open access
Association of tissue inhibitor of metalloproteinase-3 (TIMP-3) serum level and its genetic polymorphism with pregnancy outcome of patients undergoing in vitro fertilization and embryo transfer
, 2, 3, 1
Affiliations- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
- Reproductive Health Research Center, Department of Obstetrics&Gynecology, Alzahra Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
open access
Abstract
Objectives: Tissue inhibitors of metalloproteinase-3 (TIMP-3) and matrix metalloproteinases (MMPs) play a major role in embryo implantation and placentation. This study aimed to investigate the relationship between TIMP-3 serum level and TIMP-3 genetic polymorphism with pregnancy outcome in patients undergoing in vitro fertilization and embryo transfer (IVF-ET).
Material and methods: This project included 100 infertile women who became pregnant after IVF (IVF+) and 100 infertile women who failed to conceive after IVF (IVF–). Genotyping was performed using Restriction Fragments Length Polymorphism Polymerase Chain Reaction (PCR-RFLP), and the serum level was measured by Enzyme-Linked Immunosorbent Assay (ELISA).
Results: The frequencies of TT, TC, and CC in the IVF+ group were 41%, 37% and 22%, respectively, while in the IVF– group were 18%, 43% and 39%, respectively. The C and T allele frequencies were 40.5% and 59.5% in the IVF+ group and 60.5% and 39.5% in IVF- group, respectively. The C allele conferred a 2.25-fold increased risk of IVF failure (OR 2.25; 95% CI 1.5–3.35; p = 0.0001). Also, there was a significant increase in TIMP-3 serum levels in the IVF– group (193.29 ± 29.50 ng/mL), which was higher than the IVF+ group (166.74 ± 17.60 ng/mL; p = 0.00002), was demonstrated. It was shown that the TT genotype is associated with decreased TIMP-3 serum levels in IVF– group (CC, CT, and TT, values were 143.19 ± 88.49 ng/mL, 117.55 ± 15.73 ng/mL, 61.17 ± 44.36 ng/mL, respectively).
Conclusions: It is concluded that there is a relationship between TIMP-3 gene polymorphism and its serum concentration with IVF-ET outcome. We also suggest that the TT genotype might be involved in IVF-ET outcome.
Abstract
Objectives: Tissue inhibitors of metalloproteinase-3 (TIMP-3) and matrix metalloproteinases (MMPs) play a major role in embryo implantation and placentation. This study aimed to investigate the relationship between TIMP-3 serum level and TIMP-3 genetic polymorphism with pregnancy outcome in patients undergoing in vitro fertilization and embryo transfer (IVF-ET).
Material and methods: This project included 100 infertile women who became pregnant after IVF (IVF+) and 100 infertile women who failed to conceive after IVF (IVF–). Genotyping was performed using Restriction Fragments Length Polymorphism Polymerase Chain Reaction (PCR-RFLP), and the serum level was measured by Enzyme-Linked Immunosorbent Assay (ELISA).
Results: The frequencies of TT, TC, and CC in the IVF+ group were 41%, 37% and 22%, respectively, while in the IVF– group were 18%, 43% and 39%, respectively. The C and T allele frequencies were 40.5% and 59.5% in the IVF+ group and 60.5% and 39.5% in IVF- group, respectively. The C allele conferred a 2.25-fold increased risk of IVF failure (OR 2.25; 95% CI 1.5–3.35; p = 0.0001). Also, there was a significant increase in TIMP-3 serum levels in the IVF– group (193.29 ± 29.50 ng/mL), which was higher than the IVF+ group (166.74 ± 17.60 ng/mL; p = 0.00002), was demonstrated. It was shown that the TT genotype is associated with decreased TIMP-3 serum levels in IVF– group (CC, CT, and TT, values were 143.19 ± 88.49 ng/mL, 117.55 ± 15.73 ng/mL, 61.17 ± 44.36 ng/mL, respectively).
Conclusions: It is concluded that there is a relationship between TIMP-3 gene polymorphism and its serum concentration with IVF-ET outcome. We also suggest that the TT genotype might be involved in IVF-ET outcome.
Keywords
TIMP-3; genetic polymorphism; in vitro fertilization embryo transfer; serum
About this articleTitle
Association of tissue inhibitor of metalloproteinase-3 (TIMP-3) serum level and its genetic polymorphism with pregnancy outcome of patients undergoing in vitro fertilization and embryo transfer
Journal
Issue
Article type
Research paper
Pages
400-406
Published online
2022-06-15
Page views
1826
Article views/downloads
432
DOI
Pubmed
Bibliographic record
Ginekol Pol 2023;94(5):400-406.
Keywords
TIMP-3
genetic polymorphism
in vitro fertilization embryo transfer
serum
Authors
Mahdis Meraji Masouleh Moghaddam
Farhad Mashayekhi
Ziba Zahiri
Akram Eidi
References (35)- Vander Borght M, Wyns C. Fertility and infertility: Definition and epidemiology. Clin Biochem. 2018; 62: 2–10.
- Carson SA, Kallen AN. Diagnosis and Management of Infertility: A Review. JAMA. 2021; 326(1): 65–76.
- Akhondi MM, Ranjbar F, Shirzad M, et al. Practical Difficulties in Estimating The Prevalence of Primary Infertility in Iran. Int J Fertil Steril. 2019; 13(2): 113–117.
- Horka P, Malickova K, Jarosova R, et al. Matrix metalloproteinases in serum and the follicular fluid of women treated by in vitro fertilization. J Assist Reprod Genet. 2012; 29(11): 1207–1212.
- Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17: 463–516.
- Benkhalifa M, Zayani Y, Bach V, et al. Does the dysregulation of matrix metalloproteinases contribute to recurrent implantation failure? Expert Rev Proteomics. 2018; 15(4): 311–323.
- Nissi R, Talvensaari-Mattila A, Kotila V, et al. Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy failure. Reprod Biol Endocrinol. 2013; 11: 2.
- Lochter A, Galosy S, Muschler J, et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol. 1997; 139(7): 1861–1872.
- Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006; 69(3): 562–573.
- Li F, Curry TE. Regulation and function of tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP3 in periovulatory rat granulosa cells. Endocrinology. 2009; 150(8): 3903–3912.
- Minoura N, Aiba S, Higuchi M, et al. Attachment and growth of fibroblast cells on silk fibroin. Biochem Biophys Res Commun. 1995; 208(2): 511–516.
- Abdallah MW, Michel TM. Matrix metalloproteinases in autism spectrum disorders. J Mol Psychiatry. 2013; 1(1): 16.
- Enginsu ME, Pieters MH, Dumoulin JC, et al. Male factor as determinant of in-vitro fertilization outcome. Hum Reprod. 1992; 7(8): 1136–1140.
- Kaarouch I, Bouamoud N, Madkour A, et al. Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years. Mol Reprod Dev. 2018; 85(3): 271–280.
- Hamutoğlu R, Bulut HE, Kaloğlu C, et al. The regulation of trophoblast invasion and decidual reaction by matrix metalloproteinase-2, metalloproteinase-7, and metalloproteinase-9 expressions in the rat endometrium. Reprod Med Biol. 2020; 19(4): 385–397.
- Reponen P, Leivo I, Sahlberg C, et al. 92-kDa type IV collagenase and TIMP-3, but not 72-kDa type IV collagenase or TIMP-1 or TIMP-2, are highly expressed during mouse embryo implantation. Dev Dyn. 1995; 202(4): 388–396.
- Argente MJ, Merchán M, Peiró R, et al. Candidate gene analysis for reproductive traits in two lines of rabbits divergently selected for uterine capacity. J Anim Sci. 2010; 88(3): 828–836.
- Pilka R, Oborna I, Lichnovsky V, et al. Endometrial expression of the estrogen-sensitive genes MMP-26 and TIMP-4 is altered by a substitution protocol without down-regulation in IVF patients. Hum Reprod. 2006; 21(12): 3146–3156.
- Su RW, Fazleabas AT. Implantation and Establishment of Pregnancy in Human and Nonhuman Primates. Adv Anat Embryol Cell Biol. 2015; 216: 189–213.
- Wu Rj, Zhou Fz. Expression of matrix metalloproteinases-9 and tissue inhibitor of metalloproteinases-1 mRNA in the endometrium during mid- luteal phase in women with unexplained infertility. Zhonghua Fu Chan Ke Za Zhi. 2003; 38(6): 346–349.
- Komosinska-Vassev K, Olczyk P, Winsz-Szczotka K, et al. Age- and gender-dependent changes in connective tissue remodeling: physiological differences in circulating MMP-3, MMP-10, TIMP-1 and TIMP-2 level. Gerontology. 2011; 57(1): 44–52.
- Boumiza S, Chahed K, Tabka Z, et al. MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity. Sci Rep. 2021; 11(1): 20052.
- Salamonsen LA, Woolley DE. Matrix metalloproteinases in normal menstruation. Hum Reprod. 1996; 11 Suppl 2: 124–133.
- Grzechocińska B, Dąbrowski F, Cyganek A, et al. The role of metalloproteinases in endometrial remodelling during menstrual cycle. Ginekol Pol. 2017; 88(6): 337–342.
- Wysocka U, Sakowicz A, Jakubowski L, et al. Association between idiopathic recurrent pregnancy loss and genetic polymorphisms in cytokine and matrix metalloproteinase genes. Ginekol Pol. 2021 [Epub ahead of print].
- Shabanipour S, Mashayekhi F, Bahadori MH, et al. The relationship between MMP-9 promoterpolymorphism and IVF outcome. Cell Mol Biol (Noisy-le-grand). 2015; 61(1): 64–67.
- Roshankhah S, Mansouri K, Bakhtiari M, et al. Synergistic effects of TIMP2-418G/C and MMP9-1562C/T variants on the male infertility risk. Mol Biol Rep. 2019; 46(1): 861–866.
- Cardoso JV, Machado DE, da Silva MC, et al. Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study. Eur J Obstet Gynecol Reprod Biol X. 2019; 3: 100041.
- Kurzawski M, Kaczmarek M, Kłysz M, et al. MMP2, MMP9 and TIMP2 polymorphisms affect sperm parameters but not fertility in Polish males. Andrologia. 2017; 49(5).
- Sakkas D, Seli E, Bizzaro D, et al. Abnormal spermatozoa in the ejaculate: abortive apoptosis and faulty nuclear remodelling during spermatogenesis. Reprod Biomed Online. 2003; 7(4): 428–432.
- Higuchi T, Kanzaki H, Nakayama H, et al. Induction of tissue inhibitor of metalloproteinase 3 gene expression during in vitro decidualization of human endometrial stromal cells. Endocrinology. 1995; 136(11): 4973–4981.
- Singh K, Nair RR, Khanna A. Functional SNP -1562C/T in the promoter region of MMP9 and recurrent early pregnancy loss. Reprod Biomed Online. 2012; 24(1): 61–65.
- Konac E, Alp E, Onen HI, et al. Endometrial mRNA expression of matrix metalloproteinases, their tissue inhibitors and cell adhesion molecules in unexplained infertility and implantation failure patients. Reprod Biomed Online. 2009; 19(3): 391–397.
- Shibahara H, Suzuki T, Kikuchi K, et al. Serum matrix metalloproteinase and tissue inhibitor of metalloproteinase concentrations in infertile women achieved pregnancy following IVF-ET. Am J Reprod Immunol. 2005; 54(4): 186–192.
- Malvezzi H, Aguiar VG, Paz CC, et al. Increased circulating MMP-2 levels in infertile patients with moderate and severe pelvic endometriosis. Reprod Sci. 2013; 20(5): 557–562.
