Hyperhomocysteinemia and MTHFR gene 677 C>T polymorphism: questionable role in female infertility

Vinita Das, Devyani Misra, Smriti Agrawal, Anjoo Agrawal, Amita Pandey


Background: Homocysteine is an intermediate in methionine metabolism required for the biosynthesis of nucleic acids. Hyperhomocysteinemia affects various organ systems and also has been implicated as a risk factor for infertility. Elevated levels result either from genetic mutations of the enzymes catalyzing the metabolic pathway or deficiency of micronutrients required as co-enzymes for the same. The aim of this cohort study was to evaluate serum homocysteine levels and MTHFR gene 677C>T mutation and to establish a possible relation between hyperhomocysteinemia, genetic polymorphism and female infertility.  

Methods: Ninety-five infertile women were enrolled over a period of one year and categorized as unexplained, anovulatory and male partner factor infertility according to the etiology. Thirty-one age-matched fertile women were enrolled as controls. Serum homocysteine levels were evaluated and genetic analysis for MTHFR gene mutation 677C>T was done.  

Results: Mean homocysteine levels for the women in three infertile groups were comparable (group I - 16.21 ± 3.39 µmol/l, group II - 16.36 ± 3.56 µmol/l, group III - 16.98 ± 3.14 µmol/l) within the groups as well as with the fertile group (15.85 ± 9.3 µmol/l) with no statistically significant difference (P = 0.573). Prevalence of hyperhomocysteinemia was 86.3% for infertile group and 90.3% for fertile group. Nineteen heterozygous (CT) and 3 homozygous (TT) mutations were noted among infertile subjects and 8 heterozygous (CT) mutations among fertile subjects prevalence being similar for both the groups.  

Conclusions: Significant prevalence of hyperhomocysteinemia and MTHFR polymorphism was observed in the studied population. The study did not establish a positive role of hyperhomocysteinemia and MTHFR mutation in female infertility.  


Female infertility, Hyperhomocysteinemia, MTHFR 677 C>T polymorphism

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Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.

Dwivedi MK, Tripathi AK, Shukla S, Khan S, Chauhan UK. Homocysteine and cardiovascular disease. Biotechnol Molecul Biol Rev. 2011 May;6(5):101-7.

Narayan D, Kaul S, Ravishankar K, Suryaprabha T, Bandaru VC, Mridula KR, et al. Risk factors, clinical profile, and long-term outcome of 428 patients of cerebral sinus venous thrombosis: insights from Nizam’s Institute Venous Stroke Registry, Hyderabad (India). Nurol India. 2012 Mar-Apr;60(2):154-9.

Bertsch T, Mielke O, Höly S, Zimmer W, Casarin W, Aufenanger J, et al. Homocysteine in cerebrovascular disease: An independent risk factor for subcortical vascular encephalopathy. Clin Chem Lab Med. 2001 Aug;39:721-4.

Sudha Seshadri, Alexa Beiser, Jacob Selhub, Jacques PF, Rosenberg IH, D’Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb;346:476-83.

Hibbard BN. The role of folic acid in pregnancy with particular reference to anemia, abruption and abortion. J Obstet Gynaecol Br Commonwealth. 1964;71:529-42.

Bjorke-Monsen AL, Ueland PM, Schneede J, Vollset SE, Refsum H. Elevated plasma total homocysteine and C677T mutation of methylene tetrahydrofolate reductase gene in patient with spina bifida. QJM Mon J Assoc Phys. 1997;90:593-6.

Sorensen TK, Malinow MR, Williams MA, King IB, Luthy DA. Elevated second-trimester serum homocysteine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest. 1999;48:98-103.

Ray JG, Laskin CA. Folic acid and homocysteine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta. 1999 Sep;20(7):519-29.

Leeda M, Riyazi N, de Vries JI, Jakobs C, van Geijn HP, Dekker GA. Effects of folic acid and vitamin B6 supplementation on women with hyperho- mocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol. 1998;179:135-9.

Jerzak M, Putowski L, Baranowski W. Homocysteine level in ovarian follicular fluid or serum as a predictor of successful fertilization. Ginekol Pol. 2003 Sep;74(9):949-52.

Ocal P, Ersoylu B, Cepni I, Guralp O, Atakul N, Irez T, et al. The association between homocysteine in the follicular fluid with embryo quality and pregnancy rate in assisted reproductive techniques. J Assist Reprod Genet. 2012 Apr;29(4):299-304.

Steegers-Theunissen RP, Boers GH, Blom HJ, Trijbels FJ, Eskes TK. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentace. Lancet. 1992;339:1122-3.

Steegers-Theunissen RP, Steegers EA, Thomas CM, Hollanders HM, Peereboom-Stegeman JH, Trijbels FJ, et al. Study on the presence of homocysteine in ovarian follicular fluid. Fertil Steril. 1993;60:1006-10.

Ebisch IMW, Peters WH, Thomas CM, Wetzels AM, Peer PG, Steegers-Theunissen RP. Homocysteine, glutathione and related thiols affect fertility parameters in the (sub) fertile couple. Hum Reprod. 2006;21:1725-33.

Bülent Berker, Cemil Kaya, Rusen Aytac, Hakan Satiroglu. Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. Hum Reprod. 2009;24(9):2293-302.

Boxmeer JC, Brouns RM, Lindemans J, Steegers EA, Martini E, Macklon NS, et al. Preconception folic acid treatment affects the microenvironment of the maturing oocyte in humans. Fertil Steril. 2008b;89:1766-70.

Alexander Krantz, Maryjane Ferraro, Patrick M. Sluss, Kent B. Lewandrowski. Laboratory reference values: case records of the Massachusetts general hospital. N Engl J Med. 2004;351:1548-63.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-3.

Dubey P, Gupta N, Dwivedi S, Swaroop N, Lal P, Thawani V. Hyperhomocysteinemia: a risk factor in unexplained infertility. Int J Reprod Contracept Obstet Gynecol. 2013;2:165-71.

Maristella D’Uva, Pierpaolo Di Micco, Ida Strina, Alviggi C, Iannuzzo M, Ranieri A, et al. Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from Southern Italy: a preliminary report. Thromb J. 2007;5:10.

Seema Bibi, Mohammad Ali Pir, Roshan Ara Qazi, Misbah Bibi Qureshi. Hyperhomocysteinemia in Pakistani women suffering from unexplained subfertility. Iran J Reprod Med (Spring). 2010;8(2):76-9.

Ebisch IMW, Peters WHM, Thomas CMG, Wetzels AMM, Peer PGM, Steegers-Theunissen RPM. Homocysteine, glutathione and related thiols affect fertility parameters in the (sub) fertile couple. Hum Reprod. 2006;21(7):1725-33.

Francesco Orio Jr, Stefano Palomba, Sebastiano de Biase, Annamaria Colao, Libuse Tauchmanova, Silvia Savastano, et al. Homocysteine Levels and C677T Polymorphism of methylenetetrahydrofolate reductase in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(2):673-9.

Sills ES, Genton MG, Perloe M, Schattman GL, Bralley JA, Tucker MJ. Plasma homocysteine, fasting insulin, and androgen patterns among women with polycystic ovaries and infertility. J Obstet Gynaecol Res. 2001 Jun;27(3):163-8.

Morey Schachter, Arieh Raziel, Shevach Friedler, Deborah Strassburger, Orna Bern, Raphael Ron‐El. Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine. Hum Reprod. 2003;18(4):721-7.

Madhu Jain, Priyanka Pandey, Tiwari NK, Shuchi Jain. MTHFR C677T polymorphism is associated with hyperlipidemia in women with polycystic ovary syndrome. J Hum Reprod Sci. 2012 Jan-Apr;5(1):52-8.