Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35-42 years with a body weight ≥50 kg: a randomized controlled trial.

STUDY QUESTION: Is corifollitropin alfa 150 µg equivalent to follitropin beta 300 IU/day for controlled ovarian hyperstimulation (COS) in older women weighing ≥50 kg undergoing IVF and/or ICSI in Vietnam? SUMMARY ANSWER: Corifollitropin alfa 150 µg was equivalent to follitropin beta 300 IU/day with respect to the number of oocytes retrieved, the ongoing, cumulative and live birth rates and obstetric outcomes. WHAT IS KNOWN ALREADY: Corifollitropin alfa is a recombinant FSH (rFSH) preparation with slow absorption and a long half-life allowing administration of a single dose for COS lasting 7 days. Several randomized, controlled clinical trials have reported that COS with corifollitropin alfa is associated with similar outcomes compared with COS using daily rFSH. However, limited data are available in Asian patients. STUDY DESIGN SIZE DURATION: This randomized controlled trial was conducted at a single large IVF centre in Vietnam from June 2015 to August 2016. A total of 400 patients were included, 200 in each treatment group. The primary outcome measure was the number of oocytes retrieved. Patients were followed for 1 year after randomization. PARTICIPANTS /MATERIALS SETTING METHODS: Participants aged 35-42 years with a body weight ≥50 kg who were undergoing an IVF cycle were randomized to undergo COS with a single dose of corifollitropin alfa 150 µg on Day 2 or 3 of the menstrual cycle, or follitropin beta 300 IU/day for 7 days starting on Day 2 or 3 of the menstrual cycle. All underwent ICSI according to standard institutional protocols. A beta hCG test was performed 17 days after ovum pick-up, and positive tests were confirmed on vaginal and/or abdominal ultrasound at 5-6 weeks after embryo transfer (clinical pregnancy) and at ≥10 weeks (ongoing pregnancy). Rates of ovarian hyperstimulation syndrome, and maternal and foetal outcomes after one cycle of ICSI were monitored over 12 months. MAIN RESULTS AND THE ROLE OF CHANCE: Patients in the corifollitropin alfa and follitropin beta groups were well matched at baseline (mean age 37.5 ± 1.9 vs 37.7 ± 2.0 years, mean body weight 53.7 ± 5.4 vs 52.5 ± 4.8 kg). There was no significant difference between the corifollitropin alfa and follitropin beta groups in the number of oocytes retrieved (11.4 ± 5.9 vs 10.8 ± 5.8; P = 0.338). The ongoing pregnancy rate (31.5 vs 32.0%; P = 0.99) and live birth rate (30.5 vs 32.0%; P = 0.83) (both per initiated cycle at 12 months after randomization) were also similar in the two treatment groups. Complication rates were low and similar in the corifollitropin alfa and follitropin beta groups, and there were no significant between-group differences in obstetric outcomes. LIMITATIONS REASONS FOR CAUTION: This study had an open-label design, and therefore, the potential for bias cannot be excluded. The findings are only applicable to patient populations with similar characteristics to those enroled in the study. WIDER IMPLICATIONS OF THE FINDINGS: This study adds to the body of evidence supporting the equivalence of corifollitropin alfa and follitropin beta for COS in a variety of patients undergoing IVF and/or ICSI. The ability to provide COS with corifollitropin alfa has the potential to reduce the burden of treatment for patients. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Merck Sharp and Dohme. The authors state that they have no financial or commercial conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered with clinicaltrials.gov (NCT02466204). TRIAL REGISTRATION DATE: 2 June 2015. DATE OF FIRST PATIENT'S ENROLMENT: 19 June 2015.

Brain-derived neurotrophic factor gene organization and transcription in the zebrafish embryo.

The gene encoding zebrafish brain-derived neurotrophic factor (BDNF) was cloned from a PAC genomic DNA library. The entire transcription unit was contained in two independently isolated clones that together encompass 120 kb of genomic DNA. The intron/exon organization of the zebrafish gene was found to be identical to that of the mammalian gene but only one promoter has so far been identified. The associated 5' exon is 67% identical to exon 1c of the rat BDNF gene. A search of the 5' flank of the cloned promoter for sequence similarities with known transcription factor binding sites revealed potential AP-1, CREB, and SP1 binding sites. Fusion constructs containing the cloned promoter and 1.7 kb of 5' flank and an enhanced green fluorescent protein reporter that becomes membrane-anchored were injected into 1-8 cell stage embryos. Expression was seen in notochord, muscle, epithelial and endothelial cells of the 1-day-old embryo in consonance with the endogenous gene. These results demonstrate that the cloned promoter mediates cell-specific expression.

Brain-derived neurotrophic factor and TrkB tyrosine kinase receptor gene expression in zebrafish embryo and larva.

The genes that encode the neurotrophin family of secreted polypeptides and the Trk family of high affinity neurotrophin transmembrane protein tyrosine kinase receptors are induced at the time of neurogenesis in mammals and are known to play critical roles in nervous system development. We show here that in contrast to mammals, the genes encoding the neurotrophin brain-derived neurotrophic factor (BDNF) and the neurotrophin receptor TrkB are expressed throughout embryonic development in the zebrafish. At the embryonic stages preceding transcription of endogenous genes all cells contain BDNF transcripts and immunoreactive BDNF and the trkB transcripts lack the region that encodes a kinase domain. As development proceeds, progressively fewer cells contain BDNF transcripts and by the time of neurogenesis the trkB transcripts encode a kinase-domain. In the 4-day-old larva, a small subset of specialized sensory cells on the surface and cells in deeper structures including the gill arches, fin, and cloaca express the BDNF gene at high levels in a promoter-specific fashion. This progressive restriction of BDNF gene expression must involve an extinction of BDNF gene transcription in some and induction of high levels of transcription in a promoter-specific fashion in other cells.

Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice.

The matricellular angiogenesis inhibitor, thrombospondin (TSP) 2, has been shown to be an important modulator of wound healing and the foreign body response. Specifically, TSP2-null mice display improved healing with minimal scarring and form well-vascularized foreign body capsules. In this study we performed subcutaneous implantation of sponges and investigated the resulting angiogenic and fibrogenic responses. Histological and immunohistochemical analysis of sponges, excised at 7, 14, and 21 days after implantation, revealed significant differences between TSP2-null and wild-type mice. Most notably, TSP2-null mice exhibited increased angiogenesis and fibrotic encapsulation of the sponge. However, invasion of dense tissue was compromised, even though its overall density was increased. Furthermore, histomorphometry and biochemical assays demonstrated a significant increase in the extracellular distribution of matrix metalloproteinase (MMP) 2, but no change in the levels of active transforming growth factor-beta(1). The alterations in neovascularization, dense tissue invasion, and MMP2 in TSP2-null mice coincided with the deposition of TSP2 in the extracellular matrix of wild-type animals. These observations support the proposed role of TSP2 as a modulator of angiogenesis and matrix remodeling during tissue repair. In addition, they provide in vivo evidence for a newly proposed function of TSP2 as a modulator of extracellular MMP2 levels.

Regulation of angiogenesis and matrix remodeling by localized, matrix-mediated antisense gene delivery.

Implantation of biomaterials, such as glucose sensors, leads to the formation of a poorly vascularized collagenous capsule that can lead to implant failure. This process, known as the foreign body reaction (FBR), develops in response to almost all biomaterials and consists of overlapping phases similar to those in wound healing. Implantation of porous biomaterials, such as polyvinyl alcohol sponges, also leads to granuloma formation within the interstices of the sponge prior to encapsulation by the FBR. We asked whether delivery of an antisense cDNA for the potent angiogenesis inhibitor thrombospondin (TSP) 2 would enhance blood vessel formation and alter collagen fibrillogenesis in the sponge granuloma and capsule. Collagen solutions were mixed with plasmid to generate gene-activated matrices (GAMs) and applied to biomaterials that were then implanted subcutaneously. Sustained expression of plasmid-encoded proteins was observed at 2 weeks and a month following implantation. In vivo delivery of plasmids, encoding either sense or antisense TSP2 cDNA, altered blood vessel formation and collagen deposition in TSP2-null and wild-type mice, respectively. Untreated implants, implanted next to GAM-treated implants, did not show exogenous gene expression and did not elicit altered responses, suggesting that gene delivery was limited to implant sites. This method of antisense DNA delivery has the potential to improve the performance and life span of implantable delivery devices and biosensors.