International Journal of Infertility & Fetal Medicine

Register      Login

VOLUME 8 , ISSUE 1 ( January-April, 2017 ) > List of Articles

RESEARCH ARTICLE

Role of Metalloproteinases in the Pathogenesis of Unexpected Poor Ovarian Response with a Possible Genetic Predisposition

Menelaos Tzafetas, Konstantinos Lathouras, Theocharis Tantanasis, Styliani Fidani, Konstantinos Tziomalos, Kalliroi Kalinderi, Aristotle Loufopoulos, Vassiliki Zournatzi

Citation Information : Tzafetas M, Lathouras K, Tantanasis T, Fidani S, Tziomalos K, Kalinderi K, Loufopoulos A, Zournatzi V. Role of Metalloproteinases in the Pathogenesis of Unexpected Poor Ovarian Response with a Possible Genetic Predisposition. Int J Infertil Fetal Med 2017; 8 (1):5-11.

DOI: 10.5005/jp-journals-10016-1140

License: CC BY-NC 4.0

Published Online: 01-04-2017

Copyright Statement:  Copyright © 2017; The Author(s).


Abstract

Aim

To study the role of matrix metalloproteinase (MMP- 1,2,3), inhibitor tissue inhibitors of metalloproteinase (TIMP)-2, and specific gene polymorphisms in unexpected poor ovarian responders (un-PORs).

Materials and methods

Group I consisted of 44 un-PORs, group II of 42 subfertile, normal ovarian responders (NORs), and group III of 66 fertile women in a prospective study. Matrix metalloproteinase-1,2,3 and TIMP-2 were assessed in 40 patients from groups I and II. Specific polymorphisms (SP; MMP-1 −519 A/G, MMP-2 −1575 G/A, MMP-3 −1171 5A/6A, and TIMP-2 rs55743137T/G) were investigated in group I, II, and III patients.

Results

Group I required similar amount of gonadotropins compared with group II, with fewer oocytes retrieved, lower fertilization rates, embryos/embryo transfer, clinical pregnancies/cycle, and “take-home babies” (p = 0.900, 0.001, 0.002, 0.001, 0.031, and p = 0.128) respectively, Table 1). Group I had lower MMP-2 with higher TIMP-2 (p = 0.002, 0.037 respectively; Table 2). In the same group, MMP-1 was higher in women with GG genotype of the MMP-1 polymorphism, vs GA genotype (p = 0.047; Table 3). The MMP-2, MMP-3, and TIMP-2 polymorphisms did not affect MMP-2, MMP-3, and TIMP-2 respectively. The same applied for MMP-1,2,3 and TIMP-2 in group II. Comparing frequencies of different genotypes of the MMP-1,2,3 and TIMP-2 polymorphisms, they did not differ between the three different groups: A, B, and C (Table 4).

Conclusion

Impaired MMP-2 activity, associated with significantly higher TIMP-2 detected, could be involved in un-POR pathogenesis. There was no strong association between MMP polymorphisms and un-POR susceptibility. However, women with A/G polymorphism (MMP-1 −519) had lower MMP-1 compared with GG homozygotes.

Clinical significance

Identification of patients with poor ovarian response in a pretreatment environment would help improve their ongoing fertility plan and manage their expectations. Also by having the ability to investigate if one belongs to that group, it could provide important family planning information for the patient.

How to cite this article

Tzafetas M, Lathouras K, Tantanasis T, Fidani S, Tziomalos K, Kalinderi K, Loufopoulos A, Zournatzi V. Role of Metalloproteinases in the Pathogenesis of Unexpected Poor Ovarian Response with a Possible Genetic Predisposition. Int J Infertil Fetal Med 2017;8(1):5-11.


PDF Share
  1. Aetiological factors involved in the low response to gonadotrophins in infertile women with normal basal serum follicle stimulating hormone levels. Hum Reprod 1994 May;9(5):806-811.
  2. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011 Jun;26(7):1616-1624.
  3. The Bologna criteria for poor ovarian response; has the job been accomplished? Hum Reprod 2012 Apr;27(6):1874-1875.
  4. Effects of prolonging administration gonadotropin on unexpectedly poor ovarian responders undergoing in vitro fertilization. Reprod Biol Endocrinol 2010 Mar;8:26-34.
  5. A systematic review of randomized trials for the treatment of poor ovarian responders: is there any light at the end of the tunnel? Fertil Steril 2011 Nov;96(5): 1058.e7-1061.e7.
  6. The Bologna criteria for the definition of poor ovarian responders: is there a need for revision? Hum Reprod 2014 Sep;29(9):1842-1845.
  7. Clinical application of dehydroepiandrosterone in reproduction: a review of the evidence. J Chin Med Assoc 2015 Aug;78(8):446-453.
  8. Ovarian stimulation in ART – unwinding pressing issues. Minerva Ginecol 2015 Apr;67(2):127-147.
  9. Dehydroepiandrosterone administration before IVF in poor responders: a prospective cohort study. Reprod Biomed Online 2015 Feb;30(2):191-196.
  10. Do poor-responder patients benefit from increasing the daily gonadotropin dose during controlled ovarian hyperstimulation for IVF? Gynecol Endocrinol 2014 Sep;31(1):79-82.
  11. A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders. Fertil Steril 2014 Jul;102(1):108-115.
  12. Recombinant LH administration in subsequent cycle after “unexpected” poor response to recombinant FSH monotherapy. Gynecol Endocrinol 2014 Nov;30(11):813-816.
  13. The challenge of improving IVF in normogonadotrophic (unexpected) young poor ovarian responders: the predictive value of a flexible treatment protocol based on the “Biophysical Profile of the Uterus”. Open J Obstet Gynecol 2015 Sep;5(11):654-564.
  14. Alternative splicing and promoter usage generates an intracellular stromelysin 3 isoform directly translated as an active matrix metalloproteinase. J Biol Chem 2002 Jul;277(28):227-236.
  15. Matrix metalloproteinase-2 (MMP-2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP-ribose) polymerase (PARP) in vitro. FASEB J 2004 Apr;18(6):690-692.
  16. Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders. Biomol Ther (Seoul) 2012 Mar;20(2):133-143.
  17. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle) 2015 Mar;4(3):119-136.
  18. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003 May;92(8):827-839.
  19. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010 Jan;1803(1):55-71.
  20. ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloprotease domain. Dev Biol 1995 May;169(1):378-383.
  21. Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. J Biol Chem 2000 Oct;275(43):33988-33997.
  22. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000 Mar;1477(1-2):267-283.
  23. Structure-function-relationships in the tissue inhibitors of metalloproteinases. Am J Respir Crit Care Med 1994 Dec;150(6 Pt 2):S165-S170.
  24. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function. Rev Reprod 1998 Jan;3(1):23-30.
  25. Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta 2012 Jan;1824(1):146-156.
  26. Matrix metalloproteinase inhibitors: do they have a place in anticancer therapy? Pharmacotherapy 2002 Jun;22(6):705-720.
  27. Comparisons of matrix metalloproteinase 1, 2, and 9 activity in periovulatory follicular fluid from natural and stimulated menstrual cycles. Fertil Steril 2006 Mar;85(3):800-801.
  28. TIMP1 contributes to ovarian anomalies in both an MMP-dependent and -independent manner in a rat model. Biol Reprod 2012 Feb;86(2):47-56.
  29. Gonadotropin-binding sites in the rhesus monkey ovary role of the vasculature in the selective distribution of human chorionic gonadotropin to the preovulatory follicle. Endocrinology 1981 Aug;109(2):356-362.
  30. Expression of the genes encoding the insulin-like growth factors and their receptors in the human ovary. J Clin Endocrinol Metab 1992 Feb;74(2):419-425.
  31. Anti-FSH antibodies associate with poor outcome of ovarian stimulation in IVF. Reprod Biomed Online 2008 Mar;16(3):350-355.
  32. Purification of a high molecular weight follicle-stimulating hormone receptor-binding inhibitor from human follicular fluid. J Clin Endocrinol Metab 1993 Jul;77(1):163-168.
  33. Association of MMP3, MMP9, ADAM33, and TIMP3 polymorphisms with chronic obstructive pulmonary disease and its progression. Mol Biol 2012 May;46(3):438-449.
  34. Structure and function of matrix metalloproteinases and TIMPs. Cardio Res 2006 Feb;69(3):562-573.
  35. Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells. Cancer Biol Ther 2006 Jun;5(6):657-664.
  36. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 2000 Dec;19(56):6642-6650.
  37. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002 Oct;115(Pt 19):3719-3727.
  38. Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod 1997 Jan;3(1):27-45.
  39. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol Reprod 2001 May;64(5):1285-1296.
  40. Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression in human preimplantation embryos. Fertil Steril 2003 Sep;80 (Suppl 2):736-742.
  41. Biological activity and clinical implications of the matrix metalloproteinases. Anticancer Res 2008 Mar-Apr;28(2B):1389-1397.
  42. Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development. Biol Reprod 2010 Aug;83(2):185-194.
  43. Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation. Rheumatology (Oxford) 2014 Dec;53(12):2270-2279.
  44. Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy. Front Cell Dev Biol 2014 Apr;2:11.
  45. ‘Pixie dust’ helps man grow new finger. Sunday 03 Jan 2016.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.