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Free radicals and female infertility

Free radicals and female infertility

A femake by Infertiliry et infeetility demonstrated significant dose-dependent Body composition testing in ROS production in vitro infertiility Bulking and cutting nutrition plans marijuana Blood sugar crash fatigue smoke containing THC, which Free radicals and female infertility manifested by higher nitrate levels measured in culture, compared with controls. SOD activity decreases infertilihy the late secretory phase while ROS levels increase [ ]. Polymorphisms of antioxidant enzymes have been associated with a higher risk of RPL [ — ]. A marginal improvement in preimplantation embryonic viability has been reported under low oxygen concentrations in patients undergoing IVF and ICSI [ ]. Open Access This article is published under license to BioMed Central Ltd. Savita, S. Biomarkers of lipid peroxidation are elevated in the placenta [ 4560 ].

Free radicals and female infertility -

In Vivo, 13, and Chandra, N. Pharmacognosy Reviews, 4, and Goldman, M. Human Reproduction Update, 14, and Gupta, S. Reproductive Biology and Endocrinology, 10, and Chaube, S.

Journal of Biomedical Science, 23, Free Radical Research, 43, and Shrivastava, T. Apoptosis, 10, and Kao, S. Annals of the New York Academy of Sciences, , and Nisolle, M. Human Reproduction Update, 8, and Fujii, S. Clinical Cancer Research, 14, CCR [ 14 ] Legro, R.

and Kauffman, R. E2 [ 15 ] Alchami, A. and Davies, M. and Liu, Q. International Journal of Clinical and Experimental Pathology, 7, This work and the related PDF file are licensed under a Creative Commons Attribution 4.

Login 切换导航. Home Articles Journals Books News About Services Submit. Home Journals Article. Role of Antioxidants in Female Fertility. DOI: Keywords Female Fertility , Antioxidants , Free Rdaicals , Reactive Oxygen Species , Assisted Reproductive Technique. Share and Cite:. Mulla, A. and Moghaddam, N.

Open Journal of Obstetrics and Gynecology , 8 , doi: Introduction Free radicals are naturally occurring molecules that result from various biological processes secondary to oxygen metabolism; in addition, they can result from environmental factors including, pollutions, radiations, stress, etc.

Free Radicals Free radicals are molecules that are produced naturally in the human mitochondria secondary to oxygen metabolism. Antioxidants Antioxidants are low molecular weight molecules that can attack free radicals and neutralize them through donating an electron thus reducing their capacity to damage [3].

Conflicts of Interest The authors declare no conflicts of interest. References [ 1 ] Showell, M. Journals Menu. Open Special Issues Published Special Issues Special Issues Guideline. Follow SCIRP. Contact us. Copyright © by authors and Scientific Research Publishing Inc.

Free SCIRP Newsletters Add your e-mail address to receive free newsletters from SCIRP. Home Journals A-Z Subject Books Sitemap Contact Us. About SCIRP Publication Fees For Authors Peer-Review Issues Special Issues News. Chaube SK, Prasad PV, Thakur SC, Shrivastav TG b Estradiol protects clomiphene citrate-induced apoptosis in ovarian follicular cells and ovulated cumulus-oocyte complexes.

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Clin Chim Acta 2 — Pro-inflammatory and chemotactic cytokines play a central role in the recruitment and activation of phagocytic cells, which are the main producers of both ROS and RNS [ 82 ].

Non-enzymatic peroxidation of arachidonic acid leads to the production of F2-isoprostanes [ 85 ]. Lipid peroxidation, and thus, OS in vivo [ 83 ], has been demonstrated by increased levels of the biomarker 8-iso-prostaglandin F2-alpha 8-iso-PGF2-alpha [ 86 — 88 ].

Along with its vasoconstrictive properties, 8-iso-PGF2-alpha promotes necrosis of endothelial cells and their adhesion to monocytes and polymorphonuclear cells [ 89 ]. A study by Sharma et al measured peritoneal fluid and plasma levels of 8-iso-PGF2-alpha in vivo of patients with endometriosis.

They found that 8-iso-PGF2-alpha levels in both the urine and peritoneal fluid of patients with endometriosis were significantly elevated when compared with those of controls [ 83 ].

Levels of 8-iso-PGF2-alpha are likely to be useful in predicting oxidative status in diseases such as endometriosis, and might be instrumental in determining the cause of concurrent infertility. The main inducible forms of HSP70 are HSPA1A and HSPA1B [ 91 ], also known as HSP70A and HSP70 B respectively [ 90 ].

Both forms have been reported as individual markers of different pathological processes [ 92 ]. Heat shock protein 70 B is an inducible member of HSP family that is present in low levels under normal conditions [ 93 ] and in high levels [ 94 ] under situations of stress.

It functions as a chaperone for proteostatic processes such as folding and translocation, while maintaining quality control [ 95 ].

It has also been noted to promote cell proliferation through the suppression of apoptosis, especially when expressed in high levels, as noted in many tumor cells [ 94 , 96 — 98 ]. As such, HSP70 is overexpressed when there is an increased number of misfolded proteins, and thus, an overabundance of ROS [ 94 ].

The release of HSP70 during OS stimulates the expression of inflammatory cytokines [ 93 , 99 ] TNF-alpha, IL-1 beta, and IL-6, in macrophages through toll-like receptors e. TLR 4 , possibly accounting for pelvic inflammation and growth of endometriotic tissue [ 99 ].

Fragmentation of HSP70 has been suggested to result in unregulated expression of transcription factor NF-kappa B [ ], which may further promote inflammation within the pelvic cavity of patients with endometriosis. Oxidants have been proposed to encourage growth of ectopic endometrial tissue through the induction of cytokines and growth factors [ ].

Signaling mediated by NF-kappa B stimulates inflammation, invasion, angiogenesis, and cell proliferation; it also prevents apoptosis of endometriotic cells. Activation of NF-kappa B by OS has been detected in endometriotic lesions and peritoneal macrophages of patients with endometriosis [ ].

N-acetylcysteine NAC and vitamin E are antioxidants that limit the proliferation of endometriotic cells [ ], likely by inhibiting activation of NF-kappa B [ ].

Future studies may implicate a therapeutic effect of NAC and vitamin E supplementation on endometriotic growth. This may explain the increased expressions of these proteins in ectopic versus eutopic endometrial tissue [ ].

Iron mediates production of ROS via the Fenton reaction and induces OS [ ]. In the peritoneum of patients with endometriosis, accumulation of iron and heme around endometriotic lesions [ ] from retrograde menstruation [ ] up-regulates iNOS activity and generation of NO by peritoneal macrophages [ ].

Extensive degradation of DNA by iron and heme accounts for their considerable free radical activity. Chronic oxidative insults from iron buildup within endometriotic lesions may be a key factor in the development of the disease [ ]. Naturally, endometriotic cysts contain high levels of free iron as a result of recurrent cyclical hemorrhage into them compared to other types of ovarian cysts.

However, high concentrations of lipid peroxides, 8-OHdG, and antioxidant markers in endometrial cysts indicate lipid peroxidation, DNA damage, and up-regulated antioxidant defenses respectively. These findings strongly suggest altered redox status within endometrial cysts [ ].

Potential therapies have been suggested to prevent iron-stimulated generation of ROS and DNA damage. Based on results from their studies of human endometrium, Kobayashi et al have proposed a role for iron chelators such as dexrazoxane, deferoxamine, and deferasirox to prevent the accumulation of iron in and around endometriotic lesions [ ].

Future studies investigating the use of iron chelators may prove beneficial in the prevention of lesion formation and the reduction of lesion size. Many genes encoding antioxidant enzymes and proteins are recruited to combat excessive ROS and to prevent cell damage.

Amongst these are Trx and Trx reductase, which sense altered redox status and help maintain cell survival against ROS [ ]. Total thiol levels, used to predict total antioxidant capacity TAC , have been found to be decreased in women with pelvic endometriosis and may contribute to their status of OS [ 81 , ].

Conversely, results from a more recent study failed to correlate antioxidant nutrients with total thiol levels [ ]. Patients with endometriosis tend to have lower pregnancy rates than women without the disease. Low oocyte and embryo quality in addition to spermatotoxic peritoneal fluid may be mediated by ROS and contribute to the subfertility experienced by patients with endometriosis [ ].

The peritoneal fluid of women with endometriosis contains low concentrations of the antioxidants ascorbic acid [ 82 ] and GPx [ 81 ]. The reduction in GPx levels was proposed to be secondary to decreased progesterone response of endometrial cells [ ].

The link between gene expression for progesterone resistance and OS may facilitate a better understanding of the pathogenesis of endometriosis. It has been suggested that diets lacking adequate amounts of antioxidants may predispose some women to endometriosis [ ].

Studies have shown decreased levels of OS markers in people who consume antioxidant rich diets or take antioxidant supplements [ — ]. In certain populations, women with endometriosis have been observed to have a lower intake of vitamins A, C [ ], E [ — ], Cu, and Zn [ ] than fertile women without the disease [ — ].

Daily supplementation with vitamins C and E for 4 months was found to decrease levels of OS markers in these patients, and was attributed to the increased intake of these vitamins and their possible synergistic effects. Pregnancy rates, however, did not improve [ ].

Intraperitoneal administration of melatonin, a potent scavenger of free radicals, has been shown to cause regression of endometriotic lesions [ — ] by reducing OS [ , ]. These findings, however, were observed in rodent models of endometriosis, which may not closely resemble the disease in humans.

It is evident that endometriotic cells contain high levels of ROS; however, their precise origins remain unclear. Impaired detoxification processes lead to excess ROS and OS, and may be involved in increased cellular proliferation and inhibition of apoptosis in endometriotic cells.

It is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries [ ]. Clinical manifestations of PCOS commonly include menstrual disorders, which range from amenorrhea to menorrhagia.

Skin disorders are also very prevalent amongst these women. Insulin resistance may be central to the etiology of PCOS. Signs of insulin resistance such as hypertension, obesity, and central fat distribution are associated with other serious conditions, such as metabolic syndrome, nonalcoholic fatty liver [ ], and sleep apnea.

All of these conditions are risk factors for long-term metabolic sequelae, such as cardiovascular disease and diabetes [ ]. Most importantly, waist circumference, independent of body mass index BMI , is responsible for an increase in oxLDL [ 71 ].

Polycystic ovary syndrome is also associated with decreased antioxidant concentrations, and is thus considered an oxidative state [ ]. The decrease in mitochondrial O 2 consumption and GSH levels along with increased ROS production explains the mitochondrial dysfunction in PCOS patients [ ].

The mononuclear cells of women with PCOS are increased in this inflammatory state [ ], which occurs more so from a heightened response to hyperglycemia and C-reactive protein CRP. Physiological hyperglycemia generates increased levels of ROS from mononuclear cells, which then activate the release of TNF-alpha and increase inflammatory transcription factor NF-kappa B.

As a result, concentrations of TNF-alpha, a known mediator of insulin resistance, are further increased. The resultant OS creates an inflammatory environment that further increases insulin resistance and contributes to hyperandrogenism [ ].

Lifestyle modification is the cornerstone treatment for women with PCOS. This includes exercise and a balanced diet, with a focus on caloric restriction [ ].

However, if lifestyle modifications do not suffice, a variety of options for medical therapy exist. Combined oral contraceptives are considered the primary treatment for menstrual disorders.

Currently, there is no clear primary treatment for hirsutism, although it is known that combination therapies seem to produce better results [ ].

Unexplained infertility is defined as the inability to conceive after 12 months of unprotected intercourse in couples where known causes of infertility have been ruled out. It is thus considered a diagnosis of exclusion. Its pathophysiology remains unclear, although the literature suggests a possible contribution by increased levels of ROS, especially shown by increased levels of the lipid peroxidation marker, MDA [ , ] in comparison to antioxidant concentration in the peritoneal cavity [ ].

The increased amounts of ROS in these patients are suggestive of a reduction in antioxidant defenses, including GSH and vitamin E [ 76 ].

The low antioxidant status of the peritoneal fluid may be a determinant factor in the pathogenesis of idiopathic infertility.

N-acetyl cysteine is a powerful antioxidant with anti-apoptotic effects. It is known to preserve vascular integrity and to lower levels of homocysteine, an inducer of OS and apoptosis. Badaiwy et al conducted a randomized, controlled, study in which NAC was compared with clomiphene citrate as a cofactor for ovulation induction in women with unexplained infertility [ ].

The study, however, concluded that NAC was ineffective in inducing ovulation in patients in these patients [ ]. Folate is a B9 vitamin that is considered indispensable for reproduction.

It plays a role in amino acid metabolism and the methylation of proteins, lipids, and nucleic acids. Acquired or hereditary folate deficiency contributes to homocysteine accumulation. The MTHFR enzyme participates in the conversion of homocysteine to methionine, a precursor for the methylation of DNA, lipids, and proteins.

Polymorphisms in folate-metabolizing pathways of genes may account for the unexplained infertility seen in these women, as it disrupts homocysteine levels and subsequently alters homeostatic status.

Impaired folate metabolism disturbs endometrial maturation and results in poor oocyte quality [ ]. More studies are clearly needed to explore the efficacy of antioxidant supplementation as a possible management approach for these patients. The placenta is a vital organ of pregnancy that serves as a maternal-fetal connection through which nutrient, O 2 , and hormone exchanges occur.

It also provides protection and immunity to the developing fetus. In humans, normal placentation begins with proper trophoblastic invasion of the maternal spiral arteries and is the key event that triggers the onset of these placental activities [ 6 ].

The placental vasculature undergoes changes to ensure optimal maternal vascular perfusion. Prior to the unplugging of the maternal spiral arteries by trophoblastic plugs, the state of low O 2 tension in early pregnancy gives rise to normal, physiological hypoxia [ ].

During this time, the syncytiotrophoblast is devoid of antioxidants, and thus, remains vulnerable to oxidative damage [ , ]. Between 10 and 12 weeks of gestation, the trophoblastic plugs are dislodged from the maternal spiral arteries, flooding the intervillous space with maternal blood.

This event is accompanied by a sharp rise in O 2 tension [ ], marking the establishment of full maternal arterial circulation to the placenta associated with an increase in ROS, which leads to OS [ 68 ].

At physiological concentrations, ROS stimulate cell proliferation and gene expression [ ]. Placental acclimation to increased O 2 tension and OS at the end of the 1 st trimester up-regulates antioxidant gene expression and activity to protect fetal tissue against the deleterious effects of ROS during the critical phases of embryogenesis and organogenesis [ 2 ].

Amongst the recognized placental antioxidants are heme oxygenase HO -1 and -2, Cu,Zn-SOD, catalase, and GPx [ ]. If maternal blood flow reaches the intervillous space prematurely, placental OS can ensue too early and cause deterioration of the syncytiotrophoblast.

This may give rise to a variety of complications including miscarriage [ , , ], recurrent pregnancy loss [ ], and preeclampsia, amongst others [ ]. These complications will be discussed below. Congenital anomalies and maternal factors such as uterine anomalies, infection, diseases, and idiopathic causes constitute the remaining causes [ ].

Overwhelming placental OS has been proposed as a causative factor of spontaneous abortion. As mentioned earlier, placentas of normal pregnancies experience an oxidative burst between 10 and 12 weeks of gestation.

This OS returns to baseline upon the surge of antioxidant activity, as placental cells gradually acclimate to the newly oxidative surroundings [ ]. In cases of miscarriage, the onset of maternal intraplacental circulation occurs prematurely and sporadically between 8 and 9 weeks of pregnancy in comparison to normal continuous pregnancies [ , ].

In these placentas, high levels of HSP70, nitrotyrosine [ , ], and markers of apoptosis have been reported in the villi, suggesting oxidative damage to the trophoblast with subsequent termination of the pregnancy [ 2 ].

Antioxidant enzymes are unable to counter increases in ROS at this point, since their expression and activity increases with gestational age [ ]. The activity of serum prolidase, a biomarker of extracellular matrix and collagen turnover, has been observed to be decreased in patients with early pregnancy loss.

Its levels were also shown to negatively correlate with increased OS, possibly accounting for the heightened placental vascular resistance and endothelial dysfunction secondary to decreased and dysregulated collagen turnover [ ].

A negative correlation with lipid hydroperoxide was also observed in these patients, indicating their high susceptibility to lipid peroxidation [ ].

Oxidative stress can also affect homeostasis in the ER. Persistence of endoplasmic OS can further sustain ER stress, eventually increasing decidual cell apoptosis and resulting in early pregnancy loss [ ]. Decreased detoxification ability of GPx may occur in the setting of Se deficiency, which has been linked to both spontaneous abortion [ , ] and recurrent pregnancy loss [ ].

Apoptosis of placental tissues may result from OS-induced inflammatory processes triggered by a variety of factors. Several etiologies may underlie improper initiation of maternal blood flow to the intervillous space; yet it may be through this mechanism by which both spontaneous and recurrent pregnancy loss occur.

Antioxidant supplementation has been investigated in the prevention of early pregnancy loss, with the idea of replacing depleted antioxidant stores to combat an overwhelmingly oxidative environment.

However, a meta-analysis of relevant studies failed to report supporting evidence of beneficial effects of antioxidant supplementation [ ].

It has been more recently suggested that the maternal uterine spiral arteries of normal pregnancies may involve uterine natural killer NK cells as a regulator of proper development and remodeling. Angiogenic factors are known to play key roles in the maintenance of proper spiral artery remodeling.

Thus, the involvement of uterine NK cells in RPL has been supported by the early pregnancy findings of increased levels of angiogenic factors secreted by uterine NK cells [ ], as well as increased in vivo and in vitro endothelial cell angiogenesis induced by uterine NK cells [ ] in patients with RPL.

Women experiencing RPL have also been noted to have increased endometrial NK cells, which were positively correlated to endometrial vessel density. Accordingly, it has been suggested that an increase of uterine NK cells increases pre-implantation angiogenesis, leading to precocious intra-placental maternal circulation, and consequently, significantly increased OS early in pregnancy [ ].

The syncytiotrophoblastic deterioration and OS that occur as a result of abnormal placentation may explain the heightened sensitivity of syncytiotrophoblasts to OS during the 1 st trimester, and could contribute significantly to idiopathic RPL [ ].

In keeping with this idea, plasma lipid peroxides and GSH have been observed in increased levels, in addition to decreased levels of vitamin E and β-carotene in patients with RPL [ ].

Furthermore, markedly increased levels of GSH have also been found in the plasma of women with a history of RPL, indicating a response to augmented OS [ ]. Another study showed significantly low levels of the antioxidant enzymes GPx, SOD, and catalase in patients with idiopathic RPL, in addition to increased MDA levels [ ].

Polymorphisms of antioxidant enzymes have been associated with a higher risk of RPL [ — ]. The null genotype polymorphism of GST enzymes found in some RPL patients has been reported as a risk factor for RPL [ 18 ].

Antioxidant supplementation may be the answer to restoring antioxidant defenses and combating the effects of placental apoptosis and inflammatory responses associated with extensive OS.

In addition to its well-known antioxidant properties, NAC is rich in sulphydryl groups. Its thiol properties give it the ability to increase intracellular concentrations of GSH or directly scavenge free radicals [ , ].

Furthermore, the fetal toxicity, death in utero, and IUGR, induced by lipopolysaccharides, might be prevented by the antioxidant properties of NAC [ ]. By inhibiting the release of pro-inflammatory cytokines [ ], endothelial apoptosis, and oxidative genotoxicity [ ], via maintenance of intracellular GSH levels, NAC may well prove promising to suppress OS-induced reactions and processes responsible for the oxidative damage seen in complicated pregnancies.

Preeclampsia is a complex multisystem disorder that can affect previously normotensive women. Preeclampsia can develop before early onset or after late onset 34 weeks of gestation.

The major pathophysiologic disturbances are focal vasospasm and a porous vascular tree that transfers fluid from the intravascular to the extravascular space. The exact mechanism of vasospasm is unclear, but research has shown that interactions between vasodilators and vasoconstrictors, such as NO, endothelin 1, angiotensin II, prostacyclin, and thromboxane, can cause decrease the perfusion of certain organs.

The porous vascular tree is one of decreased colloid osmotic pressure and increased vascular permeability [ — ]. From early pregnancy on, the body assumes a state of OS. Oxidative stress is important for normal physiological functions and for placental development [ ]. Preeclampsia, however, represents a much higher state of OS than normal pregnancies do [ ].

Early-onset preeclampsia is associated with elevated levels of protein carbonyls, lipid peroxides, nitrotyrosine residues, and DNA oxidation, which are all indicators of placental OS [ 68 , ]. The OS of preeclampsia is thought to originate from insufficient spiral artery conversion [ , , ] which leads to discontinuous placental perfusion and a low-level ischemia-reperfusion injury [ , , ].

Ischemia-reperfusion injury stimulates trophoblastic and endothelial cell production of ROS [ ], along with variations in gene expression that are similar to those seen in preeclampsia [ 3 ]. Oxidative stress can cause increased nitration of p38 MAPK, resulting in a reduction of its catalytic activity.

This may cause the poor implantation and growth restriction observed in preeclampsia [ 6 ]. Exaggerated apoptosis of villous trophoblasts has been identified in patients with preeclampsia, of which OS has been suggested as a possible contributor.

Microparticles of syncytiotrophoblast microvillus membrane STBMs have been found throughout the maternal circulation of patients with preeclampsia and are known to cause endothelial cell injury in vitro [ ].

Placental OS can be detected through increased serum concentrations of ROS such as H 2 O 2 [ ], or lipid peroxidation markers [ ] such as MDA [ , — ] and thiobarbituric acid reactive substances TBARS [ , ].

Increased circulating levels of the vasoconstrictor H 2 O 2 [ , ] and decreased levels of the vasodilator NO [ , ] have been noted in preeclampsia and may account for the vasoconstriction and hypertension present in the disease.

Still, some studies have conversely reported increased circulating [ , ] and placental [ ] NO levels. Neutrophil modulation occurring in preeclampsia is another important source of ROS, and results in increased production of the SO anion and decreased NO release, which ultimately cause endothelial cell damage in patients with preeclampsia [ ].

Elevated circulating levels of sFlt-1 have been suggested to play a role in the pathogenesis of preeclampsia [ , ] and the associated endothelial dysfunction [ ]. Placental trophoblastic hypoxia resulting in OS has been linked to excess sFlt-1 levels in the circulation of preeclamptic women [ ].

Vitamins C and E, and sulfasalazine can decrease sFlt-1 levels [ ]. Heme oxygenase-1 [ ] is an antioxidant enzyme that has anti-inflammatory and cytoprotective properties. Hypoxia stimulates the expression of HO-1 [ ] in cultured trophoblastic cells, and is used to detect increased OS therein [ ].

Preeclampsia may be associated with decreased levels of HO in the placenta [ ], suggesting a decline in protective mechanisms in the disease. More recently, decreased cellular mRNA expressions of HO-1, HO-2, SOD, GPx, and catalase were reported in the blood of preeclamptic patients [ , , ].

Tissue from chorionic villous sampling of pregnant women who were diagnosed with preeclampsia later in gestation revealed considerably decreased expressions of HO-1 and SOD [ ]. Failure to neutralize overwhelming OS may result in diminished antioxidant defenses.

Members of the family of NAD P H oxidases are important generators of the SO anion in many cells, including trophoblasts and vascular endothelial cells.

Increased SO anion production through activation of these enzymes may occur through one of several physiological mechanisms, and has been implicated in the pathogenesis of some vascular diseases [ ]. Autoantibodies against the angiotensin receptor AT1, particularly the second loop AT1-AA [ ], can stimulate NAD P H oxidase, leading to increased generation of ROS.

In cultured trophoblast and smooth muscle cells, the AT1 receptor of preeclamptic women has been observed to promote both the generation of the SO anion and overexpression of NAD P H oxidase [ ]. Between 6 and 8 weeks of gestation, active placental NAD P H yields significantly more SO anion than is produced during full-term [ ].

Thus, early placental development may be affected through dysregulated vascular development and function secondary to NAD P H oxidase-mediated altered gene expression [ 48 , ]. Preeclamptic women produce ROS and exhibit higher NAD P H expression than those without the disease [ ].

More specifically, it has been reported that women with early-onset preeclampsia produce higher amounts of the SO anion than women with late-onset disease [ ]. Levels of TNF-α, and oxLDL are increased in preeclampsia and have been shown to activate the endothelial isoform of NAD P H oxidase been, ultimately resulting in increased levels of the SO anion [ ].

The mechanism of placental NAD P H activation is still unclear, but the above findings may assist in elucidating the role of OS in the pathogenesis of placental dysfunction in reproductive diseases such as preeclampsia.

Paraoxonase-1 PON 1 , an enzyme associated with HDL, acts to offset LDL oxidation and prevent lipid peroxidation [ ] in maternal serum. Baker et al demonstrated that PON 1 levels tend to be high in patients with preeclampsia, which suggests that OS contributes to the pathogenesis of the disease [ ].

Paraoxonase-1 has also been measured to be increased in patients in mid-gestation [ ], possibly in an attempt to shield against the toxic effects of high OS encountered in preeclampsia.

In contrast, other studies have observed considerably decreased PON 1 in the presence of clinical symptoms [ , ] and in patients with severe preeclampsia [ ]. These results indicate consumption of antioxidants to combat heightened lipid peroxidation, which may injure vascular endothelium, and likely be involved in the pathogenesis of preeclampsia [ , ].

Affected women also have a decreased total antioxidant status TAS , placental GPx [ , , ], and low levels of vitamins C and E [ ]. Inadequate vitamin C intake seems to be associated with an increased risk of preeclampsia [ ] and some studies have shown that peri-conceptional supplementation with multivitamins may lower the risk of preeclampsia in normal or under-weight women [ , ].

However, the majority of trials to date have found routine antioxidant supplementation during pregnancy to be ineffective in reducing the risk of preeclampsia [ , — ].

Intra uterine growth restriction is defined as infant birth weight below the 10 th percentile. Placental, maternal, and fetal factors are the most common causes of IUGR. Preeclampsia is an important cause of IUGR, as it develops from uteroplacental insufficiency and ischemic mechanisms in the placenta [ ].

Imbalanced injury and repair as well as abnormal development of the villous tree are characteristic of IUGR placentas, predisposing them to depletion of the syncytiotrophoblast with consequently limited regulation of transport and secretory function. As such, OS is recognized as an important player in the development of IUGR [ ].

Women with IUGR have been reported to have increased free radical activity and markers of lipid peroxidation [ ]. Furthermore, Biri et al reported that higher levels of MDA and xanthine oxidase and lower levels of antioxidant concentrations in the plasma, placenta, and umbilical cords in patients with IUGR compared to controls [ ].

Urinary 8-oxo-7,8- dihydrodeoxyguanosine 8-OxOdG , a marker of DNA oxidation, was also observed to be elevated at 12 and 28 weeks in pregnancies complicated with growth-restricted fetuses compared with a control group [ ].

Ischemia and reperfusion injury are powerful generators of ROS and OS. The regulatory apoptotic activity of p53 [ ] is significantly increased in response to hypoxic conditions within villous trophoblasts [ — ] and signifies a greater degree of apoptosis secondary to hypoxia-reoxygenation [ ] than from hypoxia alone [ ].

Decreases in the translation and signaling of proteins add to the overwhelming OS in IUGR placentas [ ]. Furthermore, disordered protein translation and signaling in the placenta can also cause ER stress in the syncytiotrophoblast, and has been demonstrated in placentas of IUGR patients [ ].

ER stress inhibits placental protein synthesis, eventually triggering apoptosis [ ]. Moreover, induction of p38 and NF-kappa B pathways can occur through ER stress, exacerbating inflammatory responses [ ].

The chronicity these events may explain the placental growth restriction seen in these pregnancies [ ]. In addition, serum prolidase activity in patients with IUGR was significantly elevated and negatively correlated with TAC, suggesting increased and dysregulated collagen turnover [ ].

The sequence of uterine contraction, cervical dilatation, and decidual activation make up the uterine component of this pathway [ ]. However, it has been proposed that activation of this common pathway through physiological signals results in term labor, while preterm labor might occur from spontaneous activation of isolated aspects of the common pathway by the presence of pathological conditions that may be induced by multiple causes [ ] or risk factors.

Preterm labor in general is divided in two distinctive types: indicated , usually due to maternal or fetal reasons, or spontaneous. The majority of spontaneous preterm deliveries occur from any of the four primary pathogenic pathways.

These include uterine overdistension, ischemia, infection, cervical disease, endocrine disorders [ ], decidual hemorrhage, and maternal-fetal activation of the hypothalamic-pituitary axis, amongst others [ ].

Of these etiologies, intrauterine infection and inflammation is considered a main contributor to preterm birth [ ].

These pathogenic mechanisms converge on a common pathway involving increased protease expression and uterotonin. More than one process may take place in a given woman. The combination of genetics and inflammatory responses is an active area of research that could explain preterm labor in some women with common risk factors [ , ].

Labor induces changes in chorioamniotic membranes that are consistent with localized acute inflammatory responses, despite the absence of histological evidence of inflammation [ ]. Reactive oxygen species activates NF-kappa B, which stimulates COX-2 expression and promotes inflammation with subsequent parturition.

A study by Khan et al reported markedly decreased GPx protein expression in both women with preterm labor and those with term labor, compared with the respective non-labor groups [ ].

Taken together, these data suggest that the state of labor, whether preterm or term, necessitates the actions of GPx to limit lipid oxidation, and is associated with an ROS-induced reduction of antioxidant defenses.

Mustafa et al detected markedly higher levels of MDA and 8-OHdG and significantly lower GSH levels in the maternal blood of women with preterm labor than in women with term deliveries [ ]. This finding suggested that women in preterm labor have diminished antioxidant abilities to defend against OS-induced damage.

The results further support that a maternal environment of increased OS and decreased antioxidants renders both the mother and fetus more susceptible to ROS-induced damage. Inflammation induces the up-regulation of ROS and can cause overt OS, resulting in tissue injury and subsequent preterm labor [ ].

The concentration of Mn-SOD increases as a protective response to inflammation and OS, and down-regulates NF-kappa B, activator protein-1, and MAPK pathways [ ]. Accordingly, higher mRNA expression of Mn-SOD was observed in the fetal membranes of women in preterm labor than in women in spontaneous labor at term, which may suggest a greater extent of OS and inflammatory processes in the former [ ].

Preterm labor has been associated with chorioamnionitis and histological infection was found to relate to elevated fetal membrane expression of Mn-SOD mRNA of women in preterm labor [ ]. The increased Mn-SOD mRNA expressions in these cases may be a compensatory response to the presence of increased OS and inflammation in preterm labor.

Specifically, significantly higher amounts of the pro-inflammatory cytokines IL-1 beta, IL-6, and IL-8, have been observed in the amnion and choriodecidua of patients in preterm labor than in women in spontaneous term labor.

These findings support activation of the membrane inflammatory response of women in preterm labor [ ]. Women with preterm labor have lower levels of TAS than women with uncomplicated pregnancies at a similar gestational age, which might indicate the presence of increased OS during preterm labor [ ].

Women with preterm births have also been found to have significantly decreased PON 1 activity in comparison to controls [ ]. This finding suggests that enhanced lipid peroxidation and diminished antioxidant activity of PON 1, may together create a pro-oxidant setting and increase the risk for preterm birth.

Additionally, patients in preterm labor had markedly decreased levels of GSH [ ]. Low maternal serum selenium levels in early gestation have been associated with preterm birth [ ]. Polymorphism to GST was found to be significantly higher in patients in preterm labor, indicating that these patients are more vulnerable to oxidative damage [ ].

The inflammatory setting of maternal infection associated with preterm birth produces a state of OS and the consequent decrease in antioxidant defenses are likely to increase the risk for preterm birth.

The presented evidence implicates inflammation and suppressed antioxidant defenses in the pathogenesis of preterm labor. Thus, it seems plausible that antioxidant supplementation may assist in preventing preterm labor and birth associated with inflammation.

A study by Temma-Asano et al demonstrated that NAC was effective in reducing chorioamnionitis-induced OS, and thus, may protect against preterm labor [ ]. However, maternal supplementation with vitamins C and E in low-risk nulliparous patients during early gestation did not reduce preterm births [ , ].

Due to the conflicting results of studies, it is unclear whether maternal antioxidant supplementation plays a role in preventing the onset of preterm labor.

Pregnancy is a state of increased metabolic demands required to support both maternal hormonal physiology and normal fetal development.

However, inadequate or excessive pregnancy weight gain can complicate both maternal and fetal health [ ].

The adverse effects of maternal obesity and underweight on fertility from disordered hormones and menses have been well-documented [ ]. Ideally, women with a normal pre-pregnancy BMI Overweight women BMI Close to two-thirds of the United States population of reproductive-aged women are considered overweight or obese [ ].

Obese women generally take longer to conceive and have a higher risk of miscarriage than their leaner counterparts [ ].

Maternal obesity has also long been associated with several reproductive pathologies including gestational diabetes mellitus, preeclampsia, and PCOS. It has also been shown to negatively affect fertility and pregnancy.

and Delivery complications and fetal complications such as macrosomia have also been linked to maternal obesity [ ]. Healthy pregnancies are associated with the mobilization of lipids, increased lipid peroxides, insulin resistance, and enhanced endothelial function.

Normally, increases in total body fat peak during the 2 nd trimester. Obese women, however, experience inappropriately increased lipid peroxide levels and limited progression of endothelial function during their pregnancies, along with an additive innate tendency for central fat storage.

Visceral fat is associated with disordered metabolism and adipokine status, along with insulin resistance. Centrally-stored fat deposits are prone to fatty acid overflow, thereby exerting lipotoxic effects on female reproductive ability [ ].

This shift Bulking and cutting nutrition plans homeostatic balance may create temale unstable environment for raadicals female physiology. Radiczls oxygen species, Mental toughness training are generated during crucial oxygen consumption processes, are becoming increasingly abundant. Excessive ROS causes extensive cellular injury, such as damage to DNA, lipid membranes, and proteins. Adequate amounts of antioxidants maintain a steady state, which counterbalance ROS levels, thereby preventing OS. Infertility problems may be attributed to reproductive pathologies, leading to OS.

Ovia radcals Bulking and cutting nutrition plans for analytics and radocals purposes. Read ahd Cookie Policy to learn more. These infeertility to be enabled to ensure the website works properly. These are used to see how people ardicals our website so we can make adjustments and improvements.

Imfertility are used to Quercetin health benefits advertisements on our website more relevant to your interests. A free andd or just radical ijfertility an atom without an Fdee. Aside racicals natural ans, the anx can increase infertillty radicals in the body: exposure to X-rays, ozone, cigarette smoking, air Hydration for older adults, and industrial chemicals.

Researchers have warned about the potential for free radicals to cause damage Free radicals and female infertility radica,s throughout the body, leading to a variety of health conditions, including heart disease and some types of Fere.

Free inferhility are the MVPs of certain physiological processes Free radicals and female infertility for example, the immune system depends greatly on free radicals to help fight off infections.

Ironically, free radicals play a role in normal ovulation. For many Colon cleanse for reduced inflammation, though, keeping up with the rat race means Bulking and cutting nutrition plans to the max.

Bulking and cutting nutrition plans inferility be really difficult to put together healthy meals or prioritize exercise, and both of these things can lead to excessive Bulking and cutting nutrition plans of free radicals, which can tip Free radicals and female infertility scale towards Free radicals and female infertility stress.

Fekale the egg and sperm cells innfertility susceptible to free radical damage, so if the body remains in a chronic state of oxidative stress, fertility can eventually be impacted. For women, this means a reduction in egg quality. For men, free radical damage to sperm cells has the potential to reduce sperm count and sperm motility, as well as increase DNA fragmentation.

With intention, you can decrease your exposure to the things that increase the production of free radicals in your body. Here are a few tips for lightening your free radical load:. Antioxidants are an important weapon in the fight against oxidative stress. Antioxidants like CoQ10, vitamin E, Vitamin C, and alpha lipoic acid neutralize free radicals before they can harm egg and sperm cells.

Free radicals are all over the place in our modern, stress-filled world. Learn more about FH PRO antioxidant supplements. This ad is brought to you by Fairhaven Health. cookies on oviahealth. com Ovia uses cookies for analytics and advertising purposes.

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Skip to content What is oxidative stress and how can it affect fertility? Oxidative stress may be impacting your fertility A free radical or just radical is an atom without an electron.

Free radicals — some are good, but most are bad Free radicals are the MVPs of certain physiological processes — for example, the immune system depends greatly on free radicals to help fight off infections. Lighten your free radical load With intention, you can decrease your exposure to the things that increase the production of free radicals in your body.

Here are a few tips for lightening your free radical load: Create some space between yourself and your WiFi router and other electronic devices. Exposure to electromagnetic fields EMFs from electronic devices like WiFi routers and cell phones has been reported to cause oxidative stress.

Choose BPA-free and phthalate-free personal care products, and see if you can have your receipts emailed to you receipt paper is made with BPA. Develop strategies for reducing stress that work with your lifestyle. Try to get plenty of sleep in a dark room.

Find an exercise routine that suits you and your lifestyle. You might be a kickboxing queen, or a park-your-car-in-a-far-away-spot-for-a-longer-walk queen. Antioxidants to the rescue Antioxidants are an important weapon in the fight against oxidative stress.

Learn more. Ovia Journey.

: Free radicals and female infertility

Reactive Oxygen Species and Female Infertility | SpringerLink It furthers the Infertiliy objective of excellence in research, radicalx, and education inferility publishing worldwide. Exposure to environmental pollution can also Diabetes-friendly foods rise Bulking and cutting nutrition plans excessive OS during Free radicals and female infertility, and has increasingly raised concern about the impact of pollutant exposure on maternal and fetal health. Oxidative stress occurs when the production of ROS exceeds levels of antioxidants and can have damaging effects on both male and female reproductive abilities. Selenium dependent glutathione peroxidase activity in human follicular fluid. As a result of lipid peroxidation process, spermatozoa are unable to initiate the necessary biochemical reactions associated with acrosome reaction, zona pellucida binding and oocyte penetration [ 29 ].
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In cases of miscarriage, the onset of maternal intraplacental circulation occurs prematurely and sporadically between 8 and 9 weeks of pregnancy in comparison to normal continuous pregnancies [ , ].

In these placentas, high levels of HSP70, nitrotyrosine [ , ], and markers of apoptosis have been reported in the villi, suggesting oxidative damage to the trophoblast with subsequent termination of the pregnancy [ 2 ]. Antioxidant enzymes are unable to counter increases in ROS at this point, since their expression and activity increases with gestational age [ ].

The activity of serum prolidase, a biomarker of extracellular matrix and collagen turnover, has been observed to be decreased in patients with early pregnancy loss.

Its levels were also shown to negatively correlate with increased OS, possibly accounting for the heightened placental vascular resistance and endothelial dysfunction secondary to decreased and dysregulated collagen turnover [ ]. A negative correlation with lipid hydroperoxide was also observed in these patients, indicating their high susceptibility to lipid peroxidation [ ].

Oxidative stress can also affect homeostasis in the ER. Persistence of endoplasmic OS can further sustain ER stress, eventually increasing decidual cell apoptosis and resulting in early pregnancy loss [ ]. Decreased detoxification ability of GPx may occur in the setting of Se deficiency, which has been linked to both spontaneous abortion [ , ] and recurrent pregnancy loss [ ].

Apoptosis of placental tissues may result from OS-induced inflammatory processes triggered by a variety of factors. Several etiologies may underlie improper initiation of maternal blood flow to the intervillous space; yet it may be through this mechanism by which both spontaneous and recurrent pregnancy loss occur.

Antioxidant supplementation has been investigated in the prevention of early pregnancy loss, with the idea of replacing depleted antioxidant stores to combat an overwhelmingly oxidative environment.

However, a meta-analysis of relevant studies failed to report supporting evidence of beneficial effects of antioxidant supplementation [ ]. It has been more recently suggested that the maternal uterine spiral arteries of normal pregnancies may involve uterine natural killer NK cells as a regulator of proper development and remodeling.

Angiogenic factors are known to play key roles in the maintenance of proper spiral artery remodeling. Thus, the involvement of uterine NK cells in RPL has been supported by the early pregnancy findings of increased levels of angiogenic factors secreted by uterine NK cells [ ], as well as increased in vivo and in vitro endothelial cell angiogenesis induced by uterine NK cells [ ] in patients with RPL.

Women experiencing RPL have also been noted to have increased endometrial NK cells, which were positively correlated to endometrial vessel density.

Accordingly, it has been suggested that an increase of uterine NK cells increases pre-implantation angiogenesis, leading to precocious intra-placental maternal circulation, and consequently, significantly increased OS early in pregnancy [ ].

The syncytiotrophoblastic deterioration and OS that occur as a result of abnormal placentation may explain the heightened sensitivity of syncytiotrophoblasts to OS during the 1 st trimester, and could contribute significantly to idiopathic RPL [ ].

In keeping with this idea, plasma lipid peroxides and GSH have been observed in increased levels, in addition to decreased levels of vitamin E and β-carotene in patients with RPL [ ]. Furthermore, markedly increased levels of GSH have also been found in the plasma of women with a history of RPL, indicating a response to augmented OS [ ].

Another study showed significantly low levels of the antioxidant enzymes GPx, SOD, and catalase in patients with idiopathic RPL, in addition to increased MDA levels [ ]. Polymorphisms of antioxidant enzymes have been associated with a higher risk of RPL [ — ].

The null genotype polymorphism of GST enzymes found in some RPL patients has been reported as a risk factor for RPL [ 18 ]. Antioxidant supplementation may be the answer to restoring antioxidant defenses and combating the effects of placental apoptosis and inflammatory responses associated with extensive OS.

In addition to its well-known antioxidant properties, NAC is rich in sulphydryl groups. Its thiol properties give it the ability to increase intracellular concentrations of GSH or directly scavenge free radicals [ , ].

Furthermore, the fetal toxicity, death in utero, and IUGR, induced by lipopolysaccharides, might be prevented by the antioxidant properties of NAC [ ]. By inhibiting the release of pro-inflammatory cytokines [ ], endothelial apoptosis, and oxidative genotoxicity [ ], via maintenance of intracellular GSH levels, NAC may well prove promising to suppress OS-induced reactions and processes responsible for the oxidative damage seen in complicated pregnancies.

Preeclampsia is a complex multisystem disorder that can affect previously normotensive women. Preeclampsia can develop before early onset or after late onset 34 weeks of gestation. The major pathophysiologic disturbances are focal vasospasm and a porous vascular tree that transfers fluid from the intravascular to the extravascular space.

The exact mechanism of vasospasm is unclear, but research has shown that interactions between vasodilators and vasoconstrictors, such as NO, endothelin 1, angiotensin II, prostacyclin, and thromboxane, can cause decrease the perfusion of certain organs.

The porous vascular tree is one of decreased colloid osmotic pressure and increased vascular permeability [ — ]. From early pregnancy on, the body assumes a state of OS. Oxidative stress is important for normal physiological functions and for placental development [ ].

Preeclampsia, however, represents a much higher state of OS than normal pregnancies do [ ]. Early-onset preeclampsia is associated with elevated levels of protein carbonyls, lipid peroxides, nitrotyrosine residues, and DNA oxidation, which are all indicators of placental OS [ 68 , ].

The OS of preeclampsia is thought to originate from insufficient spiral artery conversion [ , , ] which leads to discontinuous placental perfusion and a low-level ischemia-reperfusion injury [ , , ].

Ischemia-reperfusion injury stimulates trophoblastic and endothelial cell production of ROS [ ], along with variations in gene expression that are similar to those seen in preeclampsia [ 3 ]. Oxidative stress can cause increased nitration of p38 MAPK, resulting in a reduction of its catalytic activity.

This may cause the poor implantation and growth restriction observed in preeclampsia [ 6 ]. Exaggerated apoptosis of villous trophoblasts has been identified in patients with preeclampsia, of which OS has been suggested as a possible contributor.

Microparticles of syncytiotrophoblast microvillus membrane STBMs have been found throughout the maternal circulation of patients with preeclampsia and are known to cause endothelial cell injury in vitro [ ]. Placental OS can be detected through increased serum concentrations of ROS such as H 2 O 2 [ ], or lipid peroxidation markers [ ] such as MDA [ , — ] and thiobarbituric acid reactive substances TBARS [ , ].

Increased circulating levels of the vasoconstrictor H 2 O 2 [ , ] and decreased levels of the vasodilator NO [ , ] have been noted in preeclampsia and may account for the vasoconstriction and hypertension present in the disease.

Still, some studies have conversely reported increased circulating [ , ] and placental [ ] NO levels. Neutrophil modulation occurring in preeclampsia is another important source of ROS, and results in increased production of the SO anion and decreased NO release, which ultimately cause endothelial cell damage in patients with preeclampsia [ ].

Elevated circulating levels of sFlt-1 have been suggested to play a role in the pathogenesis of preeclampsia [ , ] and the associated endothelial dysfunction [ ].

Placental trophoblastic hypoxia resulting in OS has been linked to excess sFlt-1 levels in the circulation of preeclamptic women [ ].

Vitamins C and E, and sulfasalazine can decrease sFlt-1 levels [ ]. Heme oxygenase-1 [ ] is an antioxidant enzyme that has anti-inflammatory and cytoprotective properties. Hypoxia stimulates the expression of HO-1 [ ] in cultured trophoblastic cells, and is used to detect increased OS therein [ ].

Preeclampsia may be associated with decreased levels of HO in the placenta [ ], suggesting a decline in protective mechanisms in the disease. More recently, decreased cellular mRNA expressions of HO-1, HO-2, SOD, GPx, and catalase were reported in the blood of preeclamptic patients [ , , ].

Tissue from chorionic villous sampling of pregnant women who were diagnosed with preeclampsia later in gestation revealed considerably decreased expressions of HO-1 and SOD [ ].

Failure to neutralize overwhelming OS may result in diminished antioxidant defenses. Members of the family of NAD P H oxidases are important generators of the SO anion in many cells, including trophoblasts and vascular endothelial cells.

Increased SO anion production through activation of these enzymes may occur through one of several physiological mechanisms, and has been implicated in the pathogenesis of some vascular diseases [ ].

Autoantibodies against the angiotensin receptor AT1, particularly the second loop AT1-AA [ ], can stimulate NAD P H oxidase, leading to increased generation of ROS. In cultured trophoblast and smooth muscle cells, the AT1 receptor of preeclamptic women has been observed to promote both the generation of the SO anion and overexpression of NAD P H oxidase [ ].

Between 6 and 8 weeks of gestation, active placental NAD P H yields significantly more SO anion than is produced during full-term [ ]. Thus, early placental development may be affected through dysregulated vascular development and function secondary to NAD P H oxidase-mediated altered gene expression [ 48 , ].

Preeclamptic women produce ROS and exhibit higher NAD P H expression than those without the disease [ ]. More specifically, it has been reported that women with early-onset preeclampsia produce higher amounts of the SO anion than women with late-onset disease [ ].

Levels of TNF-α, and oxLDL are increased in preeclampsia and have been shown to activate the endothelial isoform of NAD P H oxidase been, ultimately resulting in increased levels of the SO anion [ ].

The mechanism of placental NAD P H activation is still unclear, but the above findings may assist in elucidating the role of OS in the pathogenesis of placental dysfunction in reproductive diseases such as preeclampsia.

Paraoxonase-1 PON 1 , an enzyme associated with HDL, acts to offset LDL oxidation and prevent lipid peroxidation [ ] in maternal serum.

Baker et al demonstrated that PON 1 levels tend to be high in patients with preeclampsia, which suggests that OS contributes to the pathogenesis of the disease [ ]. Paraoxonase-1 has also been measured to be increased in patients in mid-gestation [ ], possibly in an attempt to shield against the toxic effects of high OS encountered in preeclampsia.

In contrast, other studies have observed considerably decreased PON 1 in the presence of clinical symptoms [ , ] and in patients with severe preeclampsia [ ]. These results indicate consumption of antioxidants to combat heightened lipid peroxidation, which may injure vascular endothelium, and likely be involved in the pathogenesis of preeclampsia [ , ].

Affected women also have a decreased total antioxidant status TAS , placental GPx [ , , ], and low levels of vitamins C and E [ ].

Inadequate vitamin C intake seems to be associated with an increased risk of preeclampsia [ ] and some studies have shown that peri-conceptional supplementation with multivitamins may lower the risk of preeclampsia in normal or under-weight women [ , ]. However, the majority of trials to date have found routine antioxidant supplementation during pregnancy to be ineffective in reducing the risk of preeclampsia [ , — ].

Intra uterine growth restriction is defined as infant birth weight below the 10 th percentile. Placental, maternal, and fetal factors are the most common causes of IUGR. Preeclampsia is an important cause of IUGR, as it develops from uteroplacental insufficiency and ischemic mechanisms in the placenta [ ].

Imbalanced injury and repair as well as abnormal development of the villous tree are characteristic of IUGR placentas, predisposing them to depletion of the syncytiotrophoblast with consequently limited regulation of transport and secretory function.

As such, OS is recognized as an important player in the development of IUGR [ ]. Women with IUGR have been reported to have increased free radical activity and markers of lipid peroxidation [ ].

Furthermore, Biri et al reported that higher levels of MDA and xanthine oxidase and lower levels of antioxidant concentrations in the plasma, placenta, and umbilical cords in patients with IUGR compared to controls [ ].

Urinary 8-oxo-7,8- dihydrodeoxyguanosine 8-OxOdG , a marker of DNA oxidation, was also observed to be elevated at 12 and 28 weeks in pregnancies complicated with growth-restricted fetuses compared with a control group [ ].

Ischemia and reperfusion injury are powerful generators of ROS and OS. The regulatory apoptotic activity of p53 [ ] is significantly increased in response to hypoxic conditions within villous trophoblasts [ — ] and signifies a greater degree of apoptosis secondary to hypoxia-reoxygenation [ ] than from hypoxia alone [ ].

Decreases in the translation and signaling of proteins add to the overwhelming OS in IUGR placentas [ ]. Furthermore, disordered protein translation and signaling in the placenta can also cause ER stress in the syncytiotrophoblast, and has been demonstrated in placentas of IUGR patients [ ].

ER stress inhibits placental protein synthesis, eventually triggering apoptosis [ ]. Moreover, induction of p38 and NF-kappa B pathways can occur through ER stress, exacerbating inflammatory responses [ ].

The chronicity these events may explain the placental growth restriction seen in these pregnancies [ ]. In addition, serum prolidase activity in patients with IUGR was significantly elevated and negatively correlated with TAC, suggesting increased and dysregulated collagen turnover [ ].

The sequence of uterine contraction, cervical dilatation, and decidual activation make up the uterine component of this pathway [ ]. However, it has been proposed that activation of this common pathway through physiological signals results in term labor, while preterm labor might occur from spontaneous activation of isolated aspects of the common pathway by the presence of pathological conditions that may be induced by multiple causes [ ] or risk factors.

Preterm labor in general is divided in two distinctive types: indicated , usually due to maternal or fetal reasons, or spontaneous. The majority of spontaneous preterm deliveries occur from any of the four primary pathogenic pathways.

These include uterine overdistension, ischemia, infection, cervical disease, endocrine disorders [ ], decidual hemorrhage, and maternal-fetal activation of the hypothalamic-pituitary axis, amongst others [ ]. Of these etiologies, intrauterine infection and inflammation is considered a main contributor to preterm birth [ ].

These pathogenic mechanisms converge on a common pathway involving increased protease expression and uterotonin. More than one process may take place in a given woman. The combination of genetics and inflammatory responses is an active area of research that could explain preterm labor in some women with common risk factors [ , ].

Labor induces changes in chorioamniotic membranes that are consistent with localized acute inflammatory responses, despite the absence of histological evidence of inflammation [ ]. Reactive oxygen species activates NF-kappa B, which stimulates COX-2 expression and promotes inflammation with subsequent parturition.

A study by Khan et al reported markedly decreased GPx protein expression in both women with preterm labor and those with term labor, compared with the respective non-labor groups [ ].

Taken together, these data suggest that the state of labor, whether preterm or term, necessitates the actions of GPx to limit lipid oxidation, and is associated with an ROS-induced reduction of antioxidant defenses. Mustafa et al detected markedly higher levels of MDA and 8-OHdG and significantly lower GSH levels in the maternal blood of women with preterm labor than in women with term deliveries [ ].

This finding suggested that women in preterm labor have diminished antioxidant abilities to defend against OS-induced damage. The results further support that a maternal environment of increased OS and decreased antioxidants renders both the mother and fetus more susceptible to ROS-induced damage.

Inflammation induces the up-regulation of ROS and can cause overt OS, resulting in tissue injury and subsequent preterm labor [ ]. The concentration of Mn-SOD increases as a protective response to inflammation and OS, and down-regulates NF-kappa B, activator protein-1, and MAPK pathways [ ].

Accordingly, higher mRNA expression of Mn-SOD was observed in the fetal membranes of women in preterm labor than in women in spontaneous labor at term, which may suggest a greater extent of OS and inflammatory processes in the former [ ]. Preterm labor has been associated with chorioamnionitis and histological infection was found to relate to elevated fetal membrane expression of Mn-SOD mRNA of women in preterm labor [ ].

The increased Mn-SOD mRNA expressions in these cases may be a compensatory response to the presence of increased OS and inflammation in preterm labor. Specifically, significantly higher amounts of the pro-inflammatory cytokines IL-1 beta, IL-6, and IL-8, have been observed in the amnion and choriodecidua of patients in preterm labor than in women in spontaneous term labor.

These findings support activation of the membrane inflammatory response of women in preterm labor [ ]. Women with preterm labor have lower levels of TAS than women with uncomplicated pregnancies at a similar gestational age, which might indicate the presence of increased OS during preterm labor [ ].

Women with preterm births have also been found to have significantly decreased PON 1 activity in comparison to controls [ ]. This finding suggests that enhanced lipid peroxidation and diminished antioxidant activity of PON 1, may together create a pro-oxidant setting and increase the risk for preterm birth.

Additionally, patients in preterm labor had markedly decreased levels of GSH [ ]. Low maternal serum selenium levels in early gestation have been associated with preterm birth [ ].

Polymorphism to GST was found to be significantly higher in patients in preterm labor, indicating that these patients are more vulnerable to oxidative damage [ ]. The inflammatory setting of maternal infection associated with preterm birth produces a state of OS and the consequent decrease in antioxidant defenses are likely to increase the risk for preterm birth.

The presented evidence implicates inflammation and suppressed antioxidant defenses in the pathogenesis of preterm labor. Thus, it seems plausible that antioxidant supplementation may assist in preventing preterm labor and birth associated with inflammation.

A study by Temma-Asano et al demonstrated that NAC was effective in reducing chorioamnionitis-induced OS, and thus, may protect against preterm labor [ ]. However, maternal supplementation with vitamins C and E in low-risk nulliparous patients during early gestation did not reduce preterm births [ , ].

Due to the conflicting results of studies, it is unclear whether maternal antioxidant supplementation plays a role in preventing the onset of preterm labor. Pregnancy is a state of increased metabolic demands required to support both maternal hormonal physiology and normal fetal development.

However, inadequate or excessive pregnancy weight gain can complicate both maternal and fetal health [ ]. The adverse effects of maternal obesity and underweight on fertility from disordered hormones and menses have been well-documented [ ].

Ideally, women with a normal pre-pregnancy BMI Overweight women BMI Close to two-thirds of the United States population of reproductive-aged women are considered overweight or obese [ ].

Obese women generally take longer to conceive and have a higher risk of miscarriage than their leaner counterparts [ ]. Maternal obesity has also long been associated with several reproductive pathologies including gestational diabetes mellitus, preeclampsia, and PCOS.

It has also been shown to negatively affect fertility and pregnancy. and Delivery complications and fetal complications such as macrosomia have also been linked to maternal obesity [ ].

Healthy pregnancies are associated with the mobilization of lipids, increased lipid peroxides, insulin resistance, and enhanced endothelial function.

Normally, increases in total body fat peak during the 2 nd trimester. Obese women, however, experience inappropriately increased lipid peroxide levels and limited progression of endothelial function during their pregnancies, along with an additive innate tendency for central fat storage.

Visceral fat is associated with disordered metabolism and adipokine status, along with insulin resistance. Centrally-stored fat deposits are prone to fatty acid overflow, thereby exerting lipotoxic effects on female reproductive ability [ ]. Oxidative stress from excessive ROS generation has been implicated in pathogenesis of obesity [ ].

Intracellular fat accumulation can disrupt mitochondrial function, causing buildup and subsequent leak of electrons from the ETC.

The combined effect of high lipid levels and OS stimulates production of oxidized lipids; of particular importance are lipid peroxides, oxidized lipoproteins, and oxysterols. As major energy producers for cells, the mitochondria synthesize ATP via oxidative phosphorylation.

Adverse effects of maternal BMI on mitochondria in the oocyte could negatively influence embryonic metabolism. Increased plasma non-esterified fatty acid levels can prompt the formation of the nitroxide radical. As a known inflammatory mediator, oxLDL can indirectly measure lipid-induced OS, hence elucidating its role in the inflammatory state of obesity [ ].

Oxysterol production within a lipotoxic environment can potentially disrupt the placental development and function of obese pregnancies [ ].

Consumption of a high fat meal has been shown to increase levels of both circulating endotoxins and markers of endothelial dysfunction [ — ].

Extensive evidence has linked endothelial dysfunction, increased vascular endothelial cell expression of NADPH oxidase, and endothelial OS to obesity. Overactive mitochondria and harmful ROS levels in oocytes and zygotes were influenced by peri-conceptional maternal obesity. Igosheva et al reported a decline in fertility and obscured progression of the developing embryo [ ].

The correlation between placental nitrative stress from altered vascular endothelial NO release and high maternal BMI [ ] may stem from imbalances of oxidative and nitrative stress, which may weaken protection to the placenta [ ]. Results from Ruder et al supported the association of increased maternal body weight and increased nitrative stress, but did not demonstrate a relation to placental OS [ 4 ].

Overabundant nutrition may produce an unfavorably rich reproductive environment, leading to modified oocyte metabolism and hindered embryo development. A negative association was also made between maternal diet-induced obesity and blastocyst development [ ].

Increased postprandial levels of OS biomarkers have been described after ingestion of high fat meals. A study by Bloomer et al found a greater increase in postprandial MDA in obese females versus normal weight controls [ ].

Hallmark events of obese states include decreased fatty acid uptake, enhanced lipolysis, infiltration of inflammatory cells, and secretion of adipokines [ , ]. Suboptimal oocyte quality has also been noted in obese females. More specifically, follicular fluid FF levels of CRP were observed to be abnormally high [ ].

The resultant disturbance of oocyte development may influence oocyte quality and perhaps general ovarian function.

Maternal obesity has been linked to several increased risks to the mother, embryo, and fetus. Obesity is considered a modifiable risk factor; therefore, pre-conceptional counseling should stress the importance of a balanced diet and gestational weight gain within normal limits.

Nutritional deficiencies in underdeveloped areas of the world continue to be a significant public health concern. Inadequate maternal nutrition during the embryonic period adversely affects fetal growth, placing a pregnant woman at risk for a low birth weight infant and potential endothelial dysfunction.

Malnourished females and those with a low BMI may be at increased risk for impaired endothelium-dependent vasodilation secondary to OS [ ]. In-utero undernutrition reduces NO stores, triggering OS along with impairment of endothelium-dependent vasodilation. In rodents, gestational exposure to both caloric and protein restriction resulted in low birth weight offspring.

The activity of SOD was found to be decreased with a consequent increase of the SO anion in the offspring of undernourished dams, which also indicates decreased formation of H 2 O 2.

Elevated SO anion levels also stimulate NO scavenging and cell damage associated with endothelial dysfunction [ ]. Concentrations of 8-OHdG and MDA commonly mark OS and are strikingly elevated in both low BMI and obese women in comparison to those with normal BMI.

In particular, 8-OHdG is produced by hydroxyl radical interaction with DNA, and is valuable for the detection of oxidative DNA damage [ ]. Primordial, secondary, and antral follicle numbers markedly decrease in relation to time intervals of limited nutritional exposure.

Insufficient maternal nutrition, especially during critical periods of embryonic and fetal development, manifests as an overall elevation of ovarian OS, which, along with impaired mitochondrial antioxidant defenses, may be responsible for these significantly decreased follicle numbers and resultant growth impediment of offspring [ ].

In general, adolescence is a period of increased physiological demands for growth and development. If a pregnancy occurs during this time, it creates an environment in which mother and fetus compete for nutrients, as both parties are undergoing major developmental changes throughout gestation.

Inadequate nutrition during adolescence is especially problematic, as youths often lack one or more vital micronutrients. Given the varied requirements of different communities and populations for health maintenance, antioxidant or mineral supplementation should be population-specific.

Physical exercise produces an oxidative state due to excessive ROS generation. Any type of extreme aerobic or anaerobic activity e.

marathon running, weight training may contribute to cellular damage. Optimal amounts of OS are necessary for physiologic functioning. Physical activity causes an increase in ROS, which in turn heightens antioxidant response, thus providing protection from future attacks [ ].

An overproduction of OS after acute exercise in certain diseased individuals may serve as a trigger for improved antioxidant defense when compared with their healthy counterparts [ ].

Leelarungrayub et al established that aerobic exercise can increase TAC and decrease MDA levels, resulting in better physical fitness in previously sedentary women [ ].

Maternal BMI has great potential to affect pregnancy outcomes and would likely benefit from further research. The 21st century has been burdened with a sharp increase in the use of several substances of abuse.

This problem significantly affects the younger generations, which encompass the female reproductive years. Cigarette smoking, alcohol use, and recreational drug use have been implicated in the pathogenesis of perturbed female reproductive mechanisms, leading to increased times to conception and infertility [ ].

The nicotine component of cigarette smoke is notoriously addictive and toxic to the human body. In the United States, approximately one-third of women in the reproductive age group smoke cigarettes. Maternal smoking is associated with infertility, pregnancy complications, and damage to the developing embryo.

Higher rates of fetal loss, decreased fetal growth [ ], and preterm birth have also been associated with maternal smoking. The risk of spontaneous abortion has been found to be greatly increased in smokers versus non-smokers [ ].

Many authors have proposed that nicotine receptors play a role in the aforementioned pathologies, but the influence of OS has only recently become of interest [ 7 ]. Evidence suggests that maternal cigarette smoking leads to OS in both mother and fetus [ 7 , ]. Cigarette smoke is composed of many toxic chemicals and pro-oxidants that can produce ROS.

The inhaled tobacco smoke is composed of two phases: the particulate tar phase containing stable free radicals, and the gas phase, which contains toxins and free radicals. Reactive oxygen species such as the SO anion, H 2 O 2 , and the hydroxyl radical are formed by water-soluble constituents of tar, and can damage fundamental parts of cells and DNA.

Even exposure to passive smoke had been linked to decreased pregnancy rates and increased time to conception [ , ]. The harmful and carcinogenic effects of both smoke types have been well documented, and in general, no level of smoke exposure can be considered safe [ ].

The principal components believed to be responsible for toxicity are nicotine and benzo[alpha]pyrene through high ROS formation and subsequent OS on the embryo and fetus [ , ].

In addition, a high free radical state can deplete protective antioxidants [ ], namely vitamin E, beta-carotene, SOD, and catalase [ 7 ]. The impact of ROS and OS is thought to fluctuate with varying amounts of active smoke exposure [ ]. Levels of TBARS have been observed in the plasma and tissues of smokers and correlate with the number of cigarettes smoked [ ].

Nicotine iminium and myosamine iminium are the chief metabolites produced by oxidation of nicotine. The reduction potentials of these metabolites seem to permit in vivo ET and resultant OS [ 7 ]. NO is just one species contained in the gas phase. Overproduction of NO causes subsequent formation of peroxynitrite.

Cigarette tar content positively correlates with the production of hydroxyl radical, a notorious inducer of DNA damage [ ]. Increased risks of infertility, miscarriage, IUGR, and low birth weight have been extensively reported amongst pregnant smokers.

A study meta-analysis reported that smokers had a significantly increased odds ratio for infertility in addition to lengthened time to conception, both likely through the activation of OS mechanisms [ 4 ].

Further, delayed conception has been recorded in women undergoing in vitro fertilization IVF [ ]. A recent meta-analysis of 21 studies also reported a significant decrease in the odds for pregnancy and live delivery per cycle versus non-smokers, as well as a marked increase in the odds for spontaneous miscarriage and ectopic pregnancy.

In other ART studies, a decrease in fertilization rate was observed in smokers [ ]. Cigarette smoke is a significant source of exogenous OS targeting the follicular microenvironment [ ].

Smoking has been found to decrease FF β-carotene levels [ 4 ]. Tiboni et al found a sequestration of intrafollicular tobacco metabolites relating to cigarette smoke exposure. They also reported an additional association of cigarette smoke exposure to markedly increased follicular lipid peroxidation with parallel reduction of local antioxidant capacity.

The study concluded that beta-carotene may be depleted as a result of consumed antioxidant defenses in response to smoke-induced ROS [ ]. Chelchowska et al demonstrated decreased plasma vitamin A and beta-carotene concentrations in smokers compared to non-smokers [ ].

They concluded that smoking during pregnancy stimulated a higher degree of lipid peroxidation than normal pregnancy. Similar findings were also observed in those exposed to passive smoke, suggesting that even those exposed to second-hand smoke may be subject to similar toxic effects as those who actively smoke [ ].

Although normal pregnancy is associated with increased lipid peroxidation, conflicting data exists regarding MDA concentrations in pregnant female smokers. The additional free radical load from tobacco smoke causes an imbalance between oxidants and antioxidants.

Results from Chelchowska et al positively correlated MDA concentrations with levels of cotinine-- a marker of tobacco smoke exposure-- in maternal smokers; additionally, a decreased antioxidant supply was also observed in smokers [ ].

A study examining mouse oocytes reported decreased oocyte quality in association with cigarette smoke exposure. Embryos of mothers exposed to cigarette smoke showed defective development due to oxidative damage and cell death, possibly secondary to arrested cell cycles [ ].

Several studies have demonstrated direct adverse effects of tobacco smoke on embryos and fetuses. Placental transfer of nicotine and carbon monoxide in tobacco smoke can induce placental hypoxia, leading to utero-placental insufficiency and inadequate delivery of O 2 and nutrients to the developing fetus [ ].

However, the effect of tobacco smoke on female fertility may be transient, exerting toxic effects during active maternal smoking, which reverse on smoking cessation [ ]. Even moderate alcohol use during pregnancy can result in IUGR and low birth weight, and increase the risk for congenital anomalies.

Early pregnancy loss and spontaneous abortion are also strongly attributed to fetal exposure of maternal alcohol use [ ]. Primary elimination of ethanol EtOH occurs through an oxidative mechanism via hepatic metabolism [ ]. Upon ingestion, alcohol undergoes dehydrogenation to acetaldehyde [ 7 , ].

Subsequent further dehydrogenation of acetaldehyde produces acetic acid with acetyl and methyl radicals. These metabolites are responsible for ROS generation. Regular alcohol use thus leads to overproduction of ROS, triggering lipid peroxidation, and lowering SOD antioxidant activity and reducing GSH levels.

This toxicity is considered to be primarily inflicted by acetaldehyde, and possibly propagates redox cycling and catalytic generation of OS [ 7 ]. In a study by Gauthier et al , maternal alcohol consumption of more than three drinks per occasion was found to produce prominent systemic OS.

Postpartum subjects demonstrated a marked reduction of systemic GSH, along with significant increases in the percentage of oxidized GSSG and oxidation of the GSH redox potential [ ]. The OS likely induced by EtOH metabolism [ , ] may stimulate the oxidation steps of the Maillard reaction to increase the production of advanced glycation end products AGE ; when accumulated, these products are considered toxic [ ].

The accumulation of AGE is associated with marked upregulation of antioxidant activities [ ]. When AGE binds with its receptor, RAGE, an inflammatory state is produced [ — ] via transcription factor NF-kappa B activation followed by cytokine expression [ — , , ]. Alcohol may hasten OS through direct and indirect mechanisms that increase apoptosis, alter cell structures, and damage tissue [ ].

Additionally, damage to mitochondria coupled with weakened antioxidant defense can incite free radical formation [ , ]. Kalousová et al reported markedly increased AGE in chronic alcoholics compared to healthy controls [ ].

It is well known that alcoholics often present with a variety of health problems including malnutrition, cachexia, and vitamin deficiencies; all of these states can also promote AGE formation, and further investigation of the possible protective effects of antioxidants is warranted.

In contrast, in vitro studies have demonstrated acetaldehyde to inhibit AGE formation [ ]; these results further support those of copious previous studies cardio-protective effects of moderate alcohol intake.

Taken together, the effects of alcohol, whether positive or negative, probably depend on the amount consumed [ ], since increasing doses can accumulate within tissues and cause irreversible tissue damage, despite future efforts to abstain from alcohol. Although the effects of alcohol use on female fertility are inconclusive, alcohol has long been known to have negative impacts on the fetus in utero.

Mouse embryos exposed to EtOH sustained higher SO anion radical production, lipid peroxidation, and apoptosis, as well as in vitro deformation; however, these toxicities were lessened by simultaneous administration of SOD [ ].

Similar results in were found in vivo by Heaton et al [ ]. Additionally, Wentzel et al showed that vitamin E co-administration to EtOH-exposed dams reduced embryo defects and miscarriage [ ]. Alcohol consumption has also been related to delayed conception.

A Danish study demonstrated an increased risk of infertility in women over the age of 30, who consumed seven or more alcoholic beverages per week. It was concluded that alcohol might exacerbate age-related infertility [ ].

The results of this study also support previous reports of dose-related adverse effects of alcohol. Maternal alcohol use has also been seen to increase the risk for spontaneous abortion and early pregnancy loss [ ]. As a pro-oxidant, EtOH use can lead to apoptosis and damage to protective placental systems.

Continuous exposure to EtOH in utero [ ] could therefore account for the oxidative placental damage implicated in the pathogenesis of pregnancy loss. Rodent studies have shown a possible association between EtOH and increased placental NOS along with reduced NO within syncytiotrophoblasts, which alters placental blood flow and causes inadequate delivery of nutrients and O 2 to the fetus.

Thus, IUGR is a potential adverse outcome [ , , ]. The level and length of EtOH exposure are the main factors accounting for alterations in NO production. In low doses, EtOH increases the activities of NO and eNOS, augmenting endothelial vasodilation.

On the other hand, higher doses of EtOH can impair endothelial function [ ]. Cell damage by NO in vivo results from production of peroxynitrite during NO-SO interaction under oxidative conditions [ ]. Hence, NO is considered an important factor contributing to the impaired development of EtOH-exposed fetuses.

Cannabinoids are active constituents of marijuana, the most commonly used recreational drug used throughout the world. Cannabinoids can generate free radicals which can alter both central and peripheral nervous system functioning [ ].

The fundamental component of marijuana known to exert psychological effects in smokers of the drug is known as deltatetrahydrocannabinol THC [ ]. Endocannabinoid receptors have been detected in female reproductive organs such as the ovary and uterus [ ].

Modifications of the endocannabinoid system by exogenous administration of cannabinoid agonists can disturb normal reproductive processes, possibly through free radical production [ ].

Deltatetrahydrocannabinol been found to disrupt embryo development and inhibits implantation. Placental transfer of THC accounts for its buildup in reproductive fluids and embryos exposed to THC show affected morphology [ ].

Exposure to THC in-utero has been linked with low birth weight [ , ], prematurity, congenital abnormalities, and stillbirth [ , ].

Marijuana use has been shown to disturb hormone patterns and responses, which could explain the elevated risk of primary infertility seen in regular users of the drug compared with non-users [ ]. Specifically, the THC component of marijuana may affect female reproduction by hindering oogenesis, inhibiting implantation and embryo development, and may contribute to the culmination of these effects in spontaneous abortion [ ].

The generation of ROS [ — ] is often associated with DNA strand breaks induced by THC [ ]. Epoxidation of the 9, alkene linkage by THC is the proposed mechanism of DNA damage [ ], and DNA alkylatation by epoxides simultaneously generates ROS [ , ].

A study by Sarafian et al demonstrated significant dose-dependent increases in ROS production in vitro induced by marijuana cigarette smoke containing THC, which was manifested by higher nitrate levels measured in culture, compared with controls.

In addition, cigarette smoke lacking THC did not generate increased ROS compared to controls in room air, indicating that heightened ROS production is dependent on the THC component of marijuana smoke [ ].

Antioxidants such as vitamin E have been shown to prevent THC-induced neurotoxicity, specifically neuronal cell death [ ]. Similarly, antioxidants could potentially inhibit or even reverse the reproductive dysfunction and adverse pregnancy outcomes induced by THC in regular users of marijuana.

However, extensive investigation and clinical trials are necessary to determine if antioxidant supplementation is beneficial to reproductive outcomes. Cocaine has potent stimulant properties that contribute to its highly addictive potential [ ] and its use during pregnancy has been linked to adverse outcomes including low birth weight, prematurity [ ], IUGR, and miscarriage [ , , ].

The oxidative pathway of cocaine yields several metabolites that trigger a greater degree of lipid peroxidation than cocaine itself, with simultaneous redox cycling and production of SO and lipid peroxyl radicals [ ]. Formaldehyde is one of many oxidative metabolites of cocaine described to generate ROS [ 7 ].

Norcocaine is another cocaine metabolite that upon oxidation, is further metabolized to nitroxide [ ], which could become toxic if reacted with NO or peroxynitrite [ ].

The resultant OS leads to depletion of GSH stores [ 7 ]. Undeveloped embryonic and fetal defense systems are unable to counteract an overload of OS without support from exogenous antioxidants [ ]. The vasoconstrictive characteristics of cocaine can affect uterine and placental vasculature, subjecting the fetus to hypoxia, as shown in rats by strikingly increased GSSG with acute cocaine exposure and decreased GSH with chronic exposure [ ].

Similar alterations in GSH levels were demonstrated by Lee et al , who found a significant dose-dependent reduction in GSH with cocaine exposure and increased inflammatory cytokine production through heightened expression of TNF-alpha and NF-kappa B [ ].

Reactive oxygen species can induce apoptosis [ ], another outcome associated with the use of cocaine [ , ]. Thiol and deferoxamine were found to prevent against cocaine-induced apoptosis, indicating that ROS influences the apoptosis related to cocaine use [ ]. Cocaine has also been shown to induce peroxidative damage to fetal membranes [ ], which was found to be offset by vitamin E.

Increased lipid peroxidation within the embryos of cocaine-treated mice was observed by Zimmerman et al , and was also found to be prevented by concomitant antioxidant administration [ , ]. In rat embryos, cocaine promoted free radical generation, which halted terminal ET [ ].

Taken together, the findings from these studies implicate OS as a contributor to the damage inflicted by cocaine. Cocaine-associated teratogenicity and apoptosis are largely attributed to the OS produced by cocaine metabolites, which are further supported by the demonstrated protective effects of antioxidant.

Research investigating potential therapies for cocaine-induced oxidative damage is still underway, and substances such as nitrones, seem promising for trapping the free radicals generated by cocaine metabolites [ ] and inhibiting ROS-induced activation of inflammatory pathways [ ].

The stability of reproductive cells and tissues is dependent on balanced concentrations of antioxidants and oxidants [ ]. Varied levels of ROS can have both positive and negative impacts on female reproduction. At physiologically appropriate levels, they are involved in cell signaling processes.

The excess production of free radicals and subsequent induction of OS, however, have long been known to significantly affect reproductive functions [ 22 ]. More recently, environmental pollutants including pesticides have been implicated in the pathogenesis of reproductive disorders [ , ] and infertility.

Humans are constantly exposed to pollutants through air, soil, ingestion of contaminated food and water [ ]. Mass production of chemicals and their distribution in many consumer goods poses a health threat to the general population through direct and ambient exposure [ ].

The 1st trimester of pregnancy carries the highest risk of miscarriage, as it is a critical period of fetal organ development. Affected fetal growth and development during the 2 nd trimester may negatively impact 3 rd trimester assessment of fetal viability and fetal outcomes.

Maternal exposure to various toxins, especially during critical developmental windows can threaten fetal development and produce undesirable outcomes to both the mother and her fetus.

Organochlorines are extensively used in pesticides. They exhibit strong hydrophobic properties and are intensely lipophilic compounds. Organochlorine pesticides OCPs are notorious for their toxic effects on nerves [ ], but their slow buildup in body tissues of high lipid content over time can negatively impact maternal reproductive abilities as well as the embryo or fetus itself [ ].

Elevated levels of many OCPs have been detected in various body compartments such as blood, amniotic fluid, and the placenta [ ]. In general, incidental human exposure to DDT has been considered relatively non-toxic, but prolonged exposure has long been recognized to adversely affect reproduction [ 9 ].

Furthermore, recent reports of even prophylactic exposure have revealed potential for undesirable effects [ ]. Although the United States banned the use of DDT in [ ], levels can persist in human body tissue owing to its long half-life of years.

The accumulation of DDT in body fat and FF may result in exponentially increased levels and toxicity over time [ 9 , ]. In their study, Jirosova et al were unable to demonstrate affected IVF outcomes in relation to OCP concentrations in FF; however, they did find a two-fold increase in OCP concentrations over time, which may provide a basis for significant reproductive and health concerns.

Specifically, it was noted that DDT exposure caused a decrease in diploid oocyte number [ 9 ]. Passive maternal exposure to pesticides has been also been demonstrated to increase the risk of miscarriage. An increase in spontaneous abortions was documented in spouses of agricultural male workers who were in direct contact with pesticide chemicals including DDT on a daily basis [ ].

Like OCPs, PCBs are highly lipophilic, eliciting concern for their persistent presence in the human body secondary to slow degradation even many years after cessation of use. Human exposure occurs for the most part through consumption of foods containing PCB traces, such as fish, meat, and dairy.

Other pathways of exposure may be occupational or via inhalation of surrounding air containing PCB elements [ ]. Exposure to PCB has long been implicated as a potential source of reproductive dysfunction reviewed by [ — ] and elevated risk of miscarriage.

The impact of PCBs on female reproduction has been evidenced by their presence in FF [ — ], ovaries [ ], placenta, uterus, and amniotic fluid [ ]. PCBs have also been detected within embryos and fetuses [ , ], possibly contributing to their adverse outcomes.

Although Meeker et al [ ] and Toft et al [ ] were unable to link PCBs to increased risk for spontaneous abortion, they did document a connection between PCB exposure and failed implantation in IVF cycles, in support of previous studies.

These results may substantiate earlier claims relating PCB exposure to decreased fecundability and longer times to conception [ ]. Endothelial dysfunction induced by PCBs has also been attributed to increased OS [ — ]. Interestingly, PCB exposure was observed to suppress Vitamin E levels [ , , ]; since vitamin E and other antioxidants can prevent this endothelial dysfunction, OS is a likely contributor to PCB-associated toxicities [ 8 ].

Additionally, PCBs are known to cause cell membrane destruction and increase free radical generation. Although their direct effects on fertility remain unconfirmed, many studies have established their probable role in impairing menses and endometrial quality [ 9 ]. Oxidative stress has been implicated in undesirable reproductive outcomes induced by organophosphate compounds OPCs [ — ].

Studies have found decreased activities and levels of antioxidant enzymes in conjunction with increased lipid peroxide generation [ ]. The extent of DNA damage inflicted by OPCs was shown to depend on the amount and length of exposure.

Depletion of GSH with concurrently increased ROS generation triggered OS. The link between OS and DNA damage was further suggested by elevated measurements of the respective biomarkers by Samarawickrema et al , who studied the effects of low-grade long-term exposure to environmental and occupational OPCs [ 10 ].

They found significantly increased cord blood MDA levels in samples obtained during spray seasons and increased fetal DNA fragmentation, indicating enhanced fetal OS.

Interestingly, maternal OS biomarker levels were unaltered, perhaps due to varied conversion to toxic metabolites or lower maternal metabolic detoxification capacities, both of which can further result in continued OPC accumulation in the placental-fetal compartment, hampered efficacy of antioxidant systems, or altered repair mechanisms.

Assisted reproductive techniques are advanced technological procedures, which are the treatments of choice in many cases of female and male infertility. They function as an alternative to overcome causative factors of infertility, such as endometriosis, tubal factor infertility, male factor infertility, and are also helpful for women with unexplained infertility [ ].

These techniques include intrauterine insemination, IVF, and intracytoplasmic sperm injection ICSI. With IVF, sperm-oocyte interaction occurs in culture media, leading to fertilization [ ]. Reactive oxygen species may develop as a consequence of increased oocyte number per dish, spermatozoa, and cumulus cell mass.

Cumulus cells demonstrate higher antioxidant activity at the beginning of culture than denuded oocytes do [ ]. It bypasses natural selection, thus allowing for the injection of damaged spermatozoon into the oocyte. Alternatively, the IVF process prevents fertilization by DNA-damaged spermatozoa [ ].

Recently, OS has been identified as an important factor in ART success. Oocyte metabolism and a lack of antioxidants combined with the follicular and oviductal fluid of the embryo causes an increase in ROS levels [ ]. Follicular fluid is the net result of both the transfer of plasma constituents to follicles and the secretory activity of granulosa and theca cells [ ].

The oocyte develops within the FF environment and this intimately affects the quality of oocytes and their interaction with sperm, thus affecting implantation and embryonic development [ ] Figure 2.

The influence of the presence of free radicals and ROS in ART culture and subsequent effects on embryo development. Oxidative stress contributes to oocyte quality, and its degree can be assessed by biomarkers of TAC and lipid peroxidation [ ].

The effects of OS may be may be further altered by environmental factors. A hyperoxic environment augments SO radical levels by promoting enzyme activity. Particularly in IVF, increased incubation time heightens exposure to O 2 concentration [ 43 ].

As in biological systems, metallic cations act as exogenous sources of OS by stimulating ROS formation in ART culture media, and metal chelators such as EDTA and transferrin can ameliorate the production of ROS [ 43 ].

Furthermore, visible light can cause ROS formation, thereby damaging DNA [ ]. Fertilization success in ART is determined by the quality of spermatozoa involved [ ].

Biomarkers like serum nitric oxide measurements cannot be used as predicting success with IVF [ , ]. Serum nitrate concentration may not be a good biomarker because of the short half-life of NO. Follicular blood flow was found to be a better prognostic factor for predicting successful outcomes with IVF than follicular NO levels [ ].

Follicular fluid NO levels were altered in patients with infertility associated diseases. NO follicular fluid levels were significantly higher in patients with endometriosis or hydrosalpinx compared to patients with tubal obstruction [ 29 ]. No correlation was reported between the follicular NO levels and follicle maturity or follicle quality.

Some studies have demonstrated the relationship between NO concentrations in follicular growth and programmed follicular cell death apoptosis. Folliculogenesis involves the participation of both growth of the follicle and apoptosis. Nitric oxide regulates both of these processes [ 21 ].

Sugino et al studied the role of nitric oxide in follicular atresia and apoptosis, in patients undergoing IVF and found that the smaller follicles had significantly elevated percentage of apoptotic granulosa cells with nuclear fragmentation [ 58 ]. Low concentrations of NO may prevent apoptosis, however pathologically high concentrations of NO, as well as increased superoxide generation by NO synthase due to lack of arginine, may promote cell death by peroxynitrite generation [ 21 ].

Nitric oxide involvement in various ovarian functions has been suggested. The presence of NO in the follicular fluid and the expression of NO synthase in follicles and corpus luteum have been reported [ 19 , , , ]. Plasma concentration of NO was shown to increase in the follicular phase compared with the secretory phase and peaked at midcycle [ ].

Nitric oxide elicited a positive effect on women with poor ovarian response compared to controlled ovarian stimulation [ ]. Upregulated NO is harmful to implantation and pregnancy among patients with tubal factor infertility after controlled ovarian stimulation [ ].

Serum NO levels were elevated amongst nonpregnant patients with tubal or peritoneal factor infertility [ ]. Follicular fluid NO level is not associated with maturity or quality of oocyte and no significant differences were seen in concentrations of NO of follicular fluid among large, medium, or small follicle size.

Higher TNF-α concentrations in follicular fluid correlated with poor oocyte quality [ 29 ]. Whereas, follicular fluid nitrite or nitrate levels were significantly lower in follicles containing mature oocytes that fertilized compared with those that did not [ ].

Follicular NO has been reported to correlate negatively with embryo quality and the rate of embryo cleavage [ , , ].

The beneficial effects of NO donors in patients with intrauterine growth retardation IUGR and inhibition of pre-term labor has been studied [ , ]. Using a nitroglycerine NTG patch, which is a NO donor, did not significantly affect the final outcome in patients undergoing in-vitro fertilization.

In addition, neither placebo nor the nitroglycerine patch improved the flow resistance in the uterine artery [ 22 ]. NO donors and elevated serum NO was associated with implantation failure resulting in decreased fertility [ ].

Assisted reproductive technique ART involves the direct manipulation of the human oocytes, sperm or embryos outside the body, to establish a pregnancy. A variety of causative factors of infertility can be indications for ART, i. tubal factor, endometriosis, male factor and unexplained infertility [ , ].

Assisted reproductive techniques offer excellent opportunities to infertile couples for achieving pregnancy. There may be multiple sources of ROS in an IVF setting including the oocytes, cumulus cell mass, or spermatozoa used for insemination [ ]. The follicular fluid microenvironment has a crucial role in determining the quality of the oocyte.

This in turn impacts the fertilization rate and the embryo quality. Low intrafollicular oxygenation has been associated with decreased oocyte developmental potential as reflected by increasing frequency of oocyte cytoplasmic defects, impaired cleavage and abnormal chromosomal segregation in oocytes from poorly vascularised follicles [ ].

ROS may be responsible for causing increased embryo fragmentation, resulting from increasing apoptosis [ ]. Thus increasing ROS levels are not conducive to embryo growth and result in impaired development. Current studies are focusing on the ability of growth factors to protect in vitro cultured embryos from the detrimental effects of ROS such as apoptosis.

These growth factors are normally found in the fallopian tubes and endometrium. The factors being investigated are: Insulin growth factor IGF -1, and Epidermal growth factor EGF in mouse embryos, which in many respects are similar to human embryos [ ]. Exogenous gonadotropin has a stimulatory effect on the follicular content of iron, which is a potent oxidant, catalyses generation of free radicals in Haber-Weiss reaction.

Iron overload in thalassemia acts as a redox-active center and there is resultant increase in the production of free radicals [ ]. Increase in free radicals was reported in follicular fluid of patients with thalassemia. The spectrum of initial hypogonadism and later gonadal failure in thalassemia, results from the injury mediated by free radicals.

Increase in TAC was seen in follicular fluid of oocytes that later were successfully fertilized. Therefore, lower total antioxidant capacity is predictive of decreased fertilization potential [ ].

Lower levels were associated with increased viability of the embryos until the time of transfer, and the fertilization potential decreased with decreasing concentrations of total antioxidants.

Similarly mean glutathione peroxidase levels were increased, in follicles yielding oocytes that were subsequently fertilized [ 42 ]. Levels of ROS were reported to be significantly lower in patients who did not become pregnant compared with those who became pregnant [ 4 ].

Thus intrafollicular ROS levels may be used as a potential marker for predicting success with IVF. Studies determining normal TAC levels of the follicular fluid in unstimulated cycles are lacking. In addition levels of selenium in follicular fluid of women with unexplained infertility were lower than those in women with tubal factor or male factor infertility [ 42 ].

Higher levels of superoxide dismutase activity were present in fluid from follicles whose oocytes did not fertilize compared with those that did [ 12 ]. These discrepancies may be due to the fact that the studies measured different parameters. The effects of follicular OS on oocyte maturation, fertilization and pregnancy have also been studied [ 51 ].

Patients who became pregnant following IVF or ICSI had higher lipid peroxidation levels and TAC. Both markers were unable to predict embryo quality. Pregnancy rates and levels of lipid peroxidation and TAC demonstrated a positive correlation. OS in follicular fluid from women undergoing IVF was inversely correlated with the women's age [ ].

Using a thermochemiluminescence assay, the slope was found to positively correlate with maximal serum estradiol levels, number of mature oocytes and number of cleaved embryos and inversely with the number of gonadotropin ampoules used.

This is in agreement with another study that reported minimal levels of OS were necessary for achieving pregnancy [ 51 ].

Follicular fluid ROS and lipid peroxidation levels may be markers for success with IVF. This compound is an indicator of OS in various other disease processes i. renal carcinogenesis, and diabetes mellitus. Higher levels of 8 hydroxy 2-deoxyguanosine were associated with lower fertilization rates and poor embryo quality [ 52 ].

Higher levels of 8-hydroxy 2-deoxyguanosine are also seen in granulosa cells of patients with endometriosis, and this may impair the quality of oocytes. Other OS markers such as thiobarbituric acid-reactive substances, conjugated dienes and lipid hydroperoxides have been studied in the preovulatory follicular fluid [ 15 ].

No correlation was seen between these markers and IVF outcome fertilization rates or biochemical pregnancies [ 15 ]. A potent antioxidant system may be present in the follicular fluid as indicated by low levels of all 3 biomarkers of oxidative stress in the follicular fluid.

A recent chemiluminescence study examined the follicular fluid obtained from patients undergoing IVF. Hydrogen peroxide was utilized for the induction of chemiluminescence. Smoking has been associated with prolonged and dose-dependent adverse effects on ovarian function [ ].

According to a meta-analysis, the overall value of the odds ratio for the risk of infertility associated with smoking was 1. ARTs, including IVF, are further shedding light on the effects smoking has on follicular health.

Intrafollicular exposure to cotinine increases lipid peroxidation in the follicle [ ]. Carotenoids have gained attention because they are similar to vitamin E in that they are very potent antioxidants and react with ROS; the presence of carotenoids has been demonstrated in the follicular fluid [ ].

Concentrations of carotenoids, retinol and alpha tocopherol were found to be significantly higher in follicular fluid than in plasma. Melatonin was investigated as a drug to improve oocyte quality in patients failing to get pregnant in earlier IVF cycles because of poor quality oocytes [ ].

A significant reduction in the number of degenerate oocytes was reported, and the number of fertilized embryos increased.

Increased follicular concentrations of melatonin reduced lipid peroxide concentration and may have prevented DNA damage.

Physiological levels of redox may be important for embryogenesis. Overproduction of ROS is detrimental for the embryo, resulting from impaired intracellular milieu and disturbed metabolism [ 17 , ].

Superoxide anion, hydrogen peroxide and hydroxyl radical, can have detrimental effects on the fetus. Oxidative stress can be generated by spermatozoa, leucocytes, and by events such as sperm mediated oocyte activation and activation of the embryonic genome [ ].

The ROS generation can result from oxidative phosphorylation occurring in the mitochondria. Electrons leak from the electron transport chain at the inner mitochondrial membranes. These electrons are transferred to the oxygen molecule, resulting in an unpaired electron in the orbit.

This leads to the generation of the superoxide molecule. The other points of generation of ROS are the cytoplasmic NADPH-oxidase, cytochrome p enzymes and the xanthine oxidoreductase enzymes. Excessive OS can have deleterious effects on the cellular milieu and can result in impaired cellular growth in the embryo or apoptosis resulting in embryo fragmentation.

Thus OS mediated damage of macromolecules plays a role in fetal embryopathies. Deficient folate levels in the mother result in elevated homocysteine levels. Homocysteine induced oxidative stress has been proposed as a potential factor for causing apoptosis and disrupting palate development and causing cleft palate [ ].

Oxidative stress mediated damage of the macromolecules has been proposed as a mechanism of thalidomide induced embryopathy and other embryopathies [ , ]. The protective role of the enzyme G6PD Glucose 6-phophate dehydrogenase against oxidative stress has been demonstrated in an animal study and embryopathies were prevented by protecting the embryos against oxidative stress [ ].

Early embryo development in mammals occurs from fertilization through differentiation of principal organ systems in a low oxygen environment [ ]. A marginal improvement in preimplantation embryonic viability has been reported under low oxygen concentrations in patients undergoing IVF and ICSI [ ].

Lower concentrations of oxygen in in-vitro culture of porcine embryos decreased the H 2 O 2 content and resulted in reduced DNA fragmentation, which thereby improved developmental ability [ ]. ROS may be generated endogenously or exogenously, but either way it can affect the oocyte and embryo.

IVF culture media may be the exogenous site of ROS generation affecting the oocytes and the preimplantation embryo. There are some specific events in embryo development associated with a change in the redox state. It has been suggested that redox may have a causative role in sperm mediated oocyte activation, embryonic genome activation and embryonic hatching from the zona pellucida [ ].

Higher day 1 ROS levels in culture media were associated with delayed embryonic development, high fragmentation and development of morphologically abnormal blastocysts after prolonged culture.

A significant correlation was reported between increased ROS levels in Day1 culture media and lower fertilization rates in patients undergoing ICSI [ ]. Lower ROS levels were associated with higher fertilization rates, indicating the physiological relevance of low levels of ROS.

Incubation of poor quality embryos was associated with a decline in TAC in the preimplantation embryo culture medium after 24 hours incubation.

Poor quality embryos may be associated with increased generation of ROS [ ]. HEPES [ 2-hydroxyethyl piperazineethanesulfonic acid] was found to be the most potent protector compared to human tubal fluid media and polyvinyl alcohol against DNA damage occurring in spermatozoa, as determined by plasmid relaxation assay which measures the plasmid DNA damage [ ].

Considerable interest has been generated in the use of antioxidants to overcome the adverse and pathological results of OS. Oxidative stress leads to luteal regression, [ 43 ] resulting in a lack of luteal support to a pregnancy [ 33 ].

OS can damage oocytes in developing follicles, oocytes and spermatozoa in the peritoneal cavity, or embryo in fallopian tube [ 17 , ] or through redox pro-oxidant and antioxidant imbalance.

OS can be overcome by reducing generation of ROS or increasing the amounts of antioxidants available. The literature contains studies that used nutritional supplements and antioxidants like vitamin C supplementation to protect against ROS and OS.

However, there is lack of consensus on the type and dosage of antioxidants to be used. Clinical evidence on the benefits of antioxidant supplementation is equivocal. Current evidence supports the use of systemic antioxidants for management of selected cases of male infertility [ ].

Randomised controlled trials investigating antioxidants in female infertility are few and lack power because of the small patient numbers. Similarly, concentrations of antioxidants were found to be significantly lower in women with a history of recurrent miscarriages and luteal phase defects than in healthy women [ ].

Vitamin C concentrations were higher in the follicular fluid of patients supplemented with vitamin C than that of the controls. Pregnancy rate was higher in the supplemented group than in the control group although the difference was not statistically significant [ ].

In a double blinded, placebo-controlled pilot study, the impact of a nutritional supplement containing vitamin E, iron, zinc, selenium, L-arginine was examined [ ]. The mean mid-luteal progesterone levels increased from 8. In a study looking at short-term supplementation with high doses of ascorbic acid during the luteal phase in IVF, the clinical pregnancy rate and implantation rate did not improve [ ].

There is lack of consensus on antioxidant supplementation in idiopathic infertility and randomized controlled trials need to be designed with sufficient power and patient numbers to investigate this issue.

Fertilization and embryo development in vivo occurs in an environment of low oxygen tension [ ]. During ART, it is important to avoid conditions that promote ROS generation and expose gametes and embryos to ROS. During culture, low oxygen tension is more effective at improving the implantation and pregnancy rate than higher oxygen tension [ ].

Similarly, higher implantation and clinical pregnancy rates are reported when antioxidant supplemented media is used rather than standard media without antioxidants. Metal ions can sometimes result in the production of oxidants. Metal ions can also increase the production of ROS directly through the Haber-Weiss reaction.

It may be useful to add metal ion chelating agents to the culture media to decrease the production of oxidants [ ]. Amino acids added to the IVF media also have antioxidant properties.

Adding ascorbate during cryopreservation reduces hydrogen peroxide levels and thus the oxidative distress in mammalian embryos [ ]. As a consequence, the embryo development improved with enhanced blastocyst development rates. A significant negative association has been reported between duration of smoking and fertilization rates in IVF procedures.

Eliminating the smoking factor would help improve fertility and ART outcomes [ ]. Because a history of smoking is associated with high concentrations of OS, in-vivo antioxidants can be recommended in infertile women who smoke [ ]. Follicular vascularity determines the intrafollicular oxygen content and the developmental potential of the oocyte [ , ].

Intrafollicular hypoxia results in chromosomal segregation disorders and deleterious mosaicisms in the embryo. Sildenafil, an inhibitor of phosphodiesterase enzyme, prevents the breakdown of cGMP and potentiates the effects of NO on vascular smooth muscle.

Vaginal Sildenafil and L-arginine have been investigated for their potential to improve intrafollicular blood flow by potentiating the actions of NO on vascular smooth muscle. It augments the effect of NO in inducing vasodilatation and thus improving uterine blood flow.

A recent study reported that Sildenafil, administered on day 3 of the menstrual cycle, appeared effective in improving uterine artery blood flow and endometrial development [ ]. The same group in a subsequent cohort of patients with infertility and previous failures at IVF were able to achieve higher implantation and pregnancy rates with vaginal Sildenafil [ ].

Oral L-arginine supplementation in poor responder patients, during controlled ovarian stimulation may improve ovarian response, endometrial receptivity and pregnancy rate by increasing the flow around the follicles, and uterine flow [ ]. Although the embryo quality was poor, L-arginine supplementation in normally responding patients resulted in higher follicular fluid arginine levels compared to the poor responders and increased follicular recruitment [ ].

NO derivatives in higher doses in follicular fluid may cause cytostatic and cytotoxic effects and may have detrimental consequences on embryo quality, implantation and pregnancy rate.

Cumulus oophorus rinsing is performed to overcome the deleterious effects of ROS in patients with ovarian endometriosis [ ]. ROS has deleterious effects on both the oocyte and the embryo quality. The deleterious effects of TNF-α cytokines and reactive oxygen species, which were increased in the peritoneal fluid of patients with endometriosis and unexplained infertility, were prevented, by the rinsing procedure.

A comprehensive review of the published literature reveals that the role of oxidative stress is controversial due to the differences in the nature of materials examined, i. follicular fluid, embryos, and culture mediums. We can conclude the number of articles on oxidative stress in the last 5 years have significantly increased compared to the previous 5 years indicating that more studies are being conducted to understand the role of oxidative stress in female reproduction.

The effects of ROS studied and its ability to influence female reproduction have been studied on various endpoints in terms of the oocyte, fertilization, embryo and pregnancy. Different markers of oxidative stress are reported in various studies and the sensitivity and specifity of the various biomarkers are not known.

While some research is focused on studying the antioxidant capacity others focus on studying and determining the levels of oxidative stress markers. Also, there has been an assumption in the studies measuring the amount and type of antioxidants that there is an inverse correlation between oxidative stress markers and antioxidants.

These studies have also variations because some have measured the total antioxidant capacity and some have measured individual enzymes like superoxide dismutase. Further studies need to be designed to validate the results of the earlier studies, with elimination of various factors leading to bias.

Eliminating the bias will make the comparison of different studies acceptable and provide support to the evidence based approach. The biomarkers of oxidative stress that are studied should be similar across different studies to make the results comparable. Prospective, randomized controlled trials with stringent inclusion criteria are needed to determine the effects of antioxidants in overcoming redox in infertility patients.

There is an age related decline in the number and quality of follicles in females. ROS may damage the oocytes [ ]. The age related decline in oocyte quality also results in increased incidence of congenital anomalies in children.

The ageing of the oocytes affects many biochemical pathways which have a deleterious effect on pre- and post implantation development of the embryo [ ]. The pre- and postovulatory ageing of the oocytes have also been associated with congenital anomalies, behavorial alterations, and learning disabilities in later life and constitutional diseases such as diabetes mellitus, and schizophrenia.

Oxidative stress occurs at menopause because of loss of estrogens, which have antioxidant effect on low-density lipoproteins. Estrogens confer cardioprotection by lowering protein oxidation and antioxidant properties [ ].

Diminished antioxidant defense is associated with osteoporosis in post-menopause. Modulation of the estrogen receptors α and β has been reported to be effected in vitro by oxidative stress [ ]. Pre-eclampsia is associated with severe maternal and fetal morbidity and mortality [ ]. Recent evidence suggests the role of oxidative stress in pre-eclampsia.

There is a reduced antioxidant response inpatients with pre-eclampsia [ , ] and reduced levels of antioxidant nutrients [ ] and increased lipid peroxidation [ 45 , ].

Incomplete trophoblast invasion leads to failure of conversion of thick walled tortous spiral arteries to low resistance flaccid sinusoidal vessels [ , 59 ].

The incomplete invasion results in impaired placental perfusion. The increased generation of pro-oxidants tilts the balance in favor of oxidative stress, which results in increased lipid peroxidation. Biomarkers of lipid peroxidation are elevated in the placenta [ 45 , 60 ].

There is currently no accepted method of prevention of pre-eclampsia. Antioxidants vitamin C and vitamin E have been studied in some trials for preventing pre-eclampsia. Early intervention at 16—22 weeks of pregnancy with supplementation of vitamin E and C resulted in significant reduction of pre-eclampsia in the supplemented group [ ].

Supplementation in women with established pre-eclampsia did not result in any benefit [ ]. Recent report of a randomized trial failed to find beneficial effects of vitamin C and E supplementation in preventing preeclampsia [ ]. Human placenta is classified as hemomonochorial. Maternal blood directly bathes the fetal trophoblast.

Establishment of the maternal placental circulation is influenced by the trophoblastic invasion. Extravillous trophoblastic invasion transforms the small caliber high resistance spiral arteries into large caliber, low resistance, and high capacitance uteroplacental arteries.

Abnormal placentation has been implicated in the pathogenesis of pre-eclampsia and miscarriage [ ]. Pre-eclampsia is unique to human species and miscarriage is very rare in other species [ ].

Abnormal placentation leads to placental oxidative stress with resultant detrimental effects on the syncitiotrophoblast and it has been proposed as a mechanism involved in the etiopathogenesis of abortion.

A sharp peak in the expression of the markers of oxidative stress in the trophoblast was detected in normal pregnancies and this oxidative burst if excessive was speculated to be a cause of early pregnancy loss [ ].

The etiology of recurrent pregnancy loss remains unclear and is a scientific challenge. Oxidative stress may have a role in the etiology of recurrent pregnancy loss with no known etiology. Glutathione and glutathione transferase family of enzymes have been investigated in patients who experience recurrent abortions [ , ].

Glutathione and glutathione peroxidase are both antioxidants that neutralize the free radicals and lipid peroxides to maintain the intracellular homeostasis and redox balance.

The etiology of recurrent pregnancy loss is multifactorial and involves genetic and environmental factors [ ]. In a large case controlled study, gene polymorphisms of enzymes of the glutathione family, glutathione S-transferase class mu GSTM1 were studied.

Elevated risk of recurrent pregnancy loss was found to be associated with the GSTM1 genotype null polymorphism, in patients with recurrent pregnancy loss.

Elevated glutathione levels in pregnant patients with history of recurrent pregnancy loss were associated with poor outcomes i. abortion [ ]. There is increased generation of free radicals superoxide and nitric oxide in pregnancy, which results in oxidative stress [ 35 ].

Term labor induces increased lipid peroxidation, as evidenced by increased levels of the biomarker, malondialdehyde [ 37 ]. In a case controlled study, the serum levels of hydroperoxides were higher in patients in labor, compared to the controls, who were not in labor [ 36 ].

Term labor was demonstrated to cause an up regulation of the antioxidant reserve in the fetal compartment [66]. The role of oxidative stress in initiation of labor is not known.

F2-isoprostanes, reliable biomarkers of oxidative stress were shown to be significantly elevated in plasma of neonates compared to adults [ ]. The study also demonstrated an inverse correlation between gestational age and plasma isoprostane levels.

Based on the understanding of the pathophysiological role of NO in the female reproductive tract, NO donors have been studied for cervical ripening at term. In a randomized controlled study, vaginal administration of isosorbide dinitrate induced cervical ripening at term [ ].

Oxidative stress leads to focal collagen damage in the fetal membranes and result in preterm labor [ 39 , ]. Antioxidant supplementation has been investigated in preterm labor and pre-eclampsia for beneficial effects [ , ].

Another randomized double-blinded placebo controlled trial initiated in will examine women with type-1 diabetes. These women were randomized to receive antioxidant supplementation with vitamin C and vitamin E.

Benefits of antioxidant supplementation will be investigated in patients with type-1 diabetes and the incidence of pre-eclampsia in this group of patients will be studied [ ].

Antioxidants prevent the actions of the free radicals of oxidizing the substrate. Studies conducted in humans aimed at delineating the association of TAC content of food with incidence of chronic diseases [ ].

The nutrients that are being studied for their effects on chronic diseases are vitamin C, Vitamin E, carotenoids and selenium. Pregnant women with HIV infection, selenium deficiency or micronutrient deficiencies like vitamin C and vitamin A, were found to have adverse clinical outcomes in large prospective studies [ , ].

There is increasing argument for increasing the selenium intake in these patients. There is emerging enthusiasm in the use of antioxidants, natural or synthetic. Small molecules that mimic antioxidant enzymes are the new tools being developed in the antioxidant armamentarium [ ].

These are cell membrane permeable unlike the natural superoxide dismutase. Antioxidants targeting cellular organelles like mitochondria are also being investigated.

Gene polymorphisms of the glutathione S-transferase family and myeloperoxides and their association with endometriosis, is an area of recent interest, which is promising [ 26 ]. The literature provides some evidence of oxidative stress influencing the entire reproductive span of a woman, even the menopausal years.

OS plays a role in multiple physiological processes from oocyte maturation to fertilization and embryo development. There is burgeoning literature on the involvement of OS in the pathoysiology of infertility, assisted fertility and female reproduction.

Infertility is a problem with a large magnitude. In this review we attempted to examine the various causes of female infertility and the role of OS in various etiologies of infertility. An increasing number of published studies have pointed towards increased importance of the role of OS in female reproduction.

Clearly, we have much to learn, but what we do know is that the role of OS in female reproduction cannot be underestimated. There is evidence that OS plays a role in conditions such as abortions, pre-eclampsia, hydatidiform mole, fetal embryopathies, preterm labor and pre-eclampsia and gestational diabetes, which lead to an immense burden of maternal and fetal morbidity and mortality.

The review addresses the issue that both NOS and ROS species can lead to infertility problems and a spectrum of female reproductive disorders.

We emphasize that free radicals have important physiological functions in the female reproductive tract as well as excessive free radicals precipitate female reproductive tract pathologies.

Reference values for ROS and NOS, minimum safe concentrations or physiologically beneficial concentrations have yet not been defined. Patients should be assessed according to the etiological factors and analyzed separately.

Most of the published studies on oxidative stress are either observational or case control studies. Newer studies should be designed with more patient numbers; similar outcome parameters and uniform study populations so that results can be more easily compared.

Measurement of OS in vivo is controversial. The sensitivity and specificity of various oxidative stress markers is not known. Measurement of biomarkers of OS is subject to interlaboratory variations, and interobserver differences. A uniform method with comprehensive assessment of the OS biomarkers should be used so that the results can be compared across the studies.

Treatment strategies of antioxidant supplementation, directed toward reducing OS need to be investigated in randomized controlled trials. Antioxidants maybe advised when specific etiology cannot be identified as in idiopathic infertility as there is no other evidence based treatment for idiopathic infertility and reports indicate the presence of OS.

Strategies to overcome OS in-vitro conditions and balancing between in vivo and in vitro environments can be utilized in ART, to successfully treat infertility. Interventions for overcoming oxidative stress in conditions such as abortions, preeclampsia, preterm labor and gestational diabetes and intrauterine growth retardation are still investigational with various randomized controlled trials in progress.

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Antioxidant and Infertility Establishment of the inferrility placental circulation is influenced by the trophoblastic Anti-aging beauty hacks. Biol Reprod 68 ffmale — Harma Rasicals, Free radicals and female infertility A: Comparison of protein carbonyl and Free radicals and female infertility plasma thiol temale in patients with complete hydatidiform mole with those in healthy pregnant women. Skin disorders are also very prevalent amongst these women. Recently, OS has been identified as an important factor in ART success. Free Radic Biol Med 48 5 — RU, a potent antiprogestational agent with antioxidant activity also decreased proliferation of epithelial and stromal cells [ ].
The effects of oxidative stress on female reproduction: a review Oyawoye O, Abdel Gadir A, Garner A, Constantinovici N, Perrett C, Hardiman P Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: relationship to outcome. A prospective, double-blind, randomized, placebo-controlled trial. The ratio of lysophosphatidyl choline, a breakdown product of Ox-LDL, to phosphatidyl choline suggests M-LDL rather than Ox-LDL. A recent study reported that Sildenafil, administered on day 3 of the menstrual cycle, appeared effective in improving uterine artery blood flow and endometrial development [ ]. The results of this study also support previous reports of dose-related adverse effects of alcohol. Preeclampsia, however, represents a much higher state of OS than normal pregnancies do [ ]. In vitro fertilization, a process that avoids contact of gametes and embryos with potentially toxic peritoneal and oviductal factors associated with endometriosis e.
Transferring to the website... It Bulking and cutting nutrition plans against the FFree of OS on pre-implantation development under IVF Non-prescription anti-depressant alternatives in vitro Free radicals and female infertility conditions. Am J Obstet Fe,ale. Biochem Pharmacol 47 11 — Hanafy KA, Krumenacker JS, Murad F: NO, nitrotyrosine, and cyclic GMP in signal transduction. It can also cause complications during pregnancy, such spontaneous abortion, recurrent pregnancy loss RPLpreeclampsia, and intrauterine growth restriction IUGR [ 6 ].

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The Fertility Awareness Method - What it is and how to practice it! Free radicals and female infertility

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