Search

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., Methods: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed., Findings: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups)., Interpretation: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy., Funding: ObsEva., Competing Interests: Declaration of interests JD is a member of the scientific advisory board of ObsEva and Preglem. EAS reports institutional grants from the National Institutes for Health related to adenomyosis and from Agency for Healthcare Research and Quality related to uterine fibroids; royalties or licenses from UpToDate; consulting fees from AbbVie, Bayer, Myovant, and ObsEva; honoraria for Continuing Medical Education course presentations from MED-IQ, Physicians’ Education Resource, and WEB MD; and for written work from the American College of Obstetricians and Gynecologists and Massachusetts Medical Society; an issued patent (6440445) with no commercial activity; participation in a phase 3 advisory board for Myovant; and is an unpaid advisory board member of the Fibroid Foundation, outside the current work. EM reports National Institute for Health grants paid to the institution; consulting fees from the University of Washington, Pfizer, and Myovant Sciences; and payments or honoraria for MED-IQ, StartART nursing, and Prime Education Continuing Medical Education. DA reports payments to institution from ObsEva and Abbvie; and payments to self from ObsEva and Vindico Medical Education. AA-H reports funding from the National Institutes for Health and consulting fees from Abbvie, Bayer, Myovant, Novartis, ObsEva, and Pfizer, outside the current work. NW reports consulting payments from Abbvie and ObsEva. J-PG is a full-time employee and a stockholder of ObsEva. EB is a full-time employee and a stockholder of ObsEva. AH is a full-time employee and a stockholder of ObsEva. EG is a full-time employee and a stockholder of ObsEva. EL is the founder, a board member, and a stockholder of ObsEva. PT is contracted by Cytel, who received fees from ObsEva for statistical services for the current work and other work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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). Bone mineral density (BMD) was assessed at baseline and 24 weeks., Results: At baseline, uterine volume (mean ± SD) was 333 ± 250 cm 3 . After 24 weeks, it was 204 ± 126 cm 3 , a reduction of 32% from baseline (P = 0.0057). After 12 weeks, it was 159 ± 95 cm 3 , a reduction of 55% (P < 0.0001). Median serum oestradiol was suppressed below 20 pg/ml during the 12 weeks on 200 mg linzagolix, and maintained below 60 pg/ml on 100 mg linzagolix. Improvements in overall pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, dyspareunia, dyschezia and QoL were observed. Mean percentage change in BMD loss at 24 weeks was -2.4%, -1.3% and -4.1% for the spine, femoral neck and total hip, respectively. The most common adverse events were hot flushes., Conclusions: A once-daily regimen of 200 mg linzagolix for 12 weeks and then 100 mg for another 12 weeks decreased adenomyotic uterine volume and improved associated symptoms., (Copyright © 2021. Published by Elsevier Ltd.)

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. Previous work confirmed the peroxidase activity of AmPrx6 in the presence of dithiotreitol. Herein, we performed an in vitro kinetic characterization of the recombinant enzyme. AmPrx6 reduced hydrogen peroxide and peroxynitrite with rate constants of 1.1×10(7) and 2×10(6)M(-1)s(-1), respectively, at pH 7.4 and 25°C. Reduction of tert-butyl hydroperoxide was slower. The pK(a) of the peroxidatic thiol of AmPrx6 was determined as 5.1±0.2, indicating that it exists as thiolate, the reactive species, at physiological pH. The reductive part of the catalytic cycle was also explored. Hydrogen sulfide, present in millimolar concentrations in marine sediments where the annelid lives and that is able to reduce the mammalian 1-Cys peroxiredoxin, did not support AmPrx6 peroxidase activity. The enzyme was not reduced by other potential physiological reductants tested. Our data indicate that in this annelid, Prx6 could contribute to peroxide detoxification in the presence of a so far unidentified reducing counterpart., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Traditionally, therapeutic preparations of gonadotrophins are quantified with a rat in-vivo bioassay in biological international units (IU). This method was developed to cope with variability of production batch quality. The bioassay, however, presents some limitations, and differences in clinical responses when using different batches of urine-derived gonadotrophins have been reported. The production of human FSH by recombinant technology now allows the use of advanced physicochemical methods for quantifying FSH, which can be measured in microg of FSH proteins (in mass). The study reported here was designed and conducted to assess the clinical relevance of this new method for quantifying therapeutic preparation of FSH. Four bulk lots of recombinant human FSH (r-hFSH) were used to prepare batches filled by IU (FbIU) and four batches filled by mass (FbM). These eight batches were compared in a double-blind, randomized study in patients undergoing assisted reproductive technology. One hundred and thirty-one patients were enrolled in this study and met protocol criteria (66 in the FbM group and 65 in the FbIU group). The starting dose of recombinant human FSH (r-hFSH) was either 150 IU or 11 microg/day. Both preparations induced multiple follicular development and all patients underwent oocyte retrieval. The number of follicles >/= 11mm was 14.85 and 14.91, serum oestradiol concentration on day of human chorionic gonadotrophin (HCG) administration was 6524 and 6350 pmol/l, number of oocytes retrieved was 10.76 and 11.28, number of two-pronuclear (2 PN) oocytes was 5.2 and 5.00, number of viable embryos (replaced or cryopreserved) was 4.15 and 3.72, and clinical pregnancy rate was 30.3 and 26.2% respectively in the FbM and FbIU groups. Overall, the patients' response consistency was found to be superior with FbM (P = 0.039), and in particular for clinical pregnancy rates (P < 0.001). This new method for quantifying r-hFSH delivers an improved consistency in clinical outcome.

FSH and LH play an essential but different role in the growth of ovarian follicles during the cycle. In stimulation protocols, good follicular development is obtained in most patients treated with FSH alone whereas the role of LH is more complex and controversial. Clinical and pre-clinical studies have shown that optimal follicular development is obtain if (i) exposure to endogenous and/or exogenous LH is sufficient ("threshold" concept) and (ii) exposure to LH is not excessive ("ceiling" concept). The recombinant luteinizing hormone (r-hLH, Luveris) is the only available stand-alone preparation of LH. Its characteristics are a high specific activity, the absence of undesirable proteins and an excellent batch to batch consistency. Luveris is indicated in association with FSH for stimulating follicular development in LH and FSH deficient women (defined by an endogenous LH level < 1.2 UI/l). In this subgroup of patients, the therapeutic benefit of exogenous LH at a daily dose of 75 IU is only observed when endogenous serum LH is below than 1.2 IU/l: LH threshold concept. In ART, the combination of exogenous LH at a daily dose from 75 to 150 IU and recombinant FSH improved the ovarian stimulation results only in a minority of patients (5 to 17%). On the opposite, studies conducted in OMS I and II patients showed that high doses of exogenous LH lead to atresia of secondary follicles. So, a daily dose of exogenous LH greater than 225 IU had a deleterious effect on follicular growth: LH ceiling concept.

Late miscarriage is a well-known complication in multiple pregnancies. Two cases were presented with rupture of the membranes and prolapse of the cord with the death of the presenting fetus are reported. In both cases extraction of the presenting fetus was carried out at 21 weeks of pregnancy followed by cervical cerclage. A triplet pregnancy which was reduced to two fetuses reached 30 weeks and two healthy infants were delivered. A twin pregnancy which was reduced to one fetus, resulted in that one being lost two weeks later when the patient developed chorioamnionitis and septicaemia.

Radio-immuno-assay estimations of urinary hCG were carried out with pharmacia Kit beta hCG Riact on 36 women who had received embryo transfers. The analysis was carried in order to try and find how and at what moment in time it is possible to diagnose very early a developing pregnancy after embryo transfer. In this work we have found that the mean level of urinary hCG was significantly higher (P less than 0.001) in women who became pregnant (group B) than in those who did not become pregnant (group A). The difference in mean hormone levels in these two groups became more marked in the following days. The time doubling of the hCG level varied between 1.21 and 3.24 days in group B. By the eighth day the level of urinary hCG was less in group B than in group A, probably due to rapid renal breakdown of hCG. In summary these results show that the level of urinary hCG estimated from the 11th day onwards after an embryo transfer repeated two or three days later makes it possible to detect early pregnancies.

We have assessed the beneficial effects of administering a short course of an agonist of LHRH (Buserelin) in vitro fertilisation. 274 cycles were treated with CC-HMG, 159 were treated with HMG alone and 253 by Buserelin-HMG. These were compared retrospectively. The use of a short course of Buserelin lowered significantly the rate of failed treated cycles (7% instead of 19% when it was used with CC-HMG and 27% when used with HMG). This made it possible to administer hCG in all cases in the programme (100% as against 69% and 89% respectively for CC-HMG and HMG without Buserelin), and increase significantly the number of oocytes that could be recovered and the number of embryos available for transfer. The overall number of pregnancies per cycle treated is significantly raised when Buserelin is used with HMG (20.4% as against 13.5% for CC-HMG and HMG). The number of pregnancies that progressed, on the other hand, was similar when the cycle was stimulated with HMG alone (10.6%) or with Buserelin-HMG (10.6%).