Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.

Background: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids.

Uterine Adenomyosis Treated by Linzagolix, an Oral Gonadotropin-Releasing Hormone Receptor Antagonist: A Pilot Study with a New 'Hit Hard First and then Maintain' Regimen of Administration.

(1) Background: The aim of the present pilot study was to study the effect of a new oral gonadotropin-releasing hormone antagonist on adenomyosis. (2) Methods: Eight premenopausal women, aged between 37 and 45 years, presenting with heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis, confirmed by magnetic resonance imaging (MRI), received 200 mg linzagolix once daily for a period of 12 weeks, after which they were switched to 100 mg linzagolix once daily for another 12 weeks. The primary efficacy endpoint was the change in volume of the adenomyotic uterus from baseline to 24 weeks, evaluated by MRI.

Treatment of symptomatic uterine adenomyosis with linzagolix, an oral gonadotrophin-releasing hormone antagonist: a pilot study.

Research Question: Does a once-daily regimen of linzagolix, a new oral gonadotrophin-releasing hormone (GnRH) antagonist, given at a fully suppressive dose (200 mg) for 12 weeks, followed by a partially suppressive dose (100 mg) for a further 12 weeks, reduce adenomyotic uterine size and associated symptoms?

Design: Eight women (aged 37-45 years) with adenomyosis confirmed by magnetic resonance imaging (MRI) were enrolled in a single-centre, open-label pilot study. The primary efficacy end-point was the change in uterine volume on MRI at 24 weeks. Secondary efficacy end-points included serum oestradiol, overall pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, dyspareunia, dyschezia and quality of life (QoL).

Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.

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.

Gonadotropin-Releasing Hormone Receptor Antagonist Mono- and Combination Therapy With Estradiol/Norethindrone Acetate Add-Back: Pharmacodynamics and Safety of OBE2109.

Context: OBE2109 is a potent, oral gonadotropin-releasing hormone receptor antagonist being developed for the treatment of sex-hormone-dependent diseases in women.

Objective: We assessed the pharmacodynamics and safety of OBE2109 alone and combined with estradiol (E2)/norethindrone acetate (NETA) add-back therapy on E2 levels and vaginal bleeding.

Design, Setting, And Participants: This was a single-center, open-label, randomized, parallel-group study in 76 healthy premenopausal women.

Long-term medical management of uterine fibroids with ulipristal acetate.

Objective: To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids.

Design: Double-blind, randomized administration of four 12-week courses of ulipristal acetate.

Setting: Gynecology centers.

Contribution to More Patient-Friendly ART Treatment: Efficacy of Continuous Low-Dose GnRH Agonist as the Only Luteal Support-Results of a Prospective, Randomized, Comparative Study.

Background. The aim of this pilot study was to evaluate intranasal buserelin for luteal phase support and compare its efficacy with standard vaginal progesterone in IVF/ICSI antagonist cycles. Methods.

Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids.

Objective: To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily of ulipristal acetate for intermittent treatment of symptomatic uterine fibroids.

Design: Double-blind, randomized administration of two 12-week courses of ulipristal acetate.

Setting: Gynecology centers.

Recombinant human luteinizing hormone to trigger ovulation: randomized, controlled, dose-finding pilot study in ovulation induction.

Objective: To evaluate recombinant human luteinizing hormone (r-hLH) versus urine-derived human chorionic gonadotropin (u-hCG) to trigger ovulation in women (aged 20-40 years) with WHO Group II anovulatory infertility undergoing ovulation induction (OI) with recombinant human follicle-stimulating hormone (r-hFSH) (150 IU/day starting dose).

Study Design: For this Phase II, open-label, dose-finding pilot study, patients were randomized to doses of 825, 2,750, 5,500, 11,000, or 22,000 IU r-hLH or u-hCG (5,000 IU). Primary endpoints were ovulation and ratio of ruptured follicles/follicle > or = 15 mm (day of r-hLH/ u-hCG administration).

Long-term treatment of uterine fibroids with ulipristal acetate ☆.

Objective: To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids.

Design: Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo.

Setting: European clinical gynecology centers.

Ulipristal acetate versus leuprolide acetate for uterine fibroids.

Background: The efficacy and side-effect profile of ulipristal acetate as compared with those of leuprolide acetate for the treatment of symptomatic uterine fibroids before surgery are unclear.

Methods: In this double-blind noninferiority trial, we randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral ulipristal acetate (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (at a dose of 3.75 mg).

Ulipristal acetate versus placebo for fibroid treatment before surgery.

Background: The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain.

Methods: We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women).

Kinetic studies of peroxiredoxin 6 from Arenicola marina: rapid oxidation by hydrogen peroxide and peroxynitrite but lack of reduction by hydrogen sulfide.

Arenicola marina lives in marine environments where hydrogen peroxide concentrations reach micromolar levels. The annelid also forms reactive species through metabolic pathways. Its antioxidant systems include a cytosolic peroxiredoxin, peroxiredoxin 6 (AmPrx6 or AmPRDX6) that shows high homology to the mammalian 1-Cys peroxiredoxin.

Inhibition of steroid sulfatase decreases endometriosis in an in vivo murine model.

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.

Kit ligand and the somatostatin receptor antagonist, BIM-23627, stimulate in vitro resting follicle growth in the neonatal mouse ovary.

In the mammalian ovary, kit ligand (KL), coded by a cAMP-stimulatable gene, is a protein that promotes initiation of follicle growth. The neuropeptide somatostatin (SST) is a small peptide that inhibits cAMP generation in many cell types. Consequently, SST receptor agonists might alter KL production and subsequent follicle growth.

Evaluation of estrogen treatment in an immunodeficient mouse endometriosis model.

Background/aims: Endometriosis is known to be an estrogen-dependent disease. However, only a few studies have analyzed the effect of estrogen treatment in mice xenotransplanted with human endometrium. The objective of this study was to adapt a previously developed heterologous murine model to the study of estrogens and test the impact of estrone treatment on endometriosis development.

Absence of aromatase protein and mRNA expression in endometriosis.

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.

Methods: Human peritoneal, ovarian and rectovaginal endometriotic lesions and matched eutopic endometrium were collected from patients during laparoscopy.

Cloning and characterization of Arenicola marina peroxiredoxin 6, an annelid two-cysteine peroxiredoxin highly homologous to mammalian one-cysteine peroxiredoxins.

Peroxiredoxins (PRDXs) are a superfamily of thiol-dependent peroxidases found in all phyla. PRDXs are mechanistically divided into three subfamilies, namely typical 2-Cys, atypical 2-Cys, and 1-Cys PRDXs. To reduce peroxides, the N-terminal peroxidatic Cys of PRDXs is first oxidized into sulfenic acid.

The crystal structure of the C45S mutant of annelid Arenicola marina peroxiredoxin 6 supports its assignment to the mechanistically typical 2-Cys subfamily without any formation of toroid-shaped decamers.

The peroxiredoxins (PRDXs) define a superfamily of thiol-dependent peroxidases able to reduce hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite. Besides their cytoprotective antioxidant function, PRDXs have been implicated in redox signaling and chaperone activity, the latter depending on the formation of decameric high-molecular-weight structures. PRDXs have been mechanistically divided into three major subfamilies, namely typical 2-Cys, atypical 2-Cys, and 1-Cys PRDXs, based on the number and position of cysteines involved in the catalysis.

Evolution of the peroxiredoxins.

Peroxiredoxins compose a superfamily of peroxidases ubiquitously found throughout evolution in prokaryotes, archaea and eukaryotes. These enzymes contain a conserved catalytic peroxidatic cysteine (Cp) in the N-terminal region of the protein. The residues surrounding Cp and the catalytic site appear also to be well conserved.

GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study.

Background: The aim of the study was to investigate whether intranasal (IN) administration of a GnRH agonist could provide luteal support in IVF/ICSI patients.

Methods: Controlled ovarian hyperstimulation (COH) was performed using hMG/FSH and a GnRH antagonist. Patients were then randomly allocated to either 10,000 IU hCG, followed by vaginal administration of micronized progesterone (3x 200 mg/day) (group A), or 200 microg IN buserelin followed by either 100 microg every 2 days (group B), or 100 microg every day (group C), or 100 microg twice a day (group D), or 100 microg three times a day (group E).

GnRH agonist as novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin.

Background: The study objective was to investigate whether repeated intranasal administration of a GnRH agonist could provide convenient and safe luteal support.

Methods: Twenty-four patients with unexplained infertility were enrolled. All patients were treated with an aromatase inhibitor.

Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase.