GDF9 polymorphisms: influence on ovarian response in women undergoing controlled ovarian hyperstimulation

Abstract

Objective: The study looked into the possible influence of GDF9 polymorphisms on ovarian response in women with a normal ovarian reserve undergoing controlled ovarian hyperstimulation for in vitro fertilization (IVF). Methods: This cross-sectional study included 67 women with normal ovarian reserve aged 30-39 years submitted to controlled ovarian hyperstimulation for IVF. We sequenced four polymorphisms in the GDF9 gene (C398G, C447T, G546A, and G646A) and analyzed their influence on follicular and oocyte outcomes. Results: The mutant allele C398G decreased the total number of follicles >17mm (6.49 vs. 4.33, p =0.001), total number of follicles (10.11 vs. 7.33, p =0.032), number of MII oocytes retrieved, and serum progesterone levels on trigger day. The C447T polymorphism was associated with a greater number of follicles between 12 and 14 mm on the day of r-hCG, while the G546A polymorphism was associated with lower serum progesterone levels on trigger day. Conclusions: GDF9 gene polymorphisms C398G and C447T adversely affected ovarian response in women undergoing controlled ovarian hyperstimulation. These findings show that in addition to playing a role in the early stages of folliculogenesis, GDF9 polymorphisms have an important impact on the final stage of oocyte development.

Association of FSHR, LH, LHR, BMP15, GDF9, AMH, and AMHR polymorphisms with poor ovarian response in patients undergoing in vitro fertilization

“…GDF9 also regulates diverse processes and gene expression during the preovulatory stage (Elvin et al, 2000) and enhances cumulus cell expansion in the presence of FSH (Elvin et al, 1999), but not without FSH (Dragovic et al, 2005). Although animal models, in vitro studies, and humans studies have revealed the role of GDF9 in regulating follicular development, little is known about it in human ovarian function, since studies have demonstrated a strong correlation between GDF9 polymorphism in women with DOR and poor ovarian response followed by poor IVF outcomes, indicating that GDF9 plays an important role in determining ovarian reserve status and function (Wang et al, 2010b;Sanfins et al, 2018;Bilibio et al, 2020). In this study, we saw that the number of antral follicles, total follicles, oocytes retrieved, AMH, and estradiol day rhCG decreased in poor responders, suggesting that the GDF9 polymorphism affected oocyte development in all stages of folliculogenesis.…”

“…Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP-15), members of the TGFβ superfamily, are potent regulators of folliculogenesis and ovulation and are both expressed in oocytes from early stage follicles (Aaltonen et al, 1999;Chang et al, 2016;Sanfins et al, 2018). With respect to COH phenotypes, GDF9 and BMP15 alleles have been associated with stimulation outcome (Moron et al, 2006;Wang et al 2010a;Hanevik et al, 2011;Bilibio et al, 2020). Several genetic variants of GDF9 have been identified, and their correlation with POR has been noted, suggesting that these variants contribute to aberrant follicular development and oocyte loss (Di Pasquale et al, 2004;Shimizu et al, 2004;Abir et al, 2008;Wang et al, 2010a;.…”

Implication of novel BMP15 and GDF9 variants in unexpected poor ovarian response

“…The negative effects of GDF9 polymorphisms on ovarian reserve have described in previous studies [41], [42]. It is shown that this polymorphism can impair follicular growth as well [43].…”

Genetic determination of the ovarian reserve: a literature review

“…Polymorphisms in genes GDF9, C398G, C447T, BMP15 have been shown to negatively impact ovarian response among females who are subject to controlled ovarian hyperstimulation. Existing data shows that GDF9 polymerphisms plays an important role in different stages of folliculogenesis [ 35 ]. GDF9 and BMP15 belong to a superfamily of transforming growth factors (beta) [ 36 ].…”