Effects of Homocysteine Circulating Levels on Human Spontaneous Fertility and In Vitro Fertilization Outcomes: A Literature Review

Abstract

Background: Homocysteine (Hcy) plays a pivotal role in human reproduction, influencing gamete quality, embryo development, implantation, and pregnancy outcomes. It is central to folate and methionine metabolism and supports methylation-dependent epigenetic processes. Hyperhomocysteinemia (HHcy) exerts diverse biological effects and is associated with reproductive impairments in both sexes, affecting both spontaneous fertility and the outcome of assisted reproduction, including In Vitro Fertilization (IVF). Although the mechanisms of HHcy toxicity in reproduction are not fully understood, significant progress has been made in elucidating its effects. The emerging picture is complex, as Hcy and its metabolites impact biomolecules and cellular processes in a tissue- and sex-specific manner. Results: In men, HHcy compromises sperm deoxyribonucleic acid (DNA) integrity, methylation, and testicular microcirculation, reducing fertility potential. In women, HHcy disrupts follicular growth, oocyte competence, embryo quality, and endometrial receptivity, increasing the risk of implantation failure, miscarriage, and pregnancy complications. In assisted reproduction, HHcy and 5,10-methylenetetrahydrofolate reductase (MTHFR) variants may lower oocyte yield and embryo quality, although folate and B-vitamin supplementation can mitigate these effects. Conclusions: These effects largely reflect oxidative, inflammatory, vascular and epigenetic mechanisms, highlighting Hcy as a modifiable factor for improving natural fertility, optimizing IVF outcomes, and supporting healthy offspring development.

Keywords: MTHFR; folic acid; homocysteine; human fertility; hyperomocysteinemia; in vitro fertilization; micronutrients.

Figure 1

Schematic representation of Hcy metabolism. Green, folate cycle: remethylation of Hcy to methionine through folate- and vitamin B12–dependent reactions (THF—Tetrahydrofolate; 5,10-MTHF—5,10-methylenetetrahydrofolate; MTHFR—5,10-Methylenetetrahydrofolate reductase; 5-MTHF—5-methyltetrahydrofolate; MS—Methionine synthase); orange, methionine cycle: production of homocysteine from methionine (MAT—Methionine adenosyltransferase; SAM—S-adenosylmethionine; SAH—S-adenosylhomocysteine); pink, transsulfuration pathway: breakdown of homocysteine and production of cysteine (CβS—Cystathionine β-synthase; CγL—Cystathionine γ-lyase).