The Relationship Between Serum Growth Differentiation Factor-15 (GDF-15) Levels and Clinical Outcomes in Infertile Women Receiving In-vitro Fertilization Treatment

Öz

Objective: It has been reported in many studies that Growth Differentiation Factor-15 (GDF-15) has an important role in physiological or pathological processes. As there is no study in the current scientific literature examining the status of GDF-15 in infertility and its treatment outcomes, we aimed to investigate this. Material and methods: According to their ovarian reserve characteristics, 88 infertile women were divided into three groups: normal ovarian reserve (NOR), diminished ovarian reserve (DOR), and polycystic ovary syndrome (PCOS). Estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), and GDF-15 levels were measured in their serum. The antagonist protocol patients' total oocyte, meiosis II (MII) oocytes, embryo count, and clinical pregnancy rates were documented. Results: In terms of serum GDF-15 concentrations, there was no statistically significant difference among the mean values of the three study groups. The mean FSH level at baseline was substantially higher in the DOR group compared to the PCOS group. The median serum AMH levels of all three groups were found to be statistically different. The antagonist protocol patients' total oocytes, meiosis II (MII) oocytes, embryo count, and clinical pregnancy rates were documented. Conclusion: In the present study, a significant and strong correlation between serum GDF-15 level and consequent embryo number was detected. Thereby, serum GDF-15 level may be considered to be a biomarker for predicting IVF clinical outcomes.

Anahtar Kelimeler

• Keywords: Growth Differentiation Factor- 15
• GDF-15
• IVF
• Infertility
• Ovarian reserve

İn-vitro Fertilizasyon Tedavisi Alan İnfertil Kadınlarda Serum Büyüme Farklılaşma Faktörü-15 (GDF-15) Düzeyi İle Klinik Sonuçlar Arası İlişki

Öz

Amaç: Büyüme Farklılaşma Faktörü-15 (GDF-15)'in fizyolojik veya patolojik süreçlerde önemli rolu olduğu bir çok çalışmada bildirilmiştir. Güncel literatürde, GDF-15’in infertilitedeki durumunu ve tedavi sonrası sonuçlarını inceleyen bir çalışma bulunmamasından dolayı bunu araştırmayı amaçladık. Gereç ve Yöntemler: Çalışmaya 88 infertil kadın dahil edildi ve over rezerv özelliklerine göre çalışma populasyonu üç gruba ayrıldı. Bunlar; normal over rezervi (NOR) , azalmış over rezervi (AOR) grubu, polikistik over sendromu (PKOS) grubu. Serumlarında östradiol (E2), follikül uyarıcı hormon (FSH) ve luteinize edici hormon (LH), anti-müllerian hormon (AMH) ve GDF-15 düzeyleri ölçülmüştür. Antagonist protokolü ile tedaviye alınan hastaların total oosit , mayoz II (MII) oosit, embriyo sayısı ve klinik gebelik oranları dökümente edilmiştir. Bulgular: Serum GDF-15 konsantrasyonları dikkate alındığında her üç çalışma grubunun ortalama değerleri arasında istatistiksel yönden anlamlı bir fark bulunmamıştır. Bazal FSH ortalaması AOR grubunda PKOS grubundaki katılımcılara göre anlamlı düzeyde yüksekti. Her üç grubun serum AMH düzey ortancası istatistiksel anlamlılıkta farklı bulunmuştur. Total Oosit, MII oosit ve embriyo ortalama karşılaştırmalarında NOR grubu AOR grubuna göre ve PKOS grubu AOR grubuna göre daha yüksek değerlere sahiptir. Sonuç: Çalışmamızda serum GDF-15 düzeyinin in-vitro fertilizasyon (İVF) tedavisi sonucunda oluşan embriyo sayıları arasında anlamlı ve güçlü bir ilişki saptanmıştır. Dolayısı ile serum GDF-15 düzeyi İVF klinik sonuçlarını öngören bir biyobelirteç olabileceği düşünülebilir.

Anahtar Kelimeler

• Büyüme Farklılaşma Faktörü-15
• GDF-15
• İVF
• İnfertilite
• Over rezervi

Kaynakça

1. Good C, Tulchinsky M, Mauger D, Demers LM, Legro RS. Bone mineral density and body composition in lean women with polycystic ovary syndrome. Fertil Steril 1999;72:21–25.
2. Berberoglu Z, Aktas A, Fidan Y, Yazici AC, Aral Y. Association of plasma GDF-9 or GDF-15 levels with bone parameters in polycystic ovary syndrome. J Bone Miner Metab 2015;33:101–108.
3. O’Brien Y, Kelleher C, Wingfield M. “So what happens next?” exploring the psychological and emotional impact of anti-Mullerian hormone testing. J Psychosom Obstet Gynaecol 2020;41:30–37.
4. Ulrich ND, Marsh EE. Ovarian Reserve Testing: A Review of the Options, Their Applications, and Their Limitations. Clin Obstet Gynecol 2019;62:228–237.
5. Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514–11519.
6. Mimeault M, Batra SK. Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer. J Cell Physiol 2010;224:626–635.
7. Kempf T, Eden M, Strelau J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006;98:351–360.
8. Kleinert M, Clemmensen C, Sjøberg KA, et al. Exercise increases circulating GDF15 in humans. Mol Metab 2018;9:187–191.

9. Nazarova NI, Chikhirzhina GI, Tuohimaaa P. Transcriptional regulation of placental transforming growth factor-beta by calcitriol in prostate cancer cells is androgen-independent. Mol Biol 2006;40:84–89.
10. Bauskin AR, Jiang L, Luo XW, Wu L, Brown DA, Breit SN. The TGF-beta superfamily cytokine MIC-1/GDF15: secretory mechanisms facilitate creation of latent stromal stores. J Interferon Cytokine Res 2010;30:389–397.
11. Serdyńska-Szuster M, Jędrzejczak P, Ożegowska KE, Hołysz H, Pawelczyk L, Jagodziński PP. Effect of growth differentiation factor‑9 C447T and G546A polymorphisms on the outcomes of in vitro fertilization. Mol Med Rep 2016;13:4437–4442.
12. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2015;103:e9–e17.
13. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41–47.
14. Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L, ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011;26:1616–1624.
15. Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology 2016;86:2010–2015.
16. Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr Gerontol Int 2016;16 Suppl 1:17–29.
17. Conte M, Ostan R, Fabbri C, et al. Human Aging and Longevity Are Characterized by High Levels of Mitokines. J Gerontol A Biol Sci Med Sci 2019;74:600–607.
18. Tanaka T, Biancotto A, Moaddel R, et al. Plasma proteomic signature of age in healthy humans. Aging Cell 2018;17:e12799.
19. Assadi A, Zahabi A, Hart RA. GDF15, an update of the physiological and pathological roles it plays: a review. Pflugers Arch 2020;472:1535–1546.
20. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014;69 Suppl 1:S4-9.
21. Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting.. Hum. Reprod 2011.
22. Aljanabi S. Universal and rapid salt-extraction of high quality genomic DNA for PCR- based techniques. Nucleic Acids Res 1997;25:4692–4693.
23. Farquhar C, Marjoribanks J. Assisted reproductive technology: an overview of Cochrane Reviews. Cochrane database Syst Rev 2018;8:CD010537.
24. Hromas R, Hufford M, Sutton J, Xu D, Li Y, Lu L. PLAB, a novel placental bone morphogenetic protein. Biochim Biophys Acta 1997;1354:40–44.
25. Xiong Y, Walker K, Min X, et al. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys. Sci Transl Med 2017;9.
26. Moore AG, Brown DA, Fairlie WD, et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000;85:4781–4788.
27. Kaitu’u-Lino TJ, Bambang K, Onwude J, Hiscock R, Konje J, Tong S. Plasma MIC-1 and PAPP-a levels are decreased among women presenting to an early pregnancy assessment unit, have fetal viability confirmed but later miscarry. PLoS One 2013;8:e72437.
28. Lyu C, Ni T, Guo Y, et al. Insufficient GDF15 expression predisposes women to unexplained recurrent pregnancy loss by impairing extravillous trophoblast invasion. Cell Prolif 2023;e13514.