spermatogenesis is the process by which a complex , interdependent population of germ cells produces spermatozoa by mitosis and meiosis . the process of spermatogenesis takes place within the coiled seminiferous tubules , and continues from puberty to old age . it consists of various stages beginning with the formation of germ cells ( spermatogonia ) in the germinal epithelium followed by their progressive development into primary and secondary spermatocytes , and finally mature spermatozoa . spermatogenesis is highly dependent upon optimal conditions for the process to occur correctly , and is essential for sexual reproduction . dna methylation and histone modification have been implicated in the regulation of this process ( 1 ) . the process of spermatogenesis is highly organized ; proliferation and differentiation of the male germ cells and the intratesticular and extratesticular mechanisms of regulation of spermatogenesis can be disturbed at every level ( 2 ) . this may occur as a result of environmental influences or may be due to diseases that directly or indirectly affect spermatogenesis , leading to infertility in men . male factors have been reported to contribute between 3055% ( 36 ) to global cases of infertility . ( 2009 ) reported that male factor contributes averagely to half of the cases of infertility in couples ( 7 ) . male factor infertility is seen as an alteration in sperm concentration and/or motility or morphology in at least one sample of two sperm analyses , collected between 1 and 4 weeks ( 8) . apart from known hormonal disturbances ( 9 ) , other physical and psychological problems may also contribute to male infertility . these include environmental factors such as diet and toxic elements ( 1011 ) , genetic aberrations ( 1213 ) , infection and inflammation ( 14 ) etc . infection remains the commonest cause of infertility in africa particularly in sub - saharan africa ( 1516 ) . when there is an infection to the reproductive tract , one important function of the innate immune system is to recruit more phagocytic cells and effector molecules to the site of the infection through the release of a battery of cytokines and other inflammatory mediators that have profound effects on subsequent events . these include ( i ) ejaculatory duct obstruction : this is a common cause of male infertility and infections have been reported to be present in at least 2050% of these men ( 17 ) . ( ii ) epididymitis : this is the inflammation of the epididymis , a structure in the male reproductive system that joins the testes and the vas deferens . inflammation of the epididymis may result in further complications such as scrotal swelling , pain , penile discharge and blood in urine . ( iii ) infections : inflammation results from sexually transmitted infections e.g. gonorrhoea , chlamydia , escherichia coli was reported to be the main cause of epididymitis in older men , but other types of bacteria including mycobacteria and ureaplasma may also cause this condition . ( iv ) urethritis : there could also be bladder or urethral infection that moves to the epididymis . in children , mumps and other viral infections testicular torsion : this is a common problem affecting fertility that is caused by a supportive tissue abnormality which allows the testes to twist inside the scrotum which is characterized by extreme swelling . ( vi ) varicocoele : this is an enlargement of the internal spermatic veins that drain blood from the testicle to the abdomen ( back to the heart ) . a varicocoele develops when the one way valves in the spermatic veins are damaged causing an abnormal back flow of blood from the abdomen into the scrotum creating a hostile environment for sperm development . ( vii ) several other causes include male urogenital obstruction , chronic prostatitis , inflammation of one or both testes ( orchitis ) , and drug therapy . it is important to note that when any or the above processes occur in the male genital tract , the immune system will respond to the pathogens and possible tissue damage . the collateral damage caused by this type of inflammation usually accumulates slowly , sometimes asymptomatically for years and further leads to tissue deterioration ( 18 ) . the inflammatory system can be linked to a sprinkler system that prevents fire from spreading in a building . while the intention of the process is to limit damage and restore function ( positive ) , the response itself can cause significant harm . one undesirable consequence of inflammation , for example , is that some enzymes and toxic products contained within phagocytic tissues are inevitably released , damaging cells and tissues . three principal changes occur when there is a case of acute inflammation ; an increased blood supply to the affected area , an increase in capillary permeability allowing larger serum molecules to enter the tissues and an increase in leukocyte migration into the tissue . when there is a failure to eliminate the infectious agent , it leads to chronic inflammation . this is characterized with recruitment and activation of macrophages , lymphocytes and other cells which trigger a coordinated action of cytokines . in contrast to acute inflammation , where the host response leads to elimination of the irritant , followed by recovery involving tissue regeneration or repair , chronic inflammation is characterized by inflammation and repair occurring concurrently , rather than consecutively . note that repair is always a feature of chronic inflammation because it is associated with irritants that cause destruction of tissue architecture . repair is typically achieved by ingrowth of granulation tissue , which includes macrophages , fibroblasts and new blood vessels ( 19 ) . the direct association between acute or chronic inflammation and the development of infertility constitute important issues in contemporary medicine . the reduced semen quality during the inflammatory process can result from impairment of accessory gland functions , obstruction of sperm transport , and dysregulation of spermatogenesis ( 2021 ) . inflammatory cytokines usually act locally , since they are produced by locally activated cells or produced temporarily after the stimulus has been activated . in male gonads , cytokines are also produced physiologically and have been reported to be involved in the normal function of the organ ( 2223 ) . in this respect , they appear as the natural components of seminal plasma ( 24 ) . the main source of cytokines in the male gonad is testicular macrophages , although some cytokines ( il1 and il6 ) were also observed by some authors to be produced by leydig and sertoli cells ( 25 ) . cytokines , particularly tnf , controls movement of leukocytes into tissues when there is tissue damage . tnf is produced primarily by macrophages and other mononuclear phagocytes and has many functions in the development of inflammation and the activation of other leukocytes . notably , tnf induces adhesion molecules and chemokines on the endothelium and activates the microbial systems of phagocytes . inflammatory responses , which are operationally characterized by pain , redness , heat and swelling at the site of infection in the male genital tract reflect two types of changes in the seminal vesicles . the first of these is an increase in diameter , leading to an increased local seminal flow  hence the heat and redness and a reduction in the velocity of seminal flow , especially along the surface of local seminal vesicles . inflammatory damage on the male genital tract leads to the increased generation of reactive oxygen species ( ros ) . in addition , ros or free radical overproduction associated with inflammatory reactions may be caused by pathological , bacterial strains that colonize the reproductive tract ( 2728 ) . free radicals are group of highly reactive chemical molecules with one or more unpaired electrons that can oxidatively modify bio - mole cules they encounter . reacting almost immediately with any substance in their environment , results in chains of reaction leading to cellular damage ( 29 ) . ( 2003 ) showed superoxide , hydroxyl and hydrogen hydroxide radicals as the major ros present in seminal plasma ( 30 ) . to maintain normal cell function , excess ros must be continuously inactivated by seminal plasma antioxidants . oxidative stress arises when excess free radicals overwhelm the antioxidant defence of the male reproductive tract ( 3132 ) , thereby damaging male reproductive tract . it is interesting to note that seminal oxidative stress was earlier reported to correlate negatively with sperm concentration , motility and function ( 33 ) . these observations also suggest that cytokines , mediators of oxidative damage may also have an impact on the quality of semen and male fertility . the participation of some cytokines in the regulation of fertility is dependent upon their concentration ; for example , a study by naz and evans ( 1998 ) showed that interleukin 12 correlated with sperm density and sperm morphology ( 34 ) . increased levels of interleukin 6 were also observed in infertile men by the same author in an earlier study conducted . high levels of certain cytokines in semen are often linked with a decrease in the quality of the seminological parameters ( 35 ) . more recent studies have shown increased tnf in semen to be associated with reduced sperm count , sperm motility , and sperm morphology ( 3637 ) . the increased levels of this cytokine cause apoptosis in semen as a result of proliferation and differentiation of beta cells , proliferation of t cells and natural killer cells . interleukin1 alpha ( il1  ) and interleukin1 beta ( il1 ) also induce apoptosis in semen via proliferation and differentiation of beta cells , chemoattraction of leucocytes to the site of inflammation and induction of neutrophils and monocyte generation . these cytokines were also observed to adversely affect quality of semen . in another study reported by the same author , increased levels of il1  were associated with a decrease in sperm motility ( 38 ) . these results were associated with a simultaneous increase in seminal levels of reactive oxygen species as well as malondiadehyde ( mda ) ; a product of lipid peroxidation , consequent to oxidative damage . the same cytokines that act as elements of immune modulation for the male gonad appear in large concentrations in semen during infection and when the tissues are damaged . while some studies have associated with disturbed spermatogenesis ( 4142 ) , others have linked it to harmful influence of environmental factors ( 43 ) , and atypical sexual behavior ( 44 ) . under inflammatory conditions , white blood cells ( wbc ) in the semen leak from the site of infection or inflammation . in normal conditions , leukocytes are restricted to the center of seminal vesicles , where the flow is fastest . in inflammatory sites , the blood vessels feeding the testis are dilated allowing the leukocytes to move out of the center of the blood vessels and interact with the vascular endothelium . in addition to these changes , there is an increase in permeability , leading to the local accumulation of fluid  hence the swelling and pain as well as the accumulation of immunoglobulins , complement and other semen proteins in the genital tract . the migration of leukocytes out of the seminal vesicles depends on adhesive interactions activated by the release of inflammatory mediators . thus , infection or physical damage to male genital tract sets in motion the recruitment of phagocytic cells to the site of damage . neutrophils exposed to tnf are activated to mediate a respiratory burst that generates oxygen radicals and nitric oxide , and release their stored granule contents , contributing both to host defence and to local tissue destruction . in a study designed to evaluate the clinical relevance of inflammatory cytokines , such as tnf and il1 in seminal plasma of infertile men , the levels of these cytokines correlated significantly with leukocyte counts ( 45 ) . levels of ros can be reduced by augmenting the scavenging capacity of the seminal plasma with antioxidants ( 46 ) . administration of antioxidants to infertile men has been reported to reduce oxidative stress in their sperm cells , improving motility , particularly in asthenospermic patients ( 47 ) . although the advantage of micronutrients and antioxidant supplementations as interventions in male infertility remains controversial , in a previous study , an inverse relationship of sperm count and viability was seen in serum and seminal zinc levels , respectively in infertile african men ( 48 ) . oxidants can also damage cells by starting chemical chain reactions such as lipid peroxidation , or by oxidizing dna or proteins ( 49 ) . damage to dna can cause mutations and possibly cancer , and can be reversed by dna repair mechanism ( 5051 ) while damage to proteins causes enzyme inhibition , denaturation , and protein degradation ( 52 ) . in sperm cells , lipid peroxidation reduces membrane fluidity , resulting in the inhibition of normal cellular components for fertilization . patients with high oxidative stress were found to have sperm with multiple genes and double genes dna strand breaks in their seminal fluid ( 53 ) . sperm dna is usually protected by its compact organization and by antioxidants in the seminal plasma . spermatozoa themselves are incapable of dna repair and must depend on the oocyte for repair after fertilization ; however , knowledge concerning the process remains limited ( 54 ) . ros exposure may result in dna base modification , production of free base sites , deletions , frame shifts , dna cross  links and chromosomal aberrations ( 5556 ) . sikka ( 2004 ) reported that ros promoted apoptosis ( 57 ) , which may lead to a decrease in sperm viability and density . it is not fully established if sperm apoptosis caused by oxidative stress can also be reversed . however , with proper molecular framework of apoptosis , specific apoptosis inhibitors may have a role in promoting germ cell survival . current research is underway to identify the agents that may manipulate the apoptotic machinery for therapeutic benefits . one should bear in mind that in the context of male infertility , seminal oxidative stress , sperm dna damage and apoptosis are interlinked and constitute a unified pathogenic mechanism . the impact of these factors , their clinical significance and management options have always been a subject of controversy . despite few clinical trials reporting the positive effects of antioxidant administration on sperm dna integrity , such as n - acetyl  cysteine , studies on apoptotic inhibitors have only been evaluated in vitro ; their efficacy still remains to be validated in vivo . selenium was reported to protect against sperm dna damage and is required for normal testicular development , spermatogenesis , motility , and sperm function ( 59 ) . selenium , an integral part of the antioxidant enzyme ; glutathione peroxidase was implicated to play important role in male fertility in a previous study ( 60 ) . assisted reproductive technologies ( arts ) , which include in vitro fertilization ( ivf ) , and intracytoplasmic sperm injection ( icsi ) , currently been used to treat infertility may not be successful when semen samples that contain a high dna damage are involved . levels of the oxidative dna damage marker , 8hydroxyl2deoxyguanosine have been reported to be elevated in infertile men ( 61 ) . studies have associated a high rate of miscarriage after icsi , which possibly reflects the fact that compromised spermatozoa are sometimes used and they lead to irreparable dna damage in the embryo ( 62 ) . in patients with obstructive azoospermia , spermatozoa are often surgically retrieved from epididymis or testicular tissue . in general , however , the use of testicular spermatozoa is preferred over epididymal spermatozoa , because the former have less dna damage and a better developmental potential ( 63 ) . these include ( i ) ejaculatory duct obstruction : this is a common cause of male infertility and infections have been reported to be present in at least 2050% of these men ( 17 ) . ( ii ) epididymitis : this is the inflammation of the epididymis , a structure in the male reproductive system that joins the testes and the vas deferens . inflammation of the epididymis may result in further complications such as scrotal swelling , pain , penile discharge and blood in urine . ( iii ) infections : inflammation results from sexually transmitted infections e.g. gonorrhoea , chlamydia , escherichia coli was reported to be the main cause of epididymitis in older men , but other types of bacteria including mycobacteria and ureaplasma may also cause this condition . ( iv ) urethritis : there could also be bladder or urethral infection that moves to the epididymis . in children , mumps and other viral infections testicular torsion : this is a common problem affecting fertility that is caused by a supportive tissue abnormality which allows the testes to twist inside the scrotum which is characterized by extreme swelling . ( vi ) varicocoele : this is an enlargement of the internal spermatic veins that drain blood from the testicle to the abdomen ( back to the heart ) . a varicocoele develops when the one way valves in the spermatic veins are damaged causing an abnormal back flow of blood from the abdomen into the scrotum creating a hostile environment for sperm development . ( vii ) several other causes include male urogenital obstruction , chronic prostatitis , inflammation of one or both testes ( orchitis ) , and drug therapy . it is important to note that when any or the above processes occur in the male genital tract , the immune system will respond to the pathogens and possible tissue damage . the collateral damage caused by this type of inflammation usually accumulates slowly , sometimes asymptomatically for years and further leads to tissue deterioration ( 18 ) . the inflammatory system can be linked to a sprinkler system that prevents fire from spreading in a building . while the intention of the process is to limit damage and restore function ( positive ) , the response itself can cause significant harm . one undesirable consequence of inflammation , for example , is that some enzymes and toxic products contained within phagocytic tissues are inevitably released , damaging cells and tissues . three principal changes occur when there is a case of acute inflammation ; an increased blood supply to the affected area , an increase in capillary permeability allowing larger serum molecules to enter the tissues and an increase in leukocyte migration into the tissue . when there is a failure to eliminate the infectious agent , it leads to chronic inflammation . this is characterized with recruitment and activation of macrophages , lymphocytes and other cells which trigger a coordinated action of cytokines . in contrast to acute inflammation , where the host response leads to elimination of the irritant , followed by recovery involving tissue regeneration or repair , chronic inflammation is characterized by inflammation and repair occurring concurrently , rather than consecutively . note that repair is always a feature of chronic inflammation because it is associated with irritants that cause destruction of tissue architecture . repair is typically achieved by ingrowth of granulation tissue , which includes macrophages , fibroblasts and new blood vessels ( 19 ) . the direct association between acute or chronic inflammation and the development of infertility constitute important issues in contemporary medicine . the reduced semen quality during the inflammatory process can result from impairment of accessory gland functions , obstruction of sperm transport , and dysregulation of spermatogenesis ( 2021 ) . inflammatory cytokines usually act locally , since they are produced by locally activated cells or produced temporarily after the stimulus has been activated . in male gonads , cytokines are also produced physiologically and have been reported to be involved in the normal function of the organ ( 2223 ) . in this respect , they appear as the natural components of seminal plasma ( 24 ) . the main source of cytokines in the male gonad is testicular macrophages , although some cytokines ( il1 and il6 ) were also observed by some authors to be produced by leydig and sertoli cells ( 25 ) . cytokines , particularly tnf , controls movement of leukocytes into tissues when there is tissue damage . tnf is produced primarily by macrophages and other mononuclear phagocytes and has many functions in the development of inflammation and the activation of other leukocytes . notably , tnf induces adhesion molecules and chemokines on the endothelium and activates the microbial systems of phagocytes . inflammatory responses , which are operationally characterized by pain , redness , heat and swelling at the site of infection in the male genital tract reflect two types of changes in the seminal vesicles . the first of these is an increase in diameter , leading to an increased local seminal flow  hence the heat and redness and a reduction in the velocity of seminal flow , especially along the surface of local seminal vesicles . inflammatory damage on the male genital tract leads to the increased generation of reactive oxygen species ( ros ) . in addition , ros or free radical overproduction associated with inflammatory reactions may be caused by pathological , bacterial strains that colonize the reproductive tract ( 2728 ) . free radicals are group of highly reactive chemical molecules with one or more unpaired electrons that can oxidatively modify bio - mole cules they encounter . reacting almost immediately with any substance in their environment , results in chains of reaction leading to cellular damage ( 29 ) . ( 2003 ) showed superoxide , hydroxyl and hydrogen hydroxide radicals as the major ros present in seminal plasma ( 30 ) . to maintain normal cell function , excess ros must be continuously inactivated by seminal plasma antioxidants . oxidative stress arises when excess free radicals overwhelm the antioxidant defence of the male reproductive tract ( 3132 ) , thereby damaging male reproductive tract . it is interesting to note that seminal oxidative stress was earlier reported to correlate negatively with sperm concentration , motility and function ( 33 ) . these observations also suggest that cytokines , mediators of oxidative damage may also have an impact on the quality of semen and male fertility . the participation of some cytokines in the regulation of fertility is dependent upon their concentration ; for example , a study by naz and evans ( 1998 ) showed that interleukin 12 correlated with sperm density and sperm morphology ( 34 ) . increased levels of interleukin 6 were also observed in infertile men by the same author in an earlier study conducted . high levels of certain cytokines in semen are often linked with a decrease in the quality of the seminological parameters ( 35 ) . more recent studies have shown increased tnf in semen to be associated with reduced sperm count , sperm motility , and sperm morphology ( 3637 ) . the increased levels of this cytokine cause apoptosis in semen as a result of proliferation and differentiation of beta cells , proliferation of t cells and natural killer cells . interleukin1 alpha ( il1  ) and interleukin1 beta ( il1 ) also induce apoptosis in semen via proliferation and differentiation of beta cells , chemoattraction of leucocytes to the site of inflammation and induction of neutrophils and monocyte generation . these cytokines were also observed to adversely affect quality of semen . in another study reported by the same author , increased levels of il1  were associated with a decrease in sperm motility ( 38 ) . these results were associated with a simultaneous increase in seminal levels of reactive oxygen species as well as malondiadehyde ( mda ) ; a product of lipid peroxidation , consequent to oxidative damage . the same cytokines that act as elements of immune modulation for the male gonad appear in large concentrations in semen during infection and when the tissues are damaged . while some studies have associated with disturbed spermatogenesis ( 4142 ) , others have linked it to harmful influence of environmental factors ( 43 ) , and atypical sexual behavior ( 44 ) . under inflammatory conditions , white blood cells ( wbc ) in the semen leak from the site of infection or inflammation . in normal conditions , leukocytes are restricted to the center of seminal vesicles , where the flow is fastest . in inflammatory sites , the blood vessels feeding the testis are dilated allowing the leukocytes to move out of the center of the blood vessels and interact with the vascular endothelium . in addition to these changes , there is an increase in permeability , leading to the local accumulation of fluid  hence the swelling and pain as well as the accumulation of immunoglobulins , complement and other semen proteins in the genital tract . the migration of leukocytes out of the seminal vesicles depends on adhesive interactions activated by the release of inflammatory mediators . thus , infection or physical damage to male genital tract sets in motion the recruitment of phagocytic cells to the site of damage . neutrophils exposed to tnf are activated to mediate a respiratory burst that generates oxygen radicals and nitric oxide , and release their stored granule contents , contributing both to host defence and to local tissue destruction . in a study designed to evaluate the clinical relevance of inflammatory cytokines , such as tnf and il1 in seminal plasma of infertile men , the levels of these cytokines correlated significantly with leukocyte counts ( 45 ) . levels of ros can be reduced by augmenting the scavenging capacity of the seminal plasma with antioxidants ( 46 ) . administration of antioxidants to infertile men has been reported to reduce oxidative stress in their sperm cells , improving motility , particularly in asthenospermic patients ( 47 ) . although the advantage of micronutrients and antioxidant supplementations as interventions in male infertility remains controversial , in a previous study , an inverse relationship of sperm count and viability was seen in serum and seminal zinc levels , respectively in infertile african men ( 48 ) . oxidants can also damage cells by starting chemical chain reactions such as lipid peroxidation , or by oxidizing dna or proteins ( 49 ) . damage to dna can cause mutations and possibly cancer , and can be reversed by dna repair mechanism ( 5051 ) while damage to proteins causes enzyme inhibition , denaturation , and protein degradation ( 52 ) . in sperm cells , lipid peroxidation reduces membrane fluidity , resulting in the inhibition of normal cellular components for fertilization . patients with high oxidative stress were found to have sperm with multiple genes and double genes dna strand breaks in their seminal fluid ( 53 ) . sperm dna is usually protected by its compact organization and by antioxidants in the seminal plasma . spermatozoa themselves are incapable of dna repair and must depend on the oocyte for repair after fertilization ; however , knowledge concerning the process remains limited ( 54 ) . ros exposure may result in dna base modification , production of free base sites , deletions , frame shifts , dna cross  links and chromosomal aberrations ( 5556 ) . sikka ( 2004 ) reported that ros promoted apoptosis ( 57 ) , which may lead to a decrease in sperm viability and density . it is not fully established if sperm apoptosis caused by oxidative stress can also be reversed . however , with proper molecular framework of apoptosis , specific apoptosis inhibitors may have a role in promoting germ cell survival . current research is underway to identify the agents that may manipulate the apoptotic machinery for therapeutic benefits . one should bear in mind that in the context of male infertility , seminal oxidative stress , sperm dna damage and apoptosis are interlinked and constitute a unified pathogenic mechanism . the impact of these factors , their clinical significance and management options have always been a subject of controversy . despite few clinical trials reporting the positive effects of antioxidant administration on sperm dna integrity , such as n - acetyl  cysteine , studies on apoptotic inhibitors have only been evaluated in vitro ; their efficacy still remains to be validated in vivo . selenium was reported to protect against sperm dna damage and is required for normal testicular development , spermatogenesis , motility , and sperm function ( 59 ) . selenium , an integral part of the antioxidant enzyme ; glutathione peroxidase was implicated to play important role in male fertility in a previous study ( 60 ) . assisted reproductive technologies ( arts ) , which include in vitro fertilization ( ivf ) , and intracytoplasmic sperm injection ( icsi ) , currently been used to treat infertility may not be successful when semen samples that contain a high dna damage are involved . levels of the oxidative dna damage marker , 8hydroxyl2deoxyguanosine have been reported to be elevated in infertile men ( 61 ) . studies have associated a high rate of miscarriage after icsi , which possibly reflects the fact that compromised spermatozoa are sometimes used and they lead to irreparable dna damage in the embryo ( 62 ) . the degree of inflammations in other genital tract may also affect success rate . in patients with obstructive azoospermia , spermatozoa however , the use of testicular spermatozoa is preferred over epididymal spermatozoa , because the former have less dna damage and a better developmental potential ( 63 ) . varieties of disorders ranging from hormonal disturbances to physical problems , to psychological anomaly have been implicated in male infertility . although many treatment options are now available , in many cases success rate is still low . often , male infertility is caused by infections and testicular damage with resultant inflammation . inflammatory reactions within the male genital tract have a negative impact on sperm quality and consequently , infertility . furthermore , the process of inflammation generates ros in addition to inherent oxidative stress generated by sperm cells increasing exerted toxic effects on human spermatozoa . the imbalance between prooxidative and antioxidative substances in semen leads to metabolic and functional disorders of the male germ cells and may be a primary cause of some types of infertility . art may be more successful when markers of oxidative stress and dna damage in semen , such as 8hydroxyl2deoxyguanosine are evaluated prior to insemination . all possible interventions to abrogate or reduce the consequential effect of inflammation on male reproduction , particularly seminal oxidative stress , sperm dna damage and apoptosis will not only reduce male reproductive failure but may also increase success rate of assisted reproductive technology .