O-27: Low Dose Aspirin Administration During IVF: Molecular Changes Potentially Involved in Detrimental Effects on Oocytes Maturation and Fertilization Rate
The hypothesis that the LDA (low-dose-aspirin) could improve ovarian and uterine perfusion induced clinicians to administer it in women undergoing IVF. Unfortunately, no studies have shown significant differences in terms of pregnancy rate among patients treated or untreated with LDA. The absence of proven clinical benefits of LDA supplementation, led us to wonder whether aspirin, administered during COH could worsen the ovarian response and the oocyte fertilization rate. During the peri-ovulatory period and LH trigger, different intracellular signaling pathways (including SCF, EGF and ERK-1/2, AKT-1 phosphorylation) have been demonstrated to be involved in both follicular growth and oocytes maturation. At the same time, the local production of prostaglandins derived by LH surge is considered essential for oocytes maturation and ovulation process. The aim of this study project is to understand if LDA administration during COH may be associated to alterations in ovarian follicle intracellular signaling pathways by the analysis of follicular fluid concentrations of several growth factors such as SCF, EGF, ERK-1/2, p-ERK-1/2, AKT-1, p-AKT-1.
Materials and methods
We recruited 55 normo-responder women (25-45 years) undergoing 2 fresh non-donor IVF cycle for idiopathic primary infertility. All patients underwent long COH protocol using r (recombinant)-FSH at starting dose of 250 IU daily after the check of correct hypothalamic inhibition. All eligible patients were treated in the first cycle with 100 mg/daily LDA starting from the first gonadotropin stimulation day until hCG administration (LDA-Group). In the following cycle (within 6 months from the initial cycle) the same patients repeated COH using the same protocols and gonadotropin drugs without LDA supplementation (control- Group). When an adequate number of follicles was found at transvaginal sonography (TVS), we administrated rhCG. Oocyte retrieval took place 35h after hCG administration and all oocytes were fertilized by ICSI technique. We compared the follicular concentrations of SCF, EGF, Erk 1-2, p-Erk 1-2, Akt-1 and p-Akt-1 in both groups. Follicular levels of SCF, EGF, Erk 1-2, p-Erk-1/2, Akt-1, p-Akt-1 were detected using appropriate ELISA-Kit and reported in pg/mL, ng/mL or Unit/ mL, according to the manufacturer’s indications.
Follicular levels (110 samples) of EGF,Erk 1-2, p- Erk-1/2, Akt-1, p-Akt-1 were significantly different between LDA-Group versus control-Group, except for SCF concentration. Mean value of EGF was 8.12 ± 1.81 vs. 12.73 ± 3.25 pg/mL (P<0.01), ERK 1-2 was 248.73 ± 49.16 vs. 345.21 ± 115.12 pg/mL (P<0.001), p-ERK-1/2 13.48 ± 4.02 vs. 37.33 ± 12.42 U/mL (P<0.001), AKT-1 7.99 ± 3.25 vs. 12.18 ± 3.64 ng/mL (P<0.001), p-AKT-1 19.12 ± 10.17 vs. 44.18 ± 12.81 U/mL (P<0.001), SCF 769.32 ± 361.02 vs. 802.64 ± 298.35 pg/mL (p: n. s.).
The increasing of intracellular and intra-follicular levels of several growth factors represent one of the most reported mechanism through rLH improve the oocytes quality during IVF in poor responders patients. During spontaneous ovulation cycle, the physiological LH raise increases the oxidative status of follicular environment via COX-2 induction as effects of post-receptor signaling. LDA acting as an non selective COX 1-2 inhibitor may potentially reduce the expression of several growth factors involved in oocytes maturation. Our data clearly showed that follicular levels of EGF, ERK-1/2, AKT-1, and their phosphorylated forms p-ERK-1/2 and p-AKT-1 were significantly reduced in patients receiving LDA as opposite was demonstrated in other our research project in which rLH supplementation increased the levels of the above mentioned growth factors.