■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

WHO laboratory manual for the examination and processing of human semen

Reactive oxygen species

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

/pdf/role-of-oxidative-stress-in-female-reproduction-2fcw0uqz6p.pdf

Role of oxidative stress in female reproduction

Oxidative stress occurs when the production of potentially destructive reactive oxygen species (ROS) exceeds the bodies own natural antioxidant defenses, resulting in cellular damage. Oxidative stress is a common pathology seen in approximately half of all infertile men. ROS, defined as including oxygen ions, free radicals and peroxides are generated by sperm and seminal leukocytes within semen and produce infertility by two key mechanisms. First, they damage the sperm membrane, decreasing sperm motility and its ability to fuse with the oocyte. Second, ROS can alter the sperm DNA, resulting in the passage of defective paternal DNA on to the conceptus. This review will provide an overview of oxidative biochemistry related to sperm health and will identify which men are most at risk of oxidative infertility. Finally, the review will outline methods available for diagnosing oxidative stress and the various treatments available.

/pdf/oxidative-stress-and-male-infertility-a-clinical-perspective-2nu3kdi0jn.pdf

Oxidative stress and male infertility—a clinical perspective

Sperm DNA integrity is essential for the accurate transmission of genetic information. It has a highly compact and complex structure and is capable of decondensation-features that must be present in order for a spermatozoon to be considered fertile. Any form of sperm chromatin abnormalities or DNA damage may result in male infertility. In support of this conclusion, it was reported that in-vivo fecundity decreases progressively when > 30% of the spermatozoa are identified as having DNA damage. Several methods are used to assess sperm chromatin/DNA, which is considered an independent measure of sperm quality that may yield better diagnostic and prognostic approaches than standard sperm parameters (concentration, motility and morphology). The clinical significance of this assessment lies in its association not only with natural conception rates, but also with assisted reproduction success rates. Also, it has a serious impact on the offspring and is highly prognostic in the assessment of fertility in cancer patients. Therefore, screening for sperm DNA damage may provide useful information in cases of male idiopathic infertility and in those men pursuing assisted reproduction. Treatment should include methods for prevention of sperm DNA damage.

/pdf/role-of-sperm-chromatin-abnormalities-and-dna-damage-in-male-5a2riixlg7.pdf

Role of sperm chromatin abnormalities and DNA damage in male infertility

Seminal oxidative stress in the male reproductive tract is known to result in peroxidative damage of the sperm plasma membrane and loss of its DNA integrity. Normally, a balance exists between concentrations of reactive oxygen species and antioxidant scavenging systems. One of the rational strategies to counteract the oxidative stress is to increase the scavenging capacity of seminal plasma. Numerous studies have evaluated the efficacy of antioxidants in male infertility. In this review, the results of different studies conducted have been analysed, and the evidence available to date is provided. It was found that although many clinical trials have demonstrated the beneficial effects of antioxidants in selected cases of male infertility, some studies failed to demonstrate the same benefit. The majority of the studies suffer from a lack of placebo-controlled, double-blind design, making it difficult to reach a definite conclusion. In addition, investigators have used different antioxidants in different combinations and dosages for varying durations. Pregnancy, the most relevant outcome parameter of fertility, was reported in only a few studies. Most studies failed to examine the effect of antioxidants on a specific group of infertile patients with high oxidative stress. Multicentre, double-blind studies with statistically accepted sample size are still needed to provide conclusive evidence on the benefit of antioxidants as a treatment modality for patients with male infertility.

https://www.clevelandclinic.org/reproductiveresearchcenter/docs/agradoc139.pdf

Role of antioxidants in treatment of male infertility: an overview of the literature

clearly independent measures of sperm quality. Therefore, pathogenic ROS levels or poor-quality sperm chromatin structure may be considered indicative of male subfertility [1,2].IDIOPATHIC INFERTILITYMen with idiopathic infertility generally present with signiﬁcantly higher seminal ROS levels and lower antioxidant properties than healthy controls [3]. Therefore, it appears that the presence of OS in infertile normozoospermic men may be the cause behind previously unexplained cases of infertility. Similarly, sperm DNA damage analysis may reveal hidden sperm DNA abnormalities in infertile men with normal standard sperm values who were diagnosed with idiopathic infertility. The increase in sperm DNA damage in these patients may be partly related to high levels of seminal OS.Finally and importantly, some conditions may pass unnoticed but still affect the sperm genomic integrity. In one case report [4], a fertile patient who had inﬂuenza and a 1-day fever of 39.9 ∞ C presented with a relatively high percentage of sperm with damaged DNA (36%) 18 days after the onset of his fever.GENITAL TRACT INFECTIONSGenital tract infections are usually associated with leukocytospermia and elevated ROS levels, as leukocytes represent the major source of ROS production in ejaculates. Although leukocytes are a constant component of human ejaculates and virtually no semen sample is free of them, if the prevalence of leukocytes exceeds normal values (1 ¥ 10

/pdf/oxidative-stress-dna-damage-and-apoptosis-in-male-5eod5ckxjh.pdf

Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach

http://ccf.org/reproductiveresearchcenter/docs/agradoc217.pdf

Oxidative stress in an assisted reproductive techniques setting.

The greatest paradox of aerobic respiration is that oxygen, which is essential for energy production, may also be detrimental because it leads to the production of reactive oxygen species (ROS) (Saleh and Agarwal, 2002). When levels of reactive oxygen species (ROS) overwhelm the body’s antioxidant defense system, oxidative stress (OS) occurs. OS is a condition in which the elevated levels of ROS damage cells, tissues, or organs (Moller et al, 1996; Sharma and Agarwal, 1996; Saleh et al, 2003). ROS are free radicals that play a significant role in many of the sperm physiological processes such as capacitation, hyperactivation, and sperm-oocyte fusion (Aitken et al, 2004; Allamaneni et al, 2004; de Lamirande et al, 1998). However, they also trigger many pathological processes in the male reproductive system, and these processes have been implicated in cancers of the bladder and prostate, as well as in male infertility (Bankson et al, 1993; Hietanen et al, 1994; Agarwal and Saleh, 2002). Spermatozoa are sensitive to OS because they lack cytoplasmic defenses (Donnelly et al, 1999; Saleh and Agarwal, 2002). Moreover, the sperm plasma membrane contains lipids in the form of polyunsaturated fatty acids, which are vulnerable to attack by ROS. ROS, in the presence of polyunsaturated fatty acids, triggers a chain of chemical reactions called lipid peroxidation (Agarwal et al, 1994; Kobayashi et al, 2001; Zalata et al, 2004). ROS can also damage DNA by causing deletions, mutations, and other lethal genetic effects (Moustafa et al, 2004; Tominaga et al, 2004). It is difficult to block the OS-

https://onlinelibrary.wiley.com/doi/pdf/10.2164/jandrol.05016

Tamer M. Said

Papers

Role of sperm chromatin abnormalities and DNA damage in male infertility

Role of antioxidants in treatment of male infertility: an overview of the literature

Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach

Oxidative stress in an assisted reproductive techniques setting.

Prevention of oxidative stress injury to sperm