Down-regulated GDF9 and BMP15 mRNAs are the important determining factors for the unexplained female infertility cases advised for assisted reproductive technology

Background: In India, the potential risk factors influencing female infertility are not well-characterized. Hence, this study was initially aimed to determine the multi-factor risk-predictive models for the infertile females from different Indian ethnics. Afterwards, when treatment was performed for correcting the abnormal demographic and clinical parameters obtained from our initial findings, some of the patients were observed to be treatment-non-responsive. This further recommended assessing the expression pattern of GDF9 and BMP15 mRNAs in those unexplained infertile females. Methodology: This study included 470 Primary, 209 Secondary infertile and 419 age-matched Healthy females, where baseline demographic and clinicopathological factors were assessed. Additionally, from the treatment-non-responsive patients, laparoscopy and trans-vaginal ultrasound-guided collection of ovarian follicular fluid were done for studying the expression pattern of GDF9 and BMP15 mRNAs using q-PCR. Principal Findings: Mid-education level, no contraception usage and duration of infertility for >2 years were the critical risk factors for female infertility (OR>>1; p<0.05), whereas elevated platelet count showed ~10-fold more risk of having secondary infertility and high ESR showed 3.33-fold increased threat of primary infertility. Besides, abnormal MCV, LH/FSH ratio, mild-anaemia and hypothyroidism were the best risk-predictive multi-factor model. After correcting these abnormal clinical factors, 6.8% of the patients were treatment-non-responsive, where elevated ESR, hypothyroidism and anaemia remained uncorrected. Interestingly, in those unexplained cases, GDF9 and BMP15 mRNAs were significantly down-regulated (2-4 fold) irrespective of age groups. Additionally, for predicting female infertility, the cut-off for the expression level of GDF9 and BMP15 mRNAs were estimated -2.09 and -2.75, respectively, with a relatively high sensitivity (≥62.5%) and specificity (75%). Conclusions: GDF9 and BMP15 mRNAs may be considered as molecular markers for predicting female infertility. Their down-regulation along with hypothyroidism and anaemia probably led to the treatment-non-responsiveness, thus, those patients may be advised to assisted reproductive technology with supplementation of exogenous GDF9 and/or BMP15.