The Role of L-Arginine-NO System in Female Reproduction: A Narrative Review

Abstract

Accumulating evidence are available on the involvement of l-arginine-nitric oxide (NO) system in complex biological processes and numerous clinical conditions. Particular attention was made to reveal the association of l-arginine and methylarginines to outcome measures of women undergoing in vitro fertilization (IVF). This review attempts to summarize the expression and function of the essential elements of this system with particular reference to the different stages of female reproduction. A literature search was performed on the PubMed and Google Scholar systems. Publications were selected for evaluation according to the results presented in the Abstract. The regulatory role of NO during the period of folliculogenesis, oocyte maturation, fertilization, embryogenesis, implantation, placentation, pregnancy, and delivery was surveyed. The major aspects of cellular l-arginine uptake via cationic amino acid transporters (CATs), arginine catabolism by nitric oxide synthases (NOSs) to NO and l-citrulline and by arginase to ornithine, and polyamines are presented. The importance of NOS inhibition by methylated arginines and the redox-sensitive elements of the process of NO generation are also shown. The l-arginine-NO system plays a crucial role in all stages of female reproduction. Insufficiently low or excessively high rates of NO generation may have adverse influences on IVF outcome.

Keywords: female reproduction; l-arginine; methylarginines; nitric oxide; oxidative stress.

Figure 1

Chemical structure of the three different methylarginines.

Figure 2

The folate-dependent methionine-homocysteine cycle. Trans-sulfuration of homocysteine for cysteine and glutathione, as well as folate deficiency reduce the reaction by methionine synthase and causes homocysteine accumulation with the subsequent inhibition of the conversion of 5-methyl-tetrahydroforate to the metabolically active folate, tetrahydrofolate. Abbreviations: MAT = methionine adenosyltransferase, MT = methyltransferase, SAAH = S-adenosylhomocysteine hydrolase, MS = methionine synthase, MTAFR = methylene tetrahydrofolate reductase.

Figure 3

L-arginine catabolism pathways by nitric oxide synthases to nitric oxide and l-citrulline, and by arginase to l-ornithine and downstream metabolites. Abbreviations: eNOS, iNOS, nNOS → endothelial, inducible, and neuronal nitric oxide synthases; ODC = ornithine decarboxylase, OAT = ornithine aminotransferase.

Figure 4

Summary figure for the involvement of nitrogen monoxide (NO) in the major processes of female reproduction.