Oxidative Stress in Female Reproductive System and ART Outcomes

Of the patients attending an infertility clinic, 40% have detectable levels of ROS formation in their semen and 25% have levels higher than the normal limits [165].

Men with high levels of ROS may have a lower fertility potential compared to those with low ROS [39, 110]. A reduction in ROS production could significantly improve ART outcome [166].

Oxidative stress can originate from the early steps of ART involving the oocyte, sperm, and embryo, as well as later on in the endometrial environment following embryo transfer.

Poorly vascularized follicles may produce oocytes with increased frequency of cytoplasmic defects, impaired cleavage, and abnormal chromosomal segregation resulted in impaired development [142]. Follicular fluids of the patients undergoing IVF found to contain oxidative stress markers [ 167 . . High levels of ROS may increase embryo fragmentation and increase apoptosis ended with impaired development of the embryo [168]. ROS levels in follicular fluid can be used as potential marker for predicting success with IVF. Levels of OS in follicular fluid from women undergoing IVF were negatively associated with the outcome [169]. Low concentrations of ROS in follicular fluid are found to be critical for good IVF outcomes [93] Moreover, Pasqualooto et al. .170. reported that low levels of ROS were required to achieve pregnancy. On the other hand, it was found that increased concentration of ROS in follicular fluid leads to reduction of the fertilization capability of the oocytes in ART cycles [171].

ROS and LPO could be used as markers for success with IVF. In addition, total antioxidants capacity (TAC) levels in day 1 culture media could be another marker reflecting the OS status during early embryonic growth. Pregnant women after treatment by IVF or ICSI had higher LPO levels and TAC in their follicular fluids. TAC levels were found to be higher in fluids yielded from follicles that produce fertilized oocytes than those with unfertilized oocytes [167, 170]. Bedaiwy et al. [172] reported significant correlation between day 1 TAC levels and clinical pregnancy rates in ICSI. Moreover, in another study, they showed that high day 1 ROS levels in culture media had no relationship with the fertilization rates in conventional IVF cycles, but were significantly related to higher fertilization rates and blastocyst development rates with ICSI cycles [173].

Other OS markers include homocysteine that found to have negative correlation with embryo quality in women with endometriosis [174]. Also, 8-Hydroxy-2-deoxyguanosine (8-OHdG) is an indicator of DNA damage induced by OS. It was reported that high concentrations of 8-OHdG were inversely correlated with fertilization rates and embryo quality [175]. In addition, thiobarbituric acid-reactive substances, conjugated dienes, and lipid hydroperoxides in preovulatory follicular fluid are oxidative stress markers; they found to have no correlation with IVF outcomes [144[. Smoking, a good oxidative stress inducer, has negative effect on ovarian function [176] .

Embryos development and the effect of oxidative stress have been thoroughly studied both in animals and human systems. The energy demands of the developing embryo are high; the embryo derives energy by generating ATP through oxidative phosphorylation and glycolysis [177].

In addition, OS arising from spermatozoa induce peroxidative damage to the oocyte and its DNA, reducing the likelihood of successful fertilization [127].

Current reports implicate oxidative stress in the etiology of defective embryo development [19]. Differential growth patterns have been correlated to ROS levels on days 1-6 of embryo culture; the same study demonstrated increased embryonic fragmentation and low cleavage in ICSI cycles with increased ROS levels on day [173],

In addition, studies in which the sperm was exposed to artificially produced ROS resulted in a significant increase in DNA damage in the form of modification of all bases, production of base-free sites, deletions, frame shift, DNA cross-links, and chromosomal rearrangement [178].

Various studies suggest that DNA fragmentation in sperm is induced, for the most part, during sperm transport through the seminiferous tubules and the epididymis [179, 180].

In a recent study, Greco et al. reported that DNA fragmentation in ejaculated sperm, as measured by TUNEL in a selected group of oligozoospermic and normo-zoospermic males, was significantly higher than that found in testicular sperm from these same males (23.6% vs. 4.8%, P< 0.001). Pregnancy rates obtained with testicular sperm were significantly higher than those obtained with ejaculated sperm (44.4% vs. 5.6%, P=0.001) [180].

In a similar study, Steele et al. found that the level of DNA fragmentation in epididymal sperm was significantly higher than that of testicular sperm obtained from the same patients. All these findings support the hypothesis that ROS induces DNA fragmentation during sperm transport through the seminiferous tubules and epididymis, and that this is one of the main mechanisms for DNA damage in sperm. These results also underscore the significance of DNA fragmentation in ART outcome [181].

Several studies have shown that sperm DNA quality had robust power to predict fertilization in vitro [182-185]. In a recent report, the only parameter that showed a significant difference between pregnant and nonpregnant groups by IVF was the percentage of sperm with DNA damage after preparation, as assessed by in situ nick translation. It was significantly higher in those patients who did not establish a pregnancy [186].

High SDF levels have been shown to influence fertilization rate [187, 188] and embryo quality [189], leading to repeated pregnancy loss [190] and low ART outcome [82,191]. Failures may therefore be due to poor sperm DNA quality.

The sperm DNA fragmentation index (DFI), as measured by the sperm chroma-tin structure assay (SCSA), determines the level of sperm DNA integrity in a semen sample. Semen samples containing more than 30% sperm with fragmented DNA have been associated with reduced pregnancy rates [192]. Increased DFIs have been shown in infertile men with normal semen analyses [193]. The SCSA has been proposed as an adjunct in the infertility clinic to identify couples with poor fertility prospects [192,194-196].

In two studies including 380 couples attempting natural conception, increasing DFI values were correlated with low frequency of or failure to achieve pregnancy [197,198]. UsingaDFI cut-off value of >30%, all couples in one study either failed to achieve or achieved pregnancy only after 4 months [197]. Payne et al. [199] reported that 9 of 19 couples with DFI >27% achieved clinical pregnancy with IVF/ ICSI. On the contrary, other studies reported no pregnancy after in vitro ART procedures, both standard IVF and ICSI, when the DFI in raw semen was more than 27% [184, 200].

Previously published data suggested that an abnormal sperm DNA Fragmentation Assay (SDFA™) test predicted low success with IUI, IVF, or ICSI [134, 184, 200] . Although prediction of IUI failure appears to have been confirmed [134], several subsequent studies questioned this theory with respect to IVF and ICSI [123, 201],

High SDF values have been shown to reduce the efficacy of intrauterine insemination (IUI) from 16 to 4% [194], or lower [202]. In contrast, the same SDF values do not seem to affect the outcome of IVF or intracytoplasmic sperm injection (ICSI) techniques—the best results being obtained in ICSI [194, 203]. This is probably due to the fact that there is a selection process involved during these techniques, in which the best spermatozoon and fertilized embryo are chosen before implantation, thus reducing the impact of low sperm quality.

Recently, in the most definitive research to date, a prospective analysis of approximately 1,000 ART cycles (387:IUI, 388:IVF, 223: ICSI) from 637 patients demonstrated that an abnormal SDFA™ test is highly predictive of IUI failure [196]. Live IUI delivery rates for patients with normal and abnormal SDFA™ scores were dramatically different (19 and 1.5%, respectively). Live IVF and ICSI delivery rates were no different between SDFA™ abnormal or normal patients.

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100 Pregnancy Tips

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