Down-regulatedGDF9andBMP15mRNAs are the important determining factors for the unexplained female infertility cases advised for assisted reproductive technology

Abstract

Down-regulated GDF9 and BMP15 mRNAs are the important 2 determining factors for the unexplained female infertility cases 3 advised for assisted reproductive technology 4 5 Down-regulation of GDF9 and BMP15 mRNAs in unexplained female infertility 31 32 2 33 Abstract 34Background: In India, the potential risk factors influencing female infertility are not well-characterized. 35 Hence, this study was initially aimed to determine the multi-factor risk-predictive models for the infertile 36 females from different Indian ethnics. Afterwards, when treatment was performed for correcting the abnormal 37 demographic and clinical parameters obtained from our initial findings, some of the patients were observed to 38 be treatment-non-responsive. This further recommended assessing the expression pattern of GDF9 and 39 BMP15 mRNAs in those unexplained infertile females. 40 Methodology: This study included 470 Primary, 209 Secondary infertile and 419 age-matched Healthy 41 females, where baseline demographic and clinicopathological factors were assessed. Additionally, from the 42 treatment-non-responsive patients, laparoscopy and trans-vaginal ultrasound-guided collection of ovarian 43follicular fluid were done for studying the expression pattern of GDF9 and BMP15 mRNAs using q-PCR. 44Principal Findings: Mid-education level, no contraception usage and duration of infertility for >2 years were 45 the critical risk factors for female infertility (OR>>1; p<0.05), whereas elevated platelet count showed ~10-46 fold more risk of having secondary infertility and high ESR showed 3.33-fold increased threat of primary 47 infertility. Besides, abnormal MCV, LH/FSH ratio, mild-anaemia and hypothyroidism were the best risk-48 predictive multi-factor model. After correcting these abnormal clinical factors, 6.8% of the patients were 49 treatment-non-responsive, where elevated ESR, hypothyroidism and anaemia remained uncorrected. 50Interestingly, in those unexplained cases, GDF9 and BMP15 mRNAs were significantly down-regulated (2-4 51 fold) irrespective of age groups. Additionally, for predicting female infertility, the cut-off for the expression 52 level of GDF9 and BMP15 mRNAs were estimated -2.09 and -2.75, respectively, with a relatively high 53 sensitivity (≥62.5%) and specificity (75%). 54Conclusions: GDF9 and BMP15 mRNAs may be considered as molecular markers for predicting female 55 infertility. Their down-regulation along with hypothyroidism and anaemia probably led to the treatment-non-56 responsiveness, thus, those patients may be advised to assisted reproductive technology with supplementation 57 of exogenous GDF9 and/or BMP15. 58 59 3 60 Introduction 61A female proclaims her superiority by the power of nurturing a new life in her womb, which 62 provides a fertile ground for conception and the healthy growth of a foetus by convention. When this 63 power is curtailed due to the presence of various antagonizing factors that make pregnancy 64 unconventional and futile, the terminology infertility is applied. World Health Organisat...