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Nutrients
Volume 17
Issue 20
10.3390/nu17203211
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

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

by
Alberto Revelli
1,
Anna Maria Nuzzo
1,*,
Laura Moretti
1,
Silvana Arduino
1,
Sofia Roero
1,
Roberto Scali
1,
Lorenzo Scali
1,
Gianluca Gennarelli
2,
Francesca Gigliotti
1,
Marlisa Gatto
1 and
Alessandro Rolfo
1
1
Department of Surgical Sciences, Gynecology and Obstetrics 2, City of Health and Science-S. Anna University Hospital, University of Turin, 10126 Turin, Italy
2
Obstetrics and Gynecology 1U, Physiopathology of Reproduction and IVF Unit, Department of Surgical Sciences, Sant Anna Hospital, University of Turin, 10126 Turin, Italy
*
Author to whom correspondence should be addressed.
Nutrients 2025, 17(20), 3211; https://doi.org/10.3390/nu17203211 (registering DOI)
Submission received: 9 September 2025 / Revised: 8 October 2025 / Accepted: 11 October 2025 / Published: 13 October 2025
(This article belongs to the Section Proteins and Amino Acids)
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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: homocysteine; hyperomocysteinemia; MTHFR; folic acid; micronutrients; human fertility; in vitro fertilization homocysteine; hyperomocysteinemia; MTHFR; folic acid; micronutrients; human fertility; in vitro fertilization
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MDPI and ACS Style

Revelli, A.; Nuzzo, A.M.; Moretti, L.; Arduino, S.; Roero, S.; Scali, R.; Scali, L.; Gennarelli, G.; Gigliotti, F.; Gatto, M.; et al. Effects of Homocysteine Circulating Levels on Human Spontaneous Fertility and In Vitro Fertilization Outcomes: A Literature Review. Nutrients 2025, 17, 3211. https://doi.org/10.3390/nu17203211

AMA Style

Revelli A, Nuzzo AM, Moretti L, Arduino S, Roero S, Scali R, Scali L, Gennarelli G, Gigliotti F, Gatto M, et al. Effects of Homocysteine Circulating Levels on Human Spontaneous Fertility and In Vitro Fertilization Outcomes: A Literature Review. Nutrients. 2025; 17(20):3211. https://doi.org/10.3390/nu17203211

Chicago/Turabian Style

Revelli, Alberto, Anna Maria Nuzzo, Laura Moretti, Silvana Arduino, Sofia Roero, Roberto Scali, Lorenzo Scali, Gianluca Gennarelli, Francesca Gigliotti, Marlisa Gatto, and et al. 2025. "Effects of Homocysteine Circulating Levels on Human Spontaneous Fertility and In Vitro Fertilization Outcomes: A Literature Review" Nutrients 17, no. 20: 3211. https://doi.org/10.3390/nu17203211

APA Style

Revelli, A., Nuzzo, A. M., Moretti, L., Arduino, S., Roero, S., Scali, R., Scali, L., Gennarelli, G., Gigliotti, F., Gatto, M., & Rolfo, A. (2025). Effects of Homocysteine Circulating Levels on Human Spontaneous Fertility and In Vitro Fertilization Outcomes: A Literature Review. Nutrients, 17(20), 3211. https://doi.org/10.3390/nu17203211

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