High Peak Estradiol Predicts Higher Miscarriage and Lower Live Birth Rates in High Responders Triggered with a GnRH Agonist in IVF/ICSI Cycles.

OBJECTIVE: To investigate parameters predictive of pregnancy outcomes in high responders undergoing fresh, autologous, GnRH antagonist IVF/ICSI cycles using a GnRH agonist trigger. STUDY DESIGN: Retrospective cohort study of all patients deemed high-risk for ovarian hyperstimulation syndrome who underwent fresh, autologous IVF/ICSI using a GnRH agonist trigger at an academic fertility center from 2010-2012. RESULTS: A total of 71 first cycles were analyzed. Rates of clinical pregnancy, live birth (LB), and total (clinical plus biochemical) miscarriage (MC) were 52%, 38%, and 25%, respectively. Mean peak estradiol (E2) and the number of oocytes retrieved were 3,701 pg/mL and 15.2, respectively. Peak E2 was significantly higher in those cycles resulting in clinical MC (p = 0.003). After adjusting for age, basal follicle stimulating hormone, and the number of oocytes retrieved, elevated peak E2 remained associated with increased clinical MC (p = 0.029) and trended towards a relationship with higher total MC (p = 0.062). When peak E2 was treated as a binary variable based on the threshold value of > 5,000 pg/mL, peak E2 above this value was associated with a higher rate of clinical MC (OR = 16.14 with 95% CI 1.25-209.35, p = 0.033) and total MC (OR = 6.81 with 95% CI 1.12-41.54, p = 0.037), as well as a lower LB rate (OR = 0.095 with 95% CI 0.01-0.90, p = 0.041). CONCLUSION: Clinicians should recognize most IVF/ICSI patients triggered with a GnRH agonist as inherently in danger of excessively high serum E2 and avoid peak levels > 5,000 pg/mL in order to avoid higher MC and lower LB rates.

The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis.

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the integrin-mediated activation of focal adhesion kinase and the subsequent recruitment of the Grb2 adapter molecule. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We analyzed the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Mice with haploinsufficiency of the Grb2 gene (Grb2(+/-) mice) appear normal at birth but have defective T cell signaling. In response to pressure overload, cardiac p38 MAPK and JNK activation was inhibited and cardiac hypertrophy and fibrosis was blocked in Grb2(+/-) mice. Next, transgenic mice with cardiac-specific expression of dominant negative forms of p38alpha (DN-p38alpha) and p38beta (DN-p38beta) MAPK were examined. DN-p38alpha and DN-p38beta mice developed cardiac hypertrophy but were resistant to cardiac fibrosis in response to pressure overload. These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload, and that different signaling pathways downstream of Grb2 regulate fibrosis, fetal gene induction, and cardiomyocyte growth.

Role of 14-3-3-mediated p38 mitogen-activated protein kinase inhibition in cardiac myocyte survival.

14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. Targeted expression of dominant-negative 14-3-3eta (DN-14-3-3) to murine postnatal cardiac tissue potentiates Ask1, c-jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) activation. DN-14-3-3 mice are unable to compensate for pressure overload, which results in increased mortality, dilated cardiomyopathy, and cardiac myocyte apoptosis. To evaluate the relative role of p38 MAPK activity in the DN-14-3-3 phenotype, we inhibited cardiac p38 MAPK activity by pharmacological and genetic methods. Intraperitoneal injection of SB202190, an inhibitor of p38alpha and p38beta MAPK activity, markedly increased the ability of DN-14-3-3 mice to compensate for pressure overload, with decreased mortality. DN-14-3-3 mice were bred with transgenic mice in which dominant-negative p38alpha (DN-p38alpha) or dominant-negative p38beta (DN-p38beta) MAPK expression was targeted to the heart. Compound transgenic DN-14-3-3/DN-p38beta mice, and to a lesser extent compound transgenic DN-14-3-3/DN-p38alpha mice, exhibited reduced mortality and cardiac myocyte apoptosis in response to pressure overload, demonstrating that DN-14-3-3 promotes cardiac apoptosis due to stimulation of p38 MAPK activity.