Empagliflozin-Metformin is Associated with Upregulation of GDF9 and BMP15 Expression in Cumulus Cells of PCOS Patients Undergoing ICSI: Correlation with Oocyte Quality and Pregnancy Outcomes

Document Type : Research Article

Authors

1 Department of Biology, Faculty of Science, Arak University, Arak, Iran

2 Department of Obstetrics and Gynecology, Zahedan University of Medical Sciences, Zahedan, Iran

10.22080/jgr.2026.32904.1487

Abstract

Oocyte-secreted factors, including growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), play critical roles in follicular development and oocyte maturation. Dysregulation of these factors is implicated in polycystic ovary syndrome (PCOS). This prespecified secondary analysis of a randomized, double-blind, placebo-controlled pilot trial evaluated the effects of empagliflozin-metformin and linagliptin-metformin compared to metformin alone and placebo on GDF9 and BMP15 expression in cumulus cells of infertile women with PCOS undergoing intracytoplasmic sperm injection (ICSI), and explored correlations between gene expression, oocyte quality, and pregnancy outcomes. Eighty women with PCOS (20 per arm) received empagliflozin-metformin (5/500 mg), linagliptin-metformin (2.5/500 mg), metformin (500 mg), or matched placebo twice daily for eight weeks prior to ovarian stimulation. Cumulus cells were collected during oocyte retrieval, and GDF9 and BMP15 mRNA expression levels were measured using qRT-PCR. Correlations between gene expression and oocyte/embryo outcomes were assessed using Pearson correlation coefficients. Expression of GDF9 and BMP15 mRNA was significantly increased in all active treatment groups compared with placebo (P< 0.001 for all comparisons), with the empagliflozin-metformin group showing the highest expression of both genes. The fold-change in GDF9 expression relative to placebo was 4.2± 0.8 for empagliflozin-metformin, 2.8± 0.6 for linagliptin-metformin, and 1.9± 0.4 for metformin. For BMP15, the fold-changes were 4.5± 0.9, 3.0± 0.7, and 2.0± 0.5, respectively. Strong correlations were observed between GDF9/BMP15 expression and improved oocyte and embryo outcomes exclusively in the empagliflozin-metformin group (r= 0.72-0.82, P<0.001). In this group, BMP15 expression was negatively correlated with free androgen index (r= -0.72), leptin (r= -0.75), and anti-Müllerian hormone (r= -0.62), and positively correlated with mature oocytes (r= 0.72), grade I embryos (r= 0.82), and clinical pregnancy (rpb= 0.68, P< 0.001). For GDF9, the point-biserial correlation with clinical pregnancy was rpb= 0.64 (P= 0.001). These findings suggest that empagliflozin-metformin is associated with significant upregulation of GDF9 and BMP15 expression in cumulus cells, correlating with improved reproductive outcomes. However, these results are exploratory and hypothesis-generating, requiring confirmation in larger mechanistic studies with protein-level validation and live birth as the primary endpoint.

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References

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Journal of Genetic Resources
Volume 12, Issue 2
In Progress
2026
Pages 232-244

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