SAT-195 Oocyte-Secreted Factors GDF9 and BMP15 Measured in Serum Correlate with Reproductive Potential in Women

Abstract

Abstract Bone morphogenetic protein-15 (BMP15) and growth differentiation factor-9 (GDF9) are oocyte-secreted factors critical for folliculogenesis, oocyte developmental competence and fertility. BMP15 and GDF9 are produced only by gametes and despite known associations with reproductive pathologies (1), concentrations in serum have not previously been reported. We have developed novel immunoassays that allow quantitative measurement of BMP15 and GDF9 in serum and have applied these to samples collected from women undergoing IVF to investigate the possibility that these proteins may be useful biomarkers of female reproductive function. The BMP15 and GDF9 immunoassays were developed in-house and validated for sensitivity (24 and 26 pg/ml, respectively), specificity (<0.01% and <0.03%, respectively) and reproducibility (inter-assay CV <10%). BMP15 and GDF9 were not detectable in a significant number of samples (33% for BMP15; 71% for GDF9) and these were assigned the sensitivity value for subsequent analyses. The effect of superovulation of patients undergoing IVF treatment on serum BMP15 and GDF9 was assessed using samples collected immediately before and on multiple days during FSH stimulation in antagonist treatment cycles (56 bloods from 14 women). BMP15 and GDF9 varied 64-and 15-fold respectively between women, but, within an individual were unchanged throughout superovulation, and were independent of FSH dose (P>0.05). Further analyses including an additional 141 women treated for infertility demonstrated no difference in BMP15 or GDF9 between GnRH antagonist (n=69) and agonist (n=17) stimulation cycles, or between these stimulated cycles and unstimulated cycles (n=41). Serum GDF9 positively correlated with the number of oocytes retrieved from non-PCO/PCOS women after superovulation (r=0.439, P=0.05, n=27), but not in PCO/PCOS patients. Serum GDF9, but not BMP15, was significantly lower in poor responders (women with <4 oocytes retrieved or cycle cancellation due to insufficient follicles on ultrasound (2)), compared with normal responders (27.2±0.8 vs 50.6±7.0 pg/ml; P<0.05). Serum BMP15 and GDF9 did not correlate with age, however BMP15 positively correlated with day 2 baseline FSH (r=0.305, P<0.05, n=52). This is the first report of quantitative measurement of BMP15 and GDF9 levels in human serum, correlating with reproductive potential. Although assay sensitivities require improvement, this study demonstrates the diagnostic potential of oocyte-secreted BMP15 and GDF9 as serum biomarkers in reproductive medicine. References: (1) Persani L et al., HRU 2014; 20(6):869-883. (2) Ferraretti et al., Hum Reprod 2011;26:1616-24. Funding: National Health and Medical Research Council, Australia.