R-Spondin1 and tumor necrosis factor-alpha in infertile women with polycystic ovary syndrome: relationships with insulin resistance and other parameters

Yıl 2023, Cilt: 6 Sayı: 2, 449 - 455, 27.03.2023

Tuğba Gürbüz , Oya Gökmen , Asena Ayar Madenli , Berna Dilbaz

https://doi.org/10.32322/jhsm.1210721

Cited By: 1

Öz

Aim: To evaluate the relationship between R-spondin1 (RSPO1) and Tumor Necrosis Factor-Alpha (TNF-α) levels with insulin resistance (IR) and other parameters in infertile women with polycystic ovary syndrome (PCOS).
Material and Method: This case-control prospective observational study was carried out on 84 patients admitted to the University of Health Sciences Etlik Zübeyde Hanım Training and Research Hospital Gynecology and IVF Clinic and Medistate Hospital Gynecology and IVF Clinic between September 2020 and June 2021. Women aged 18-36 years diagnosed with infertility and PCOS constituted the PCOS group. Women who were diagnosed with infertility but not PCOS formed the control group. Cases were divided according to their body mass index (BMI) values into obese (BMI≥25) and non-obese (BMI<25) groups.
Results: The mean age of the study group was 26.9±5.37 years. RSPO1 and TNF-α levels were higher in PCOS patients (p<0.001). Hip circumference (HC) was found to be higher in those with a diagnosis of PCOS (p<0.001). The group with the highest waist-to-hip ratio (WHR) was the obese-PCOS group (p<0.001). Glucose, insulin, and homeostatic model assessment for IR (HOMA-IR) levels were the highest in the obese-PCOS group (p<0.001). A positive correlation was found between RSPO1 and TNF-α (r=0.944, p<0.001). There was a positive correlation between the hip circumference and RSPO1 (r=0.255, p=0.0019) and TNF-α (r=0. 0.278, p=0.011). There were positive correlations between blood glucose and RSPO1 (r=0.343, p=0.001) and TNF-α levels (r=0.312, p=0.004) and between insulin and RSPO1 (r value=0.577, p<0.001) and TNF-α levels (r=0.569, p<0.001). HOMA-IR values were also found to correlate with RSPO-1 and TNF-α levels (r= 0.619 and 0.608, p<0.001).
Conclusion: It can be concluded that RSPO1 and TNF-α levels may guide the assessment and management of IR and diabetes risk in infertile women with PCOS.

Anahtar Kelimeler

Polycystic ovary syndrome, R-Spondin1, Tumor Necrosis Factor-alpha, obesity, insulin resistance

Kaynakça

• Zegers-Hochschild F, Adamson GD, Dyer S, et al. The international glossary on infertility and fertility care, 2017. Hum Reprod 2017; 32: 1786-801.
• Alanya Tosun Ş, Gurbuz T, Cebi A, Tosun A, Gokmen O, Usta M. Association of increased levels of omentin-1 and carotid intima-media thickness with early signs of cardiovascular risk in patients with polycystic ovary syndrome: A prospective case control study. J Obstet Gynaecol Res 2022; 48: 169-77.
• Gurbuz T, Alanya Tosun S, Cebi A, Gokmen O, Usta M. Investigating fetuin-A and paraoxonase-1 activity as markers in polycystic ovary syndrome based on body mass ındex: a prospective case-control study. Cureus 2021; 13: e18553.
• Gürbüz T, Dokuzeylül Güngör N. Understanding the effects of obesity over polycystic ovary syndrome by analyzing insulin resistance and thyroid hormone in different BMI levels. Ulutaş Med J 2021; 7: 8-12.
• Crosignani PG, Colombo M, Vegetti W, Somigliana E, Gessati A, Ragni G. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum Reprod 2003; 18: 1928-32.
• Deugarte CM, Bartolucci AA, Azziz R. Prevalence of IR in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril 2005; 83: 1454-60.
• Glinka A, Dolde C, Kirsch N, et al. LGR4 and LGR5 are R‐spondin receptors mediating Wnt/β‐catenin and Wnt/PCP signalling. EMBO Rep 2011; 12: 1055-61.
• De Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome Biol 2012; 13: 1-10.
• Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci USA 2011; 108: 11452-7.
• Kang YE, Kim JM, Yi HS, et al. Serum R-Spondin 1 is a new surrogate marker for obesity and insulin resistance. Diabetes Metab J 2019; 43: 368-376.
• Pan H, Cui H, Liu S, et al.. Lgr4 gene regulates corpus luteum maturation through modulation of the WNT-mediated EGFR-ERK signaling pathway. Endocrinology. 2014; 155: 3624-3637.
• Balchak SK, Marcinkiewicz JL. Evidence for the presence of tumor necrosis factor alpha receptors during ovarian development in the rat. Biol Reprod 1999; 61: 1506-12.
• Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25.
• Delitala AP, Capobianco G, Delitala G, Cherchi PL, Dessole S. Polycystic ovary syndrome, adipose tissue and metabolic syndrome. Arch Gynecol Obstet 2017; 296: 405-19.
• Kyrou I, Weickert MO, Randeva HS. Diagnosis and management of polycystic ovary syndrome (PCOS). In Ajjan R, Orme SM, editors, Endocrinology and diabetes: case studies, questions and commentaries. London (UK): Springer 2015; 99-113.
• Kyrou I, Randeva HS, Tsigos C, Kaltsas G, Weickert MO. Clinical Problems Caused by Obesity. 2018 Jan 11. In: Feingold KR, Anawalt B, Boyce A, et al. editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905207.
• Jin YR, Yoon JK. The R-spondin family of proteins: emerging regulators of WNT signaling. Int J Biochem Cell Biol 2012; 44: 2278-87.
• Kuchenbaecker KB, Ramus SJ, Tyrer J, et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet 2015; 47: 164-71.
• Tomaselli S, Megiorni F, Lin L, et al. Human RSPO1/R-spondin1 is expressed during early ovary development and augments β-catenin signaling. PLoS One 2011; 6: e16366.
• Chassot AA, Ranc F, Gregoire EP, et al. Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum Mol Genet 2008; 17: 1264-77.
• Liu Q, Zhao Y, Xing H, et al. The role of R-spondin 1 through activating Wnt/β-catenin in the growth, survival and migration of ovarian cancer cells. Gene 2019; 689: 124-30.
• Wang J, Liu R, Wang F, et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol 2013; 15: 1455-63.
• Wong VS, Yeung A, Schultz W, Brubaker PL. R-spondin-1 is a novel beta-cell growth factor and insulin secretagogue. J Biol Chem 2010; 285: 21292-302.
• Vgontzas AN, Bixler E, Chrousos G. Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med 2003; 254: 32-44.
• Sayin NC, Gücer F, Balkanli-Kaplan P, et al. Elevated serum TNF-α levels in normal-weight women with polycystic ovaries or the polycystic ovary syndrome. J Reprod Med 2003; 48: 165-70.
• Olszanecka-Glinianowicz M, Banaś M, Zahorska-Markiewicz B, et al. Is the polycystic ovary syndrome associated with chronic inflammation per se? Eur J Obstet Gynecol Reprod Biol 2007; 133: 197-202.
• Toulis KA, Goulis DG, Mintziori G, et al. Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome. Hum Reprod Update. 2011; 17: 741-60.
• Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and meta-analysis. Fertil Steril 2011; 95: 1048-58.
• Hotamisligil GS, Budavari A, Murray D, et al. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 1994; 94: 1543-9.
• Araya AV, Aguirre A, Romero C, Miranda C, Molina MC, Ferreira A. Evaluation of tumor necrosis factor alpha production in ex vivo short term cultured whole blood from women with polycystic ovary syndrome. Eur Cytokine Netw 2002; 13: 419-24.
• Gao L, Gu Y, Yin X. High serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis. PLoS One 2016; 11: e0164021.
• Krönke G, Uderhardt S, Kim KA, et al. R‐spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway. Arthritis Rheum 2010; 62: 2303-12.
• Choi BY, Chang SH, Cho HJ, et al. The association of radiographic progression with serum R-spondin 1 (RSPO1) levels or Dickkopf-1 (DKK1)/RSPO1 ratios in rheumatoid arthritis patients: clinical evidence for reciprocal inhibition between DKK1 and RSPO1. Scand J Rheumatol 2014; 43: 453-61.