Omega-3s for Male Fertility
This article at a glance 
A critical interpretation of the existing literature has led several specialists to indicate that an association between male infertility and varicocele exists, but that a causal relationship remains to be unequivocally demonstrated. Recent studies indicate that varicocele repair and removal does improve sperm development and can increase male fertility, suggesting that the impairment of testicular function by varicocele is reversible. Given the lack of a complete mechanistic understanding of how varicocele relates to male infertility, further studies are important, especially since varicocele is found in up to 15% of adolescents, and may explain 35% of male infertility prevalence. A second condition of significant relevance to male infertility is asthenozoospermia. Asthenozoospermia, roughly translated as “weak” or “soft” sperm, relates to sperm with inferior capacity to fertilize an egg mainly due to low spermatozoa motility. Reports on incremental decreases in semen quality since the 1930´s have given the impression that some environmental factors markedly and progressively affect male fertility. Critical inspections of the meta-analyses that have led to these conclusions has indicated that many factors are at play in determining semen quality, and that serious methodological inconsistencies between studies may invalidate the conclusions that a drastic rise in male infertility has occurred in the last century. Asthenozoospermia is a relevant problem though, and optimal sperm quality is certainly compromised in a very large proportion of men today. 
Spermatozoa from asthenozoospermic men have been reported to have structural defects in the energy-generating mid-piece, with deformed mitochondria and improper formation of the annulus that connects the mid-piece with the flagellum. Changes in the membrane composition of asthenozoospermic spermatozoa have also been identified. These comprise increases in specific mono-unsaturated fatty acids such as oleic acid, changes in the content of saturated fatty acids, such as stearic and palmitic acid, and decreases in omega-3 polyunsaturated fatty acids (omega-3 LCPUFA) and in the ratio of omega-3 to omega-6 PUFA. The omega-3 LCPUFA docosahexaenoic acid DHA has been identified to be lower in membranes of spermatozoa from asthenozoospermic men, suggesting that it contributes to good spermatozoal motility by providing the right biophysical properties of the spermatozoal membrane. The presence of trans-fatty acids in sperm and high intake of saturated fatty acids have also been associated with lower sperm counts. Since sustained higher intake of saturated fatty acids and trans-fatty acids, and decreased intakes of PUFA, are associated with an unhealthy diet, it is important to further assess if a relation between poor dietary habits and male infertility exists. A relationship between dietary intake of specific fatty acids and asthenozoospermia is suspected but has not been addressed. Two recent case-control studies now provide new indications that omega-3 LCPUFA have a significant influence over male fertility by reducing the incidence of asthenozoospermia and the outcome of varicocele. The first study, by Eslamian and colleagues from the National Nutrition and Food Technology Research Institute, the Shahid Beheshti University of Medical Sciences, and the Avicenna Research Institute, in Tehran, Iran, has investigated the relation between dietary intake of different fatty acids and asthenozoospermia. The second study by Tang and colleagues from the National Health and Family Planning Commission of China, in collaboration with various laboratories in China and the US, has studied PUFA content in spermatozoa from infertile men with varicocele. 
The study by Eslamian and colleagues was undertaken to examine the relationship between dietary fatty acid intake and the incidence of asthenozoospermia, with concurrent assessment of a range of additional lifestyle and demographic variables. One hundred and seven men with asthenozoospermia and 235 normozoospermic control subjects were examined. Semen was collected from men aged between 20 and 40 years at a specialized infertility clinic. The asthenozoospermic men had been recently diagnosed. The motility of sperm was determined according to WHO guidelines, with asthenozoospermia defined as motility less than 40%, and progressive motility below 32%, within one hour of ejaculation. All asthenozoospermic men produced sperm with normal sperm counts (above 15 million per ml) and normal spermatozoa morphology (less than 4% abnormally shaped cells). Participants taking fatty acid supplements or suffering from any nutrition-related condition (cardiovascular diseases, diabetes, cancer, osteoporosis) or other disorders related to male infertility (endocrine hypogonadism, varicocele), were excluded from the study. Semen analysis was carried out on two samples per subject donated within a 1 month period. Assessment of dietary intake was made through a validated semi-quantitative food-frequency questionnaire and a food content table. Information on the dietary habits of the study participants one year prior to diagnosis of asthenozoospermia or study initiation (normozoospermia) was available for all participants. Intake of fatty acids was adjusted for total energy intake. Comparison of asthenozoospermic men with normozoospermic men indicated that among the recorded lifestyle and demographic variables, asthenozoospermia was associated with higher body mass index, smoking habits, and the presence of heavy traffic near home. The total motility of spermatozoa from asthenozoospermic men was 24.6% compared to 59.2% in normozoospermia. The consumption of a number of individual fatty acids differed significantly between both groups of men. In asthenozoospermic subjects the intake of total fatty acids, saturated fatty acids, trans-fatty acids, palmitic acid, and stearic acid was higher than in normozoospermic men. In contrast, the average intake of PUFA, omega-3 PUFA, EPA and DHA was significantly lower. No significant differences were identified for the intake of oleic acid, linoleic acid, total omega-6 PUFA, and alpha-linolenic acid (ALA). Study subjects with the highest tertile of intakes of omega-3 PUFA and DHA had the lowest probability to suffer asthenozoospermia (odds ratios of 0.68 and 0.53, respectively). In contrast, total trans-fatty acid intake and saturated fatty acid intake were associated with an increased risk for asthenozoospermia (odds ratios of 2.53 and 1.85 for the highest tertiles of intake). In the second case-control study, by Tang and colleagues, semen quality, spermatozoa membrane fatty acid composition, and oxidative damage to spermatozoal DNA were studied in three groups of men. The first group was composed of 92 infertile men with varicocele, the second group (n=99) were infertile but did not have varicocele, and the third group was composed of 95 fertile male volunteers without a prior report of infertility or varicocele. There were no differences in average age (35 years), body-mass index (not overweight), abstinence before donating sperm, or ejaculate volume. Infertile men, with or without varicocele, had significantly lower sperm counts, motility, vitality (percentage of living spermatozoa), and had a higher percentage of spermatozoa that were deformed. In men with varicocele the levels of ALA, EPA, DHA and total omega-3 were significantly lower than in control subjects. The levels of AA and linoleic acid were higher. The ratio of omega-6 to omega-3 fatty acids was twice that in control subjects. There was also a small but statistically significant increase in the level of 8-hydroxy-2-deoxyguanosine (8-OHdG) in the semen plasma. 8-hydroxy-2-deoxyguanosine is formed by free-radical-mediated oxidative damage to DNA, and is indicative of a severe depletion of endogenous antioxidants when a tissue is exposed to some major noxious event. In infertile men without varicocele, significant decreases in ALA, EPA and total omega-3 PUFA and an increase in the omega-6 to omega-3 ratio were also noted, although the changes were less than in men with varicocele, and no changes in 8-OHdG were detectable. 
When varicocele was graded by severity into three classes, significantly higher levels of AA, total omega-6 and 8-OHdG were present in spermatozoa of men with the highest two grades of varicocele severity. In contrast, in men with more severe forms of varicocele, ALA, EPA, DHA and total omega-3 PUFA levels in spermatozoa were lower. The omega-6 to omega-3 ratio hence was significantly higher as varicocele severity increased. Such correlations were maintained when the relationships between fatty acid content and spermatozoal motility were inspected. Individual omega-3 LCPUFA and total omega-3 levels were positively related to motility. The levels of ALA, EPA, DHA and total omega-3 were inversely correlated with the seminal plasma level of 8-OHdG. In summary, the two studies bring forward interesting new aspects of potential deficits or derangements of omega-3 LCPUFA intake and spermatozoal membrane composition in male infertility disorders. A significant negative association between the intake of omega-3 LCPUFA, and DHA in particular, and the risk of having asthenozoospermia has been recognized. In varicocele compelling evidence has been produced that indicates that the disorder is related to lower levels of omega-3 LCPUFA in spermatozoa. In addition, varicocele appears to be associated with increased free radical-mediated macromolecular oxidative damage, and this is suggestive of a local protective role for omega-3 LC PUFA in spermatozoa. Both studies highlight the need for controlled dietary intervention trials, and further research is required to determine how dietary omega-3 LCPUFAs might improve asthenozoospermia and varicocele. It will be interesting to watch future developments that may qualify two frequent male infertility disorders to have a modifiable outcome through dietary intervention. Eslamian G, Amirjannati N, Rashidkhani B, Sadeghi MR, Baghestani AR, Hekmatdoost A. Dietary fatty acid intakes and asthenozoospermia: a case-control study. Fertil. Steril. 2015;103(1):190-198. [PubMed] Tang LX, Yuan DJ, Wang QL, Jiang F, Guo J, Tang YG, Zheng LX, Kang JX. Association of decreased spermatozoa omega-3 fatty acid levels and increased oxidative DNA damage with varicocele in infertile men: a case control study. Reprod. Fertil. Dev. 2014. [PubMed] Worth Noting Avicenna Research Institute – Infertility Clinic. http://www.avicenna.ac.ir/index.php/en/avicenna-infertility-clinic Conquer JA, Martin JB, Tummon I, Watson L,Tekpetey F. Fatty acid analysis of blood serum, seminal plasma, and spermatozoa of normozoospermic vs. asthenozoospermic males. Lipids 1999;34(8):793-799. [PubMed] Ficarra V, Crestani A, Novara G, Mirone V. Varicocele repair for infertility: what is the evidence? Curr. Opin. Urol. 2012;22(6):489-494. [PubMed] Harika RK, Eilander A, Alssema M, Osendarp SJ, Zock PL. Intake of fatty acids in general populations worldwide does not meet dietary recommendations to prevent coronary heart disease: a systematic review of data from 40 countries. Ann. Nutr. Metab. 2013;63(3):229-238. [PubMed] Jorgensen N, Joensen UN, Jensen TK, Jensen MB, Almstrup K, Olesen IA, Juul A, Andersson AM, Carlsen E, Petersen JH, Toppari J, Skakkebaek NE. Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men. BMJ Open 2012;2(4): e000990. [PubMed] Jouannet P, Wang C, Eustache F, Kold-Jensen T, Auger J. Semen quality and male reproductive health: the controversy about human sperm concentration decline. Acta Pathol. Microbiol. Immunol. Scand. 2001;109(5):333-344. [PubMed] Lhuillier P, Rode B, Escalier D, Lores P, Dirami T, Bienvenu T, Gacon G, Dulioust E, Toure A. Absence of annulus in human asthenozoospermia: case report. Hum. Reprod. 2009;24(6):1296-1303. [PubMed] Merzenich H, Zeeb H, Blettner M. Decreasing sperm quality: a global problem? BMC Public Health 2010;10:24. [PubMed] Mirmiran P, Esfahani FH, Mehrabi Y, Hedayati M, Azizi F. Reliability and relative validity of an FFQ for nutrients in the Tehran lipid and glucose study. Public Health Nutr. 2010;13(5):654-662. [PubMed] Pelliccione F, Micillo A, Cordeschi G, D'Angeli A, Necozione S, Gandini L, Lenzi A, Francavilla F, Francavilla S. Altered ultrastructure of mitochondrial membranes is strongly associated with unexplained asthenozoospermia. Fertil. Steril. 2011;95(2):641-646. [PubMed] Shahid Beheshti University of Medical Sciences. http://en.sbmu.ac.ir/ Varicocele. Weill Cornell Medical College, Department of Urology https://www.cornellurology.com/clinical-conditions/male-infertility/general-information/varicocele/ World Health Organization. Manual for the Standardized Investigation and Diagnosis and Management of the Infertile Male. Cambridge University Press, Cambridge, UK 2000. http://www.who.int/reproductivehealth/publications/infertility/0521774748/en/ World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Cambridge University Press, Cambridge, UK 2010. http://www.who.int/reproductivehealth/publications/infertility/9789241547789/en/ Zini A, Boman JM. Varicocele: red flag or red herring? Sem. Reprod. Med. 2009;27(2):171-178. [PubMed]
- Two recent studies have addressed the role of omega-3 LCPUFA in varicocele and asthenozoospermia, two relatively common disorders of male fertility.
- Higher dietary intake of EPA, DHA and total omega-3 LCPUFA was found to be associated with a reduced probability to suffer asthenozoospermia.
- In infertile men with varicocele, the levels of EPA, DHA and total omega-3 in spermatozoa were significantly lower than in control subjects.
A critical interpretation of the existing literature has led several specialists to indicate that an association between male infertility and varicocele exists, but that a causal relationship remains to be unequivocally demonstrated. Recent studies indicate that varicocele repair and removal does improve sperm development and can increase male fertility, suggesting that the impairment of testicular function by varicocele is reversible. Given the lack of a complete mechanistic understanding of how varicocele relates to male infertility, further studies are important, especially since varicocele is found in up to 15% of adolescents, and may explain 35% of male infertility prevalence. A second condition of significant relevance to male infertility is asthenozoospermia. Asthenozoospermia, roughly translated as “weak” or “soft” sperm, relates to sperm with inferior capacity to fertilize an egg mainly due to low spermatozoa motility. Reports on incremental decreases in semen quality since the 1930´s have given the impression that some environmental factors markedly and progressively affect male fertility. Critical inspections of the meta-analyses that have led to these conclusions has indicated that many factors are at play in determining semen quality, and that serious methodological inconsistencies between studies may invalidate the conclusions that a drastic rise in male infertility has occurred in the last century. Asthenozoospermia is a relevant problem though, and optimal sperm quality is certainly compromised in a very large proportion of men today. 
Spermatozoa from asthenozoospermic men have been reported to have structural defects in the energy-generating mid-piece, with deformed mitochondria and improper formation of the annulus that connects the mid-piece with the flagellum. Changes in the membrane composition of asthenozoospermic spermatozoa have also been identified. These comprise increases in specific mono-unsaturated fatty acids such as oleic acid, changes in the content of saturated fatty acids, such as stearic and palmitic acid, and decreases in omega-3 polyunsaturated fatty acids (omega-3 LCPUFA) and in the ratio of omega-3 to omega-6 PUFA. The omega-3 LCPUFA docosahexaenoic acid DHA has been identified to be lower in membranes of spermatozoa from asthenozoospermic men, suggesting that it contributes to good spermatozoal motility by providing the right biophysical properties of the spermatozoal membrane. The presence of trans-fatty acids in sperm and high intake of saturated fatty acids have also been associated with lower sperm counts. Since sustained higher intake of saturated fatty acids and trans-fatty acids, and decreased intakes of PUFA, are associated with an unhealthy diet, it is important to further assess if a relation between poor dietary habits and male infertility exists. A relationship between dietary intake of specific fatty acids and asthenozoospermia is suspected but has not been addressed. Two recent case-control studies now provide new indications that omega-3 LCPUFA have a significant influence over male fertility by reducing the incidence of asthenozoospermia and the outcome of varicocele. The first study, by Eslamian and colleagues from the National Nutrition and Food Technology Research Institute, the Shahid Beheshti University of Medical Sciences, and the Avicenna Research Institute, in Tehran, Iran, has investigated the relation between dietary intake of different fatty acids and asthenozoospermia. The second study by Tang and colleagues from the National Health and Family Planning Commission of China, in collaboration with various laboratories in China and the US, has studied PUFA content in spermatozoa from infertile men with varicocele. 
The study by Eslamian and colleagues was undertaken to examine the relationship between dietary fatty acid intake and the incidence of asthenozoospermia, with concurrent assessment of a range of additional lifestyle and demographic variables. One hundred and seven men with asthenozoospermia and 235 normozoospermic control subjects were examined. Semen was collected from men aged between 20 and 40 years at a specialized infertility clinic. The asthenozoospermic men had been recently diagnosed. The motility of sperm was determined according to WHO guidelines, with asthenozoospermia defined as motility less than 40%, and progressive motility below 32%, within one hour of ejaculation. All asthenozoospermic men produced sperm with normal sperm counts (above 15 million per ml) and normal spermatozoa morphology (less than 4% abnormally shaped cells). Participants taking fatty acid supplements or suffering from any nutrition-related condition (cardiovascular diseases, diabetes, cancer, osteoporosis) or other disorders related to male infertility (endocrine hypogonadism, varicocele), were excluded from the study. Semen analysis was carried out on two samples per subject donated within a 1 month period. Assessment of dietary intake was made through a validated semi-quantitative food-frequency questionnaire and a food content table. Information on the dietary habits of the study participants one year prior to diagnosis of asthenozoospermia or study initiation (normozoospermia) was available for all participants. Intake of fatty acids was adjusted for total energy intake. Comparison of asthenozoospermic men with normozoospermic men indicated that among the recorded lifestyle and demographic variables, asthenozoospermia was associated with higher body mass index, smoking habits, and the presence of heavy traffic near home. The total motility of spermatozoa from asthenozoospermic men was 24.6% compared to 59.2% in normozoospermia. The consumption of a number of individual fatty acids differed significantly between both groups of men. In asthenozoospermic subjects the intake of total fatty acids, saturated fatty acids, trans-fatty acids, palmitic acid, and stearic acid was higher than in normozoospermic men. In contrast, the average intake of PUFA, omega-3 PUFA, EPA and DHA was significantly lower. No significant differences were identified for the intake of oleic acid, linoleic acid, total omega-6 PUFA, and alpha-linolenic acid (ALA). Study subjects with the highest tertile of intakes of omega-3 PUFA and DHA had the lowest probability to suffer asthenozoospermia (odds ratios of 0.68 and 0.53, respectively). In contrast, total trans-fatty acid intake and saturated fatty acid intake were associated with an increased risk for asthenozoospermia (odds ratios of 2.53 and 1.85 for the highest tertiles of intake). In the second case-control study, by Tang and colleagues, semen quality, spermatozoa membrane fatty acid composition, and oxidative damage to spermatozoal DNA were studied in three groups of men. The first group was composed of 92 infertile men with varicocele, the second group (n=99) were infertile but did not have varicocele, and the third group was composed of 95 fertile male volunteers without a prior report of infertility or varicocele. There were no differences in average age (35 years), body-mass index (not overweight), abstinence before donating sperm, or ejaculate volume. Infertile men, with or without varicocele, had significantly lower sperm counts, motility, vitality (percentage of living spermatozoa), and had a higher percentage of spermatozoa that were deformed. In men with varicocele the levels of ALA, EPA, DHA and total omega-3 were significantly lower than in control subjects. The levels of AA and linoleic acid were higher. The ratio of omega-6 to omega-3 fatty acids was twice that in control subjects. There was also a small but statistically significant increase in the level of 8-hydroxy-2-deoxyguanosine (8-OHdG) in the semen plasma. 8-hydroxy-2-deoxyguanosine is formed by free-radical-mediated oxidative damage to DNA, and is indicative of a severe depletion of endogenous antioxidants when a tissue is exposed to some major noxious event. In infertile men without varicocele, significant decreases in ALA, EPA and total omega-3 PUFA and an increase in the omega-6 to omega-3 ratio were also noted, although the changes were less than in men with varicocele, and no changes in 8-OHdG were detectable. 
When varicocele was graded by severity into three classes, significantly higher levels of AA, total omega-6 and 8-OHdG were present in spermatozoa of men with the highest two grades of varicocele severity. In contrast, in men with more severe forms of varicocele, ALA, EPA, DHA and total omega-3 PUFA levels in spermatozoa were lower. The omega-6 to omega-3 ratio hence was significantly higher as varicocele severity increased. Such correlations were maintained when the relationships between fatty acid content and spermatozoal motility were inspected. Individual omega-3 LCPUFA and total omega-3 levels were positively related to motility. The levels of ALA, EPA, DHA and total omega-3 were inversely correlated with the seminal plasma level of 8-OHdG. In summary, the two studies bring forward interesting new aspects of potential deficits or derangements of omega-3 LCPUFA intake and spermatozoal membrane composition in male infertility disorders. A significant negative association between the intake of omega-3 LCPUFA, and DHA in particular, and the risk of having asthenozoospermia has been recognized. In varicocele compelling evidence has been produced that indicates that the disorder is related to lower levels of omega-3 LCPUFA in spermatozoa. In addition, varicocele appears to be associated with increased free radical-mediated macromolecular oxidative damage, and this is suggestive of a local protective role for omega-3 LC PUFA in spermatozoa. Both studies highlight the need for controlled dietary intervention trials, and further research is required to determine how dietary omega-3 LCPUFAs might improve asthenozoospermia and varicocele. It will be interesting to watch future developments that may qualify two frequent male infertility disorders to have a modifiable outcome through dietary intervention. Eslamian G, Amirjannati N, Rashidkhani B, Sadeghi MR, Baghestani AR, Hekmatdoost A. Dietary fatty acid intakes and asthenozoospermia: a case-control study. Fertil. Steril. 2015;103(1):190-198. [PubMed] Tang LX, Yuan DJ, Wang QL, Jiang F, Guo J, Tang YG, Zheng LX, Kang JX. Association of decreased spermatozoa omega-3 fatty acid levels and increased oxidative DNA damage with varicocele in infertile men: a case control study. Reprod. Fertil. Dev. 2014. [PubMed] Worth Noting Avicenna Research Institute – Infertility Clinic. http://www.avicenna.ac.ir/index.php/en/avicenna-infertility-clinic Conquer JA, Martin JB, Tummon I, Watson L,Tekpetey F. Fatty acid analysis of blood serum, seminal plasma, and spermatozoa of normozoospermic vs. asthenozoospermic males. Lipids 1999;34(8):793-799. [PubMed] Ficarra V, Crestani A, Novara G, Mirone V. Varicocele repair for infertility: what is the evidence? Curr. Opin. Urol. 2012;22(6):489-494. [PubMed] Harika RK, Eilander A, Alssema M, Osendarp SJ, Zock PL. Intake of fatty acids in general populations worldwide does not meet dietary recommendations to prevent coronary heart disease: a systematic review of data from 40 countries. Ann. Nutr. Metab. 2013;63(3):229-238. [PubMed] Jorgensen N, Joensen UN, Jensen TK, Jensen MB, Almstrup K, Olesen IA, Juul A, Andersson AM, Carlsen E, Petersen JH, Toppari J, Skakkebaek NE. Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men. BMJ Open 2012;2(4): e000990. [PubMed] Jouannet P, Wang C, Eustache F, Kold-Jensen T, Auger J. Semen quality and male reproductive health: the controversy about human sperm concentration decline. Acta Pathol. Microbiol. Immunol. Scand. 2001;109(5):333-344. [PubMed] Lhuillier P, Rode B, Escalier D, Lores P, Dirami T, Bienvenu T, Gacon G, Dulioust E, Toure A. Absence of annulus in human asthenozoospermia: case report. Hum. Reprod. 2009;24(6):1296-1303. [PubMed] Merzenich H, Zeeb H, Blettner M. Decreasing sperm quality: a global problem? BMC Public Health 2010;10:24. [PubMed] Mirmiran P, Esfahani FH, Mehrabi Y, Hedayati M, Azizi F. Reliability and relative validity of an FFQ for nutrients in the Tehran lipid and glucose study. Public Health Nutr. 2010;13(5):654-662. [PubMed] Pelliccione F, Micillo A, Cordeschi G, D'Angeli A, Necozione S, Gandini L, Lenzi A, Francavilla F, Francavilla S. Altered ultrastructure of mitochondrial membranes is strongly associated with unexplained asthenozoospermia. Fertil. Steril. 2011;95(2):641-646. [PubMed] Shahid Beheshti University of Medical Sciences. http://en.sbmu.ac.ir/ Varicocele. Weill Cornell Medical College, Department of Urology https://www.cornellurology.com/clinical-conditions/male-infertility/general-information/varicocele/ World Health Organization. Manual for the Standardized Investigation and Diagnosis and Management of the Infertile Male. Cambridge University Press, Cambridge, UK 2000. http://www.who.int/reproductivehealth/publications/infertility/0521774748/en/ World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Cambridge University Press, Cambridge, UK 2010. http://www.who.int/reproductivehealth/publications/infertility/9789241547789/en/ Zini A, Boman JM. Varicocele: red flag or red herring? Sem. Reprod. Med. 2009;27(2):171-178. [PubMed]