A new strategy in selecting oocytes with high implantation potentiality for Intracytoplasmic sperm injection procedure

Progetto: Research project

Dettagli progetto


The events leading to the rupture of the follicle and extrusion of a mature cumulus-oocyte complex (COC), competent for fertilization, are triggered by a rapid increase in circulating levels of the gonadotrophin LH (Ben-Ami et al., 2006; 2011). Although crucial for fertility, the precise role of LH in promoting the final stages of oocyte maturation is not completely understood.
Previous data have demonstrated that in selected patients, who received recombinant LH associated to recombinant FSH, as treatment for ovarian stimulation, the DNA fragmentation in cumulus cells was significantly lower and pregnancy rate higher compared to patients treated with rFSH alone. In addition, it is demonstrated that DNA fragmentation in cumulus cells was remarkably lower in patients who achieved a pregnancy after ICSI cycles, than in those who did not.
Recent genetic and molecular approaches have determined that FSH and LH activate multiple and specific intracellular signaling cascades. It is known that cumulus cells express low levels of the LH receptor, so that factors secreted from granulosa cells are required to mediate LH action in cumulus cells. In different animal species, LH receptor activation causes up-regulation of the (EGF)-like growth factor family. Studies on human oocyte maturation have shown the importance of LH-induced activation of the epidermal growth factor (EGF)-like growth factor amphiregulin (Zamah et al., 2010). This can be a potential mechanism for transducing the LH signal to oocyte.
Epidermal growth factor (EGF)-like factors [as amphiregulin (AREG), betacellulin (BTC), neuregulin (NRG) and epiregulin (EPR)] are induced by LH and activate the EGF receptor (ERBB1)/ERK1/2 pathway in granulosa cells and cumulus cells of preovulatory follicles to impact ovulation. Recent studies indicate that the ERK1/2 (also known as MAPK3/1) are essential mediators by which LH dictates the remarkable changes in follicular cell fate during ovulation and luteinization.
It is demonstrated that two transcripts of the NRG gene are expressed in granulosa cells, and that the type III NRG1 is induced during ovulation in an ERK1/2 -dependent manner. Because type III NRG1 is only expressed in granulosa cells but its receptor is expressed in both granulosa cells and cumulus cells, it is likely that NRG1 participates not only in an autocrine but also in a paracrine manner during ovulation. Results seem to demonstrate that the expression of type III NRG1 is induced in granulosa cells during ovulation and that NRG1 enhances AREG-induced ERK1/2 phosphorylation in both granulosa cells and cumulus cells. The NRG1 pathway has two roles: one is to enhance AREG-induced progesterone production in granulosa cells, and the other is to regulate oocyte maturation by a cumulus cell-dependent mechanism (Noma et al., 2011).
Promotion of cell death by ERK activation also may result from the suppression of survival signaling pathways. The pAkt pathway plays a critical role in the regulation of cell survival, and most growth and survival factors activate this pathway (Amaravadi and Thompson, 2005). Although the precise mechanism by which ERK1/2 inhibits Akt remains unclear, ERK1/2 and Akt have been reported to coexist in a multimolecular complex containing at least ERK1/2, Akt, ribosomal S6 kinase 1, and phosphoinositide-dependent kinase 1 (Sinha et al., 2004).
Although ERK has generally been considered a survival signaling pathway, clear evidence exists that the ERK pathway mediates apoptosis induced by different stimuli in different tissues. The mechanism by which ERK mediates a signaling pathway for cell survival and apoptosis is not clear. All these studies confirm that FSH and LH activate multiple cascades and specific signaling pathways. Thus, the correlation between the different factors and pathways involved, could help to identify appropriate oocyte quality markers, as proposed in the following objectives.
The aim of this research proje
Data di inizio/fine effettiva7/31/127/30/14


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