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Cited by 1,729Reproductive Biology and FertilityOvarian function and disordersAntioxidant Activity and Oxidative Stress

Role of oxidative stress in female reproduction

Open access
Agarwal, Ashok, Gupta, Sajal, Sharma, Rakesh K·2005·Reproductive Biology and Endocrinology
DOI 10.1186/1477-7827-3-28PMC PMC1215514
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Abstract

In a healthy body, ROS (reactive oxygen species) and antioxidants remain in balance. When the balance is disrupted towards an overabundance of ROS, oxidative stress (OS) occurs. OS influences the entire reproductive lifespan of a woman and even thereafter (i.e. menopause). OS results from an imbalance between prooxidants (free radical species) and the body's scavenging ability (antioxidants). ROS are a double-edged sword - they serve as key signal molecules in physiological processes but also have a role in pathological processes involving the female reproductive tract. ROS affect multiple physiological processes from oocyte maturation to fertilization, embryo development and pregnancy. It has been suggested that OS modulates the age-related decline in fertility. It plays a role during pregnancy and normal parturition and in initiation of preterm labor. Most ovarian cancers appear in the surface epithelium, and repetitive ovulation has been thought to be a causative factor. Ovulation-induced oxidative base damage and damage to DNA of the ovarian epithelium can be prevented by antioxidants. There is growing literature on the effects of OS in female reproduction with involvement in the pathophysiology of preeclampsia, hydatidiform mole, free radical-induced birth defects and other situations such as abortions. Numerous studies have shown that OS plays a role in the pathophysiology of infertility and assisted fertility. There is some evidence of its role in endometriosis, tubal and peritoneal factor infertility and unexplained infertility. This article reviews the role OS plays in normal cycling ovaries, follicular development and cyclical endometrial changes. It also discusses OS-related female infertility and how it influences the outcomes of assisted reproductive techniques. The review comprehensively explores the literature for evidence of the role of oxidative stress in conditions such as abortions, preeclampsia, hydatidiform mole, fetal embryopathies, preterm labour and preeclampsia and gestational diabetes. The review also addresses the growing literature on the role of nitric oxide species in female reproduction. The involvement of nitric oxide species in regulation of endometrial and ovarian function, etiopathogenesis of endometriosis, and maintenance of uterine quiescence, initiation of labour and ripening of cervix at parturition is discussed. Complex interplay between cytokines and oxidative stress in the etiology of female reproductive disorders is discussed. Oxidant status of the cell modulates angiogenesis, which is critical for follicular growth, corpus luteum formation endometrial differentiation and embryonic growth is also highlighted in the review. Strategies to overcome oxidative stress and enhance fertility, both natural and assisted are delineated. Early interventions being investigated for prevention of preeclampsia are enumerated. Trials investigating combination intervention strategy of vitamin E and vitamin C supplementation in preventing preeclampsia are highlighted. Antioxidants are powerful and there are few trials investigating antioxidant supplementation in female reproduction. However, before clinicians recommend antioxidants, randomized controlled trials with sufficient power are necessary to prove the efficacy of antioxidant supplementation in disorders of female reproduction. Serial measurement of oxidative stress biomarkers in longitudinal studies may help delineate the etiology of some of the diosorders in female reproduction such as preeclampsia.

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  • The placenta produces ROS because it is rich in mitochondria, is hemomonochorial, and allows electrons to pass that are converted into superoxide radicals.

    “The placenta itself produces ROS since it is rich in mitochondria, is hemomonochorial and allows electrons to pass that are converted into O2•-radicals (Casanueva and Viteri, 2003;Fuji, et al., 2005;Agarwal et al., 2005).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Agarwal et al., 2005

    Section 5.4 identifies the human placenta as hemomonochorial, and section 5.2 describes placental generation of superoxide during hypoxia/reperfusion injury. Section 3 explains how electrons leaking from mitochondrial electron transport generate superoxide, but it discusses that mechanism in the context of embryos. The copy does not say the placenta is rich in mitochondria or attribute its ROS production to that mitochondrial mechanism. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Higher levels of 8-hydroxy-2-deoxyguanosine in granulosa cells of patients with endometriosis are associated with lower fertilization rates and poor embryo quality.

    “Also, higher levels of 8-hydroxy-2-deoxyguanosine, an indicator of DNA damage caused by oxidative stress, have been observed in granulosa cells of patients with endometriosis and were associated with lower fertilization rates and poor embryo quality (Agarwal et al., 2005).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Agarwal et al., 2005

    In the Review’s ‘Assisted reproduction’ section (page unavailable), the paper reports that higher 8-hydroxy-2-deoxyguanosine levels were associated with lower fertilization rates and poor embryo quality. It separately reports higher levels in granulosa cells of patients with endometriosis, but says only that this may impair oocyte quality; it does not establish the stated association with fertilization rates and embryo quality specifically in those patients. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Oxidative stress intensifies the immune response in places affected by endometriosis, which may exacerbate development of endometriosis.

    “It is known that in places affected by endometriosis, oxidative stress further intensifies the immune response, as a result of which there may be an exacerbation of the development of endometriosis [151,152,153].”

    From Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature) (2021) · cites this paper as [151]

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Authors
Agarwal, A., Gupta, S., & Sharma, R. K.
Affiliations
Cleveland Clinic (US)
Corresponding author
Agarwal, Ashok
ORCID
Venue
Reproductive Biology and Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2005-07-14
Volume
3
Issue
1
Pages
28-28
ISSN
1477-7827 (ISSN-L)
DOI
10.1186/1477-7827-3-28
PMC
PMC1215514
OpenAlex
W2135935849
Cited by
1,729
References
218
Citations by year
2026: 82 · 2025: 106 · 2024: 121 · 2023: 114 · 2022: 140 · 2021: 118 · 2020: 109 · 2019: 101 · 2018: 93 · 2017: 84 · 2016: 85 · 2015: 90 · 2014: 85 · 2013: 72 · 2012: 69
FWCI
5.18
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Reproductive Biology and Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords
oxidative stress, reactive oxygen species, female reproduction, female infertility, antioxidants, nitric oxide, endometriosis, preeclampsia, hydatidiform mole, preterm labour, gestational diabetes mellitus, assisted reproduction, folliculogenesis, oocyte maturation, embryonic development, pregnancy, abortion, angiogenesis, cytokines, ovarian cancer, menopause, unexplained infertility
MeSH terms
Aging, Animals, Antioxidants, Female, Humans, Infertility, Female, Menopause, Pregnancy, Pregnancy Complications, Reproduction, Reactive Oxygen Species, Oxidative Stress, Nitric Oxide Synthase, Reproductive Techniques, Assisted, Embryonic Development

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