date.Wider Implications Of the Findings: The finding support the hypothesis that oxytocin receptor antagonism at the time of ET can increase pregnancy rates following IVF. The overall clinical and population PK data support future evaluation of higher doses and/or alternate regimens of nolasiban in women undergoing ET following IVF.Study Funding/competing Interests: The trials were designed, conducted and funded by ObsEva SA. A.H., O.P., E.G., E.L. are employees and stockholders of ObsEva SA. E.L. is a board member of ObsEva SA. G.G. reports honoraria and/or non-financial support from ObsEva, Merck, MSD, Ferring, Abbott, Gedeon-Richter, Theramex, Guerbet, Finox, Biosilu, Preglem and ReprodWissen GmbH. C.B. reports grants and honoraria from ObsEva, Ferring, Abbott, Gedeon Richter and MSD. P.P. reports consulting fees from ObsEva. H.T. reports grants and or fees from ObsEva, Research Fund of Flanders, Cook, MSD, Roche, Gedeon Richter, Abbott, Theramex and Ferring. H.V. reports grants from ObsEva and non-financial support from Ferring. P.T. is an employee of Cytel Inc., who provides statistical services to ObsEva. J.D. reports consulting fees and other payments from ObsEva and, Scientific Advisory Board membership of ObsEva.Trial Registration Numbers: ClinicalTrials.gov: NCT02310802, NCT03081208, NCT03758885.Trial Registration Dates: December 2014 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885).First Patient’s Enrolment: January 2015 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885). [ABSTRACT FROM AUTHOR]

BACKGROUND Steroid sulfatase (STS) is involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of disease-free and endometriosis patients. The present study was designed to investigate its role in endometriosis development. METHODS Human endometrial explants were cultured on inserts for 24 h to assess the effectiveness of an STS inhibitor (STS-I), estradiol-3-O-sulfamate (E2MATE), on STS activity in endometrial tissue. Endometriosis was induced in mice, and E2MATE (or vehicle alone) was given orally for 21 days. Plasma estradiol levels were measured, and STS activity was assessed in murine organs (uterus, liver and leukocytes) and in lesions. Lesion number, weight and size (morphometry) were quantified. Lesion STS and progesterone receptor (PR) expression, proliferation and apoptosis rates were determined by immunohistochemistry. RESULTS In vitro, addition of 1 µM E2MATE to the culture medium resulted in decreased STS activity in endometrial explants (P < 0.001). Treatment of mice with E2MATE (1.0 and 0.5 mg/kg) did not modify plasma estradiol levels, but inhibited STS activity in murine uterus (P < 0.05), liver (P < 0.001) and leukocytes (P < 0.001), as well as in induced lesions (P < 0.05). E2MATE reduced lesion weight (P < 0.01) and size (P < 0.05), but had no impact on proliferation or apoptosis rates, nor STS protein expression. Stromal edema was observed in the uterus of animals treated with E2MATE, but not in the stroma of lesions. Increased PR expression was detected in endometriotic lesions (P < 0.001). CONCLUSIONS E2MATE was shown to effectively inhibit STS activity in endometrial tissue in vitro. In vivo, E2MATE decreased endometriosis development without affecting systemic estradiol levels. Use of STS-I could therefore be of potential interest in endometriosis treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Aromatase has been reported to be involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of endometriosis patients. The objective of the present study was to investigate its expression and localization in three distinct types of endometriosis. [ABSTRACT FROM PUBLISHER]

Treatment with growth hormone-releasing factor (GRF) has been reported to improve the ovarian response to gonadotrophins in women who respond poorly to ovarian stimulation during in-vitro fertilization (IVF). The efficacy and tolerability of GRF were studied in a randomized, double-blind, placebo-controlled trial involving 196 patients. Following down-regulation with a gonadotrophin-releasing hormone agonist (GnRHa), patients were randomized to receive GRF (500 microg twice daily; n = 96) or placebo (n = 100) in addition to follicle stimulating hormone (FSH); treatment was continued until human chorionic gonadotrophin was given, or for a maximum of 14 days. GRF had no significant effect on the mean number of follicles with a diameter of >/=16 mm (GRF: 3.26 +/- 2.29; placebo: 3.27 +/- 2.30; P = 0.95), the number of FSH ampoules required to achieve ovarian stimulation (GRF: 55.2 +/- 16. 4; placebo: 54.9 +/- 17.2; P = 0.50), or on secondary measures of ovarian response and treatment outcome. There were, however, significant increases in circulating growth hormone (GH) and insulin-like growth factor (IGF)-1 concentrations. GRF was well tolerated. It is concluded that, despite producing significant increases in GH and IGF-1, concomitant treatment with GRF does not improve the ovarian response to FSH in poorly responsive women undergoing IVF. [ABSTRACT FROM AUTHOR]

Human follicle-stimulating hormone (FSH) is now produced in vitro by recombinant DNA technology. FSH being a complex heterodimeric protein, a eukaryotic cell line has been selected for expression work (Chinese hamster ovary cells). The pharmaceutical preparation of recombinant human FSH (r-FSH) differs from that of human menopausal gonadotrophin (HMG) and the first generation of urinary human FSH (u-FSH) in terms of (i) source of bulk materials, (ii) purity and specific activity, (iii) batch to batch consistency, and (iv) complete absence of luteinizing hormone (LH) activity. Pharmacokinetic characterization of r-FSH has shown an absolute bioavailability of approximately 75% after both s.c. and i.m. administration and an apparent terminal half-life of 37 +/- 25 h. These characteristics are very similar to those of u-FSH. Clinical efficacy and safety are currently demonstrated through several randomized, well controlled studies, comparing r-FSH administered s.c. with u-FSH administered i.m. for stimulating follicular development prior to assisted reproduction treatment and in World Health Organization (WHO) group II anovulation. To date, approximately 1000 patients have been treated with r-FSH. Moreover, r-FSH has recently been used successfully in association with recombinant human LH for inducing ovulation and pregnancy in WHO group I anovulatory patients. At this stage of r-FSH preparation assessment, it is likely that r-FSH will replace all urinary-derived FSH preparations for stimulating ovarian follicular development. For clinicians, current experience with r-FSH indicates that it should be used with the regimes and doses applied to u-FSH. [ABSTRACT FROM AUTHOR]

Three women with hypogonadotrophic hypogonadism, all desiring pregnancy, participated in a prospective open study attempting to assess the ability of the human corpus luteum to recover after 7 days of deprivation from gonadotrophin stimulation. Follicular growth was induced by gonadotrophins. An endogenous luteinizing hormone (LH) surge was induced by the s.c. injection of a gonadotrophin-releasing hormone agonist For luteal support, 10 mg/day oral medroxyprogesterone acetate were given for 7 days, after which a single i.m. injection of human chorionic gonadotrophin (HCG) was administered. Monitoring during the follicular phase consisted of daily measurements of serum oestradiol, LH and follicle stimulating hormone (FSH) concentrations, and of follicular growth by trans-vaginal ultrasonography. During the luteal phase, monitoring consisted of measurements of serum concentrations of LH, FSH, oestradiol, progesterone, 17-hydroxy-progesterone and β-HCG. Ovulation and luteinization occurred in two patients, demonstrated by transient marked increases in serum progesterone and 117-hydroxy-progesterone concentrations which decreased to basal pre-ovulatory values and increased again following the administration of HCG 7 days later. In the third patient, ovulation and luteinization did not occur, and the subsequent administration of HCG did not result in an increase in progesterone concentration. Of the two patients who ovulated, one conceived and the second had a luteal phase of 15 days duration. Our preliminary results suggest that the human corpus luteum can be ’rescued‘ and can function normally after 7 days of deprivation from gonadotrophin stimulation in patients with hypogonadotrophic hypogonadism. [ABSTRACT FROM PUBLISHER]

The objective of this study was to define several estimates of the success rate of in-vitro fertilization and embryo transfer treatment in relation to treatment outcome. The data were collected in a retrospective study of 591 patients treated during 3 years in one Belgian university hospital. Several models used for evaluating the treatment of infertility were fitted to the data (logistic model, binomial model, double binomial model, exponential model, the Speirs model. The number of oocytes retrieved and the proportion of fertilized oocytes at the first attempt can be used as prognostic factors. According to these factors, the success rate after five attempts varies from 28 to 88%. [ABSTRACT FROM AUTHOR]

A multicentre, multinational study was carried out between November 1990 and February 1992 to assess the safety and efficacy of a new highly purified urinary human follicle stimulating hormone (FSH; Metrodin HP®) which is practically devoid of luteinizing hormone (LH) activity. Metrodin HP was administered s.c. to stimulate multiple follicular development in women undergoing in-vitro fertilization (IVF) and embryo transfer. A total of 139 women were recruited from 10 participatin centres. Of these, 135 underwent pituitary desensitization with a long gonadotrophin-releasing hormone (GnRH) agonist protocol and following deter-mination of ovarlan inactivity (mean± SD of 12.9 ± 3.2 days), Metrodin Hp s.c. stimulation was started; 122 patients were fully eligible for efficacy analysios and 118 of these (97%) received up to 10 000 IU human chrionic gonadotrophin (HCG) to induce final folicular maturation and timed oocyte recovey. Mean plasma LH concentrations at the beginning of Metro-din HP treaement were 1.6 ± 0.8 mIU/ml and by the day of HCG administration were significantly (p<0.001) reduced (1.2 ±0.8mIU/ml). The mean plasma oestradiol and inhibin concentrations on the day of HCG were 6173±3567 pmol/l and 8.2 ±4.4 IU/ml respectively. There was a positive correlation (r= 0.49, p<0.001) between individual oestradiol and inhibin concentrations on the day of HCG. In the 118 patients who received HCG, the mean number of oocytes recovered was 8.4 ± 4.7 following stimulation with 36 ± 10, 75 IU ampoules of Metrodin HP over 12.2±2.1 days. One-hundred-and-eight patients (89% of 122 eligible) ahd 5.3±3.3 oocyted fertilized, and 105 (86%) had 2.8±1.0 embryos transferred; 28 patients (23% perinitiated cycle) had a clinical pregnancy and subsequently 18 of these (15% per initiated cycle) had a live birth. A total of 135 patients who reveiced Metrodin HP were eligible for safety analysis. One patient did not receive HCG because of the risk of developing ovarian hyperstimulation syndrome (OHSS). Seven patients (5% of those who received HCG) developed OHSS, one severe, five moderate and one mild case. Three OHSS patients were pregnant and hospitalized. The patient with severe OHSS was found to have an ectopic pregnancy. Local side effects were reported by 24 (18%) patients at the site of s.c injection. The most common compliant was brusing (48.5%). There was no development of antobodies to FSH. In conclusion Metrodln HP, a urinary gonadotrophin preparation in which>95% of the protein content is FSH, was effective in stimulating multiple follicular development and oestradol synthesis to a similar degree reported for other gonadotrophin preparations, even when endogenous LH secretion was significantly reduced by a GnRH agonist. These data support the concept that only very low concentrations of LH are required in conjunction with FSH for the stimulation of follicular development and ovarian steroidogenesis. Metrodin Hp was well tolerated locvally thus enabling convenient self-adminstration without compromising safety or efficacy [ABSTRACT FROM PUBLISHER]

Follicular fluids from eight patients with one ovary and from ten patients with two ovaries were investigated for bioactive inhibin, total renin, oestradiol (E) and progesterone (P) concentrations. Four follicular fluids were pooled per patient before assessment. All women had been stimulated similarly using a protocol including a GnRH agonist, HMG and HCG. Renin levels were significantly lower and P significantly higher in pools of follicular fluid from patients with one ovary, whereas inhibin and E concentrations were similar in both patient groups. A significant negative correlation was found in the pools of follicular fluid between inhibin and E in both groups. These results suggest a role for inhibin and renin in the paracrine and autocrine control of stimulated follicular development [ABSTRACT FROM PUBLISHER]

Repeated attempts increase the overall rate of success of sterility therapy by in-vitro fertilization. The present study, using data collected between 1983 and 1987 in a Belgian hospital, attempts to investigate the expected number of treatment cycles before success is achieved. The answer requires some knowledge about the degree of independence between success probability and treatment duration. Using mathematical models of implantation, it can be shown that success probability actually decreases during treatment. A method for updating individual probabilities is suggested; it could be used as a prognostic estimation for women undergoing this kind of therapy [ABSTRACT FROM PUBLISHER]

The induction of ovulation in women with hypogonado-trophic hypogonadism requires follicle stimulating hormone (FSH) for follicular growth and both FSH and luteinizing hormone (LH) to induce optimal follicular steroidogenesis. The development of human recombinant FSH and LH means that individually tailored doses of both hormones can be used with the aim of inducing unifollicular ovulation. This report describes the use of recombinant human FSH and LH for the induction of ovulation and conception in the second cycle of treatment, and subsequently a successfully completed pregnancy in a woman with Kallmann's syndrome. [ABSTRACT FROM PUBLISHER]