پیوندهای مفید
آمار
| تعداد نشریات | 32 |
| تعداد شماره‌ها | 597 |
| تعداد مقالات | 5,837 |
| تعداد مشاهده مقاله | 8,820,742 |
| تعداد دریافت فایل اصل مقاله | 6,459,264 |
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 | ||
| Journal of Genetic Resources | ||
| دوره 12، شماره 2، 2026، صفحه 232-244 اصل مقاله (449.61 K) | ||
| نوع مقاله: Research Article | ||
| شناسه دیجیتال (DOI): 10.22080/jgr.2026.32904.1487 | ||
| نویسندگان | ||
| Mahdieh Sadat Mousavi1؛ Malek Soleimani Mehranjani* 1؛ Forough Forghani2؛ Elnaz Salahi2 | ||
| 1Department of Biology, Faculty of Science, Arak University, Arak, Iran | ||
| 2Department of Obstetrics and Gynecology, Zahedan University of Medical Sciences, Zahedan, Iran | ||
| تاریخ دریافت: 13 خرداد 1405، تاریخ پذیرش: 13 تیر 1405 | ||
| چکیده | ||
| 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. | ||
| کلیدواژه‌ها | ||
| BMP 15؛ Cumulus cells؛ Empagliflozin؛ GDF 9؛ Linagliptin؛ Polycystic ovary syndrome | ||
| مراجع | ||
|
Alpha Scientists in Reproductive Medicine, & ESHRE Special Interest Group of Embryology. (2011). The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Human Reproduction, 26(6), 1270-1283. https://doi.org/10.1093/humrep/der037
Andersen, C. L., Jensen, J. L., & Orntoft, T. F. (2004). Normalization of Real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Research, 64(15), 5245-5250. https://doi.org/10.1158/0008-5472.CAN-04-0496
Anderson, R. A., Marston, A. L., & Telfer, E. E. (2025). Oocyte development: it's all about quality. Reproductive BioMedicine Online, 50(4), 104804. https://doi.org/10.1016/j.rbmo.2025.104804
Bouchoucha, M., Uzzan, B., & Cohen, R. (2011). Metformin and digestive disorders. Diabetes & Metabolism, 37(2), 90-96. https://doi.org/10.1016/j.diabet.2010.11.002
Daneshjou, D., Soleimani Mehranjani, M., Zadehmodarres, S., Shariatzadeh, S. M. A., & Mofarahe, Z. S. (2022). Sitagliptin/metformin improves the fertilization rate and embryo quality in polycystic ovary syndrome patients through increasing the expression of GDF9 and BMP15: a new alternative to metformin (a randomized trial). Journal of Reproductive Immunology, 150, 103499. https://doi.org/10.1016/j.jri.2022.103499
Dumesic, D. A., Meldrum, D. R., Katz-Jaffe, M. G., Krisher, R. L., & Schoolcraft, W. B. (2015). Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertility and Sterility, 103(2), 303-316. https://doi.org/10.1016/j.fertnstert.2014.11.015
Fakhreddin, M., Forghani, F., Jahantigh, D., Salahi, E., & Mousavi, M. S. (2026). Dapagliflozin-metformin combination enhances oocyte quality and reproductive outcomes in PCOS patients undergoing IVF/ICSI: a randomized controlled trial. Scientific Reports, https://doi.org/10.1038/s41598-026-69538-8
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., … & Woerle, H.-J. (2014). Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. The Journal of Clinical Investigation, 124(2), 499-508. https://doi.org/10.1172/JCI72227
Fountas, S., Petinaki, E., Bolaris, S., Kargakou, M., Dafopoulos, S., Zikopoulos, A., … & Dafopoulos, K. (2024). The roles of GDF-9, BMP-15, BMP-4 and EMMPRIN in folliculogenesis and in vitro fertilization. Journal of Clinical Medicine, 13(13), 3775. https://doi.org/10.3390/jcm13133775
Gallwitz, B. (2019). Clinical use of DPP-4 inhibitors. Frontiers in Endocrinology, 10, 389. https://doi.org/10.3389/fendo.2019.00389
Garg, D., & Tal, R. (2016). The role of AMH in the pathophysiology of polycystic ovarian syndrome. Reproductive BioMedicine Online, 33(1), 15-28. https://doi.org/10.1016/j.rbmo.2016.04.007
Garruti, G., De Palo, R., Rotelli, M. T., Nocera, S., Totaro, I., Nardelli, C., … & Giorgino, F. (2014). Association between follicular fluid leptin and serum insulin levels in nonoverweight women with polycystic ovary syndrome. BioMed Research International, 2014, Article 980429. https://doi.org/10.1155/2014/980429
Gode, F., Gulekli, B., Dogan, E., Korhan, P., Dogan, S., Bige, O., … & Atabey, N. (2011). Influence of follicular fluid GDF9 and BMP15 on embryo quality. Fertility and Sterility, 95(7), 2274-2278. https://doi.org/10.1016/j.fertnstert.2011.03.045
Hassani, F., Oryan, S., Eftekhari-Yazdi, P., Bazrgar, M., Moini, A., Nasiri, N., & Ghaheri, A. (2018). Association between the number of retrieved mature oocytes and insulin resistance or sensitivity in infertile women with polycystic ovary syndrome. International Journal of Fertility and Sterility, 12(4), 310-315. https://doi.org/10.22074/ijfs.2019.5422
Hawley, S. A., Ford, R. J., Smith, B. K., Gowans, G. J., Mancini, S. J., Pitt, R. D., … & Hardie, D. G. (2016). The Na+/glucose co-transporter inhibitor canagliflozin activates AMP-activated protein kinase by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes, 65(9), 2784-2794. https://doi.org/10.2337/db16-0058
Javed, Z., Papageorgiou, M., Deshmukh, H., Rigby, A. S., Qamar, U., Abbas, J., … & Sathyapalan, T. (2019). Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: a randomized controlled study. Clinical Endocrinology, 90(6), 805-813. https://doi.org/10.1111/cen.13968
Kamrul-Hasan, A. B. M., Mondal, S., Aalpona, F. T. Z., Nagendra, L., & Dutta, D. (2025). Role of sodium–glucose cotransporter-2 inhibitors in managing polycystic ovary syndrome: A systematic review. touchREVIEWS in Endocrinology, 21(1), 32-41. https://doi.org/10.17925/EE.2025.21.1.2
Karagul, M. I., Aktas, S., Yilmaz, B. C., Yilmaz, M., & Temel, G. O. (2018). GDF9 and BMP15 expressions and fine structure changes during folliculogenesis in polycystic ovary syndrome. Balkan Medical Journal, 35(1), 43-54. https://doi.org/10.4274/balkanmedj.2016.1110
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods, 25(4), 402-408. https://doi.org/10.1006/meth.2001.1262
Moreira, M. V., Vale-Fernandes, E., Albergaria, I. C., Alves, M. G., & Monteiro, M. P. (2023). Follicular fluid composition and reproductive outcomes of women with polycystic ovary syndrome undergoing in vitro fertilization: A systematic review. Reviews in Endocrine and Metabolic Disorders, 24, 1045-1073. https://doi.org/10.1007/s11154-023-09819-z
Mousavi, M. S., Soleimani Mehranjani, M., Forghani, F., & Salahi, E. (2026). Comparative study of the therapeutic effects of Synoripa, Melijent-M, and metformin on anthropometric, biochemical, and hormonal parameters in women with polycystic ovary syndrome undergoing ICSI. Gene, Cell and Tissue, 13(1), e169067. https://doi.org/10.5812/gct-169067
Nestler, J. E., Jakubowicz, D. J., Evans, W. S., & Pasquali, R. (1998). Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. The New England Journal of Medicine, 338(26), 1876-1880. https://doi.org/10.1056/NEJM199806253382603
Otsuka, F., & Shimasaki, S. (2002). A novel function of bone morphogenetic protein-15 in the pituitary: Selective synthesis and secretion of FSH by gonadotropes. Endocrinology, 143(12), 4938-4941. https://doi.org/10.1210/en.2002-220929
Rakic, D., Jakovljevic, V., Zivkovic, V., Jakovljevic Uzelac, J., Jovic, N., Muric, M., ... & Joksimovic Jovic, J. (2024). Multiple benefits of empagliflozin in PCOS: Evidence from a preclinical rat model. Pathophysiology, 31(4), 559-582. https://doi.org/10.3390/pathophysiology31040041
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. (2004). Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility, 81(1), 19-25. https://doi.org/10.1016/j.fertnstert.2003.10.004
Sanjari, M., Hadavizadeh, M., Sadeghi, N., & Naghibzadeh-Tahami, A. (2025). Effect of empagliflozin on weight in patients with prediabetes and diabetes. Scientific Reports, 15, 118. https://doi.org/10.1038/s41598-024-83820-7
Schulz, K. F., Altman, D. G., & Moher, D. (2010). Consort 2010 statement: updated guidelines for reporting parallel group randomised trials. Biweekly peer-reviewed Medical Journal, 340, c332. https://doi.org/10.1136/bmj.c332
Sharif, H., Arsalan, S., Rehman, N., Muzammil, A., Hatif, F., Wasti, F., … & Omair, W. (2025). Comparative effects of empagliflozin and metformin on metabolic dysfunction in polycystic ovary syndrome, a double blinded randomized control feasibility trial. BioMed Central Women's Health, 25, 565. https://doi.org/10.1186/s12905-025-04091-6
Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., & Speleman, F. (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biology, 3(7), research0034. https://doi.org/10.1186/gb-2002-3-7-research0034
Zhao, S. Y., Qiao, J., Chen, Y. J., Liu, P., Li, J., & Yan, J. (2010). Expression of growth differentiation factor-9 and bone morphogenetic protein-15 in oocytes and cumulus granulosa cells of patients with polycystic ovary syndrome. Fertility and Sterility, 94(1), 261-267. https://doi.org/10.1016/j.fertnstert.2009.03.014
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., … & Inzucchi, S. E. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. The New England Journal of Medicine, 373(22), 2117-2128. https://doi.org/10.1056/NEJMoa1504720 | ||
|
آمار تعداد مشاهده مقاله: 227 تعداد دریافت فایل اصل مقاله: 208 |
||