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Volume 13, Issue 6 (November 2011) 13, 856–861; 10.1038/aja.2011.96

Folate and vitamin B12 in idiopathic male infertility

Laurel E Murphy1, James L Mills1, Anne M Molloy2, Cong Qian3, Tonia C Carter1, Helena Strevens4, Dag Wide-Swensson4, Aleksander Giwercman5 and Richard J Levine1,*

1 Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA
2 School of Medicine, Trinity College Dublin, Dublin 2, Ireland
3 Glotech Inc., Rockville MD 20850, USA
4 Department of Obstetrics and Gynecology, Skåne University Hospital in Lund, Lund University, S-221 85 Lund, Sweden
5 Reproductive Medicine Centre, Skåne University Hospital Malmö, Lund University, S-205 02 Malmö , Sweden

* This author died during the review process.

Correspondence: Dr JL Mills , (jamesmills@nih.gov)

Received 8 April 2011; Revised 24 May 2011; Accepted 7 June 2011; Published online 22 August 2011


Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B(12) (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malm? and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

Keywords: folate; idiopathic male infertility; semen quality; vitamin B12

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