Multicentre study of the clinical relevance of screening IVF patients for carrier status of the annexin A5 M2 haplotype.

Thrombophilia and impaired placental vasculature are a major cause of adverse pregnancy outcome. In 2007, a new hereditary factor for obstetric complications and recurrent pregnancy loss (RPL) was identified as a sequence variation in the core promoter of the annexin A5 gene, ANXA5, called the M2 haplotype. M2 carriership has been demonstrated in couples with recurrent miscarriage and its origin is embryonic rather than specifically maternal, confirmed by subsequent papers. The M2 haplotype is the first report of a hereditary factor related to pregnancy pathology caused by embryonic-induced anticoagulation. It has been demonstrated that couples with RPL had equal and significantly increased M2 carriership and that maternal and paternal carriership confers equal risk. Given its importance for patients with RPL, and potentially implantation failure, this study assessed the incidence of carrier status for the M2 ANXA5 haplotype in both the male and female of couples attending five CARE IVF centres. In 314 patients (157 couples), 44% of couples (one or both partners), 24% of females, 26% of males and 37% of couples with unexplained infertility were M2 carriers. This high incidence has provoked further urgent studies on specific patient populations and on the value of post embryo-transfer therapy.

Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo.

Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present study compares the major insulin signalling pathways in skeletal muscle isolated from PCOS and controls. We measured whole-body insulin sensitivity and insulin signalling in skeletal muscle biopsies taken before and after acute exposure to hyperinsulinaemia in nine women diagnosed with PCOS and seven controls. We examined the expression, basal activity and response to in vivo insulin stimulation of three signalling molecules within these human muscle samples, namely IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was a severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and an accompanying trend towards higher basal phosphorylation of ERK1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported as defective in some previous PCOS studies. Most importantly, the molecular defect identified was independent of adiposity. The altered response of ERK to insulin in PCOS was the most obvious signalling defect associated with insulin resistance in muscle from these patients.

A prospective randomized clinical trial comparing 150 IU and 225 IU of recombinant follicle-stimulating hormone (Gonal-F*) in a fixed-dose regimen for controlled ovarian stimulation in in vitro fertilization treatment.

OBJECTIVE: To compare fixed daily doses of the recombinant FSH (rFSH) Gonal-F (150 IU vs. 225 IU) for ovarian stimulation in IVF-ET. DESIGN: Single-center prospective, randomized study. Assisted conception unit of a university hospital. One hundred twenty-four women aged 23-41 years participated in the study. Exclusion criteria were as follows: FSH of >10 IU/L, polycystic ovarian syndrome, one ovary or previous ovarian surgery, previous poor response to ovarian stimulation, or ovarian hyperstimulation syndrome (OHSS). INTERVENTION(S): Randomized to commence 150 IU or 225 IU of Gonal-F per day without dose alterations during treatment. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved and total rFSH dose. RESULT(S): More oocytes were retrieved in women aged or=33 years), the number of oocytes retrieved in the two groups were similar. No significant differences were found for fertilization rate, number of embryos formed and cryopreserved, and pregnancy rates between the two groups. The total rFSH dose used was higher in the 225-IU group (2,595.0 +/- 510.0 vs. 1,897.5 +/- 457.5 IU). The cancellation rate due to insufficient ovarian response was higher in the 150-IU group (15.0% vs. 3.3%). All cases of ovarian hyperstimulation syndrome (n = 4) occurred in the 225-IU group. CONCLUSION(S): Two hundred twenty-five IU is more effective than 150 IU in younger women but requires a higher total dose of Gonal-F. The use of 225 IU in older women did not result in a higher oocyte yield, suggesting that 225 IU of rFSH does not compensate for the age-related decline in the number of follicles available for stimulation.