- Email: [email protected]
Enhancement of Human Sperm Motility
Enhancement of Human Sperm Motility perm motility is considered one of the key semen analysis parameters. In addition to other parameters, primarily semen volume, sperm concentration and morphology, it relates not only to male fertility potential in achieving a natural pregnancy but also has a significant role in selecting the type of assisted reproductive technique (ART), if needed, and impacts the success rate of such procedures. The total motile sperm count (TMC), derived from semen volume, sperm concentration and sperm motility in a given semen sample, has been reported as a helpful tool in deciding whether intrauterine insemination (IUI) or in vitro fertilization (IVF) should be performed.1,2 Subjects with a TMC of 10 million or higher have been suggested as favorable candidates for IUI if allowed by female reproductive status, while IVF has been suggested as the preferred option when the TMC is less than 10 million.3 Human spermatozoa develop an increased capacity for motility as they migrate through the epididymis. This process of motility maturation involves a change in the pattern of sperm motility as well as an increase in the percentage of spermatozoa exhibiting more mature motility patterns, which are characterized by high frequency, low amplitude beats that result in progressive movement. Other parts of the male genital system have an effect on spermatozoal motility. Seminal vesicle secretions primarily contain carbohydrates such as fructose, a necessary component for sperm motility, as well as prostaglandins E, A and F. The mechanisms involved in sperm motility and methods for improving sperm motility have been subject to extensive research. Tyrosine phosphorylation and its up-regulation by cyclic adenosine monophosphate have been shown to be associated with capacitation and motility changes of spermatozoa. Bajpai and Doncel have suggested that protein kinase A activation may be a facilitatory rather than an indispensable step in the capacitation induced tyrosine phosphorylation mediating motility changes in human spermatozoa.4 Soluble tyrosine phosphorylated proteins, more than their insoluble counterparts, appear to be involved in the modulation of human sperm motility characteristics. Possible methods of affecting tyrosine phosphorylation in sperm to improve sperm motility have been investigated in recent years. The focus of these studies has been on in vitro enhancement of sperm motility in the setting of ARTs. Several studies have focused on the possible use of pentoxifylline. Treatment of semen samples with the phosphodiesterase (PDE) inhibitor pentoxifylline has been reported to significantly increase sperm velocity, hyperactivated motility, and tyrosine phosphorylation in normospermic and asthenozoospermic samples.5 Preliminary data on asthenozoospermic samples exhibiting altered motility characteristics and impaired phosphorylation of sperm tail proteins showed that both defects can be concomitantly overcome by pentoxifylline treatment. Yunes et al have suggested that the en-
hancement of hyperactivated motility resulting from PDE inhibition by pentoxifylline is mediated by tyrosine phosphorylation of sperm tail proteins.5 Tadalafil, a known oral selective PDE5 inhibitor used widely in the management of erectile dysfunction, has been reported to have an effect on sperm motility. In vitro use of tadalafil solution in selected concentrations was reported to have a significant stimulatory effect on asthenozoospermic sperm motility.6 Luconi et al showed that incubation of sperm with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 increases the progressive motility of human sperm by increasing tyrosine phosphorylation of the protein kinase A (PKA) anchoring protein AKAP3, as well as the AKAP3 interaction with PKA in sperm flagellum.7 Interestingly further studies using a mouse model showed that enhancement of sperm motility by this PI3K inhibitor does not result in toxic effects on preimplantation embryo development. Reactive oxygen species (ROS) and endocannabinoids, a particular group of endogenously produced cannabinoids, have been reported to have an inhibitory effect on sperm motility. While ROS exert this negative effect by damaging the sperm membrane, the effect of endocannabinoids is mediated through the activation of the cannabinoid receptor subtype 1, which has been shown to be expressed in mature sperm.8 It has been suggested that the ␦ and -opioid receptors which have been identified in sperm participate in regulating sperm motility. Progressive sperm motility was significantly reduced after incubation with the -receptor agonist morphine, whereas this effect was antagonized in the presence of the corresponding antagonist naloxone. The ␦-receptor antagonist naltrindole significantly decreased progressive motility immediately after its addition.9 These findings support further research of interventions involving ROS as well as the cannabinoid and opioid systems as tools for the treatment of male infertility. In this issue of The Journal Hatakeyama et al (page 767) present their investigation of the effect of the trophinin binding peptide GWRQ on human sperm motility. Trophinin is an integral membrane protein that has parts in the cytoplasm and the cell surface. Previous studies have shown that the cytoplasmic domain of trophinin is connected through certain intermediate proteins to the light chain of the microtubule associated adenosine triphosphatase (ATPase) dynein.10 Activation of dynein ATPase by phosphorylation leads to adenosine triphosphate hydrolysis, which is converted into force, causing microtubules to slide against each other with resultant sperm movement. Hatakeyama et al demonstrated that human sperm incubated with GWRQ showed enhanced motility in sperm counting and swim-down Transwell™ assays. Furthermore, spermatozoa incubated with GWRQ showed reduced adenosine triphosphate levels and increased intracellular calcium levels, suggesting that trophinin has a role in regulating
S
0022-5347/08/1802-0442/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
442
Vol. 180, 442-443, August 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.05.077
ENHANCEMENT OF HUMAN SPERM MOTILITY ATPase in human sperm. Interestingly the findings of this study suggest that sperm motility enhancement by GWRQ is limited to short distances. This limitation has an important impact on the potential clinical use of GWRQ, suggesting that this peptide may be useful for IVF but may have limited potential use for IUI, during which much longer sperm movement is required. Impaired sperm motility may interfere not only with the achievement of natural conception but may also require more invasive, sophisticated and expensive ARTs. Improvement of sperm motility could obviate the need for intracytoplasmic sperm injection and potentially even allow for IUI. Hatakeyama et al present an important extension of the investigational effort in this field as it suggests a role for the trophinin binding peptide GWRQ in enhancing human sperm motility. This interesting method, as well as other approaches based on cellular sperm physiology, may be further investigated to evaluate its clinical usefulness in the treatment of infertility associated with asthenospermia. Moshe Wald Department of Urology University of Iowa Iowa City, Iowa
2.
3.
4.
5.
6. 7.
8. 9.
REFERENCES 1.
van Weert JM, Repping S, Van Voorhis BJ, van der Veen F, Bossuyt PM and Mol BW: Performance of the postwash total motile sperm count as a predictor of pregnancy at the time of intrauterine insemination: a meta-analysis. Fertil Steril 2004; 82: 612.
10.
443
Repping S, van Weert JM, Mol BW, de Vries JW and van der Veen F: Use of the total motile sperm count to predict total fertilization failure in in vitro fertilization. Fertil Steril 2002; 78: 22. Van Voorhis BJ, Barnett M, Sparks AE, Syrop CH, Rosenthal G and Dawson J: Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization. Fertil Steril 2001; 75: 661. Bajpai M and Doncel GF: Involvement of tyrosine kinase and cAMP-dependent kinase cross-talk in the regulation of human sperm motility. Reproduction 2003; 126: 183. Yunes R, Fernández P, Doncel GF and Acosta AA: Cyclic nucleotide phosphodiesterase inhibition increases tyrosine phosphorylation and hyper motility in normal and pathological human spermatozoa. Biocell 2005; 29: 287. Mostafa T: Tadalafil as an in vitro sperm motility stimulant. Andrologia 2007; 39: 12. Luconi M, Torcia S, Grillo D, Fiorenza MT, Forti G, Mangia F et al: Enhancement of mouse sperm motility by the PI3kinase inhibitor LY294002 does not result in toxic effects on preimplantation embryo development. Hum Reprod 2005; 20: 3500. Tremellen K: Oxidative stress and male infertility–a clinical perspective. Hum Reprod Update 2008; 14: 243. Agirregoitia E, Valdivia A, Carracedo A, Casis L, Gil J, Subiran N et al: Expression and localization of delta-, kappa-, and mu-opioid receptors in human spermatozoa and implications for sperm motility. J Clin Endocrinol Metab 2006; 91: 4969. Nadano D, Nakayama J, Matsuzawa S, Sato TA, Matsuda T and Fukuda MN: Human tastin, a proline-rich cytoplasmic protein, associates with the microtubular cytoskeleton. Biochem J 2002; 364: 669.
hancement of hyperactivated motility resulting from PDE inhibition by pentoxifylline is mediated by tyrosine phosphorylation of sperm tail proteins.5 Tadalafil, a known oral selective PDE5 inhibitor used widely in the management of erectile dysfunction, has been reported to have an effect on sperm motility. In vitro use of tadalafil solution in selected concentrations was reported to have a significant stimulatory effect on asthenozoospermic sperm motility.6 Luconi et al showed that incubation of sperm with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 increases the progressive motility of human sperm by increasing tyrosine phosphorylation of the protein kinase A (PKA) anchoring protein AKAP3, as well as the AKAP3 interaction with PKA in sperm flagellum.7 Interestingly further studies using a mouse model showed that enhancement of sperm motility by this PI3K inhibitor does not result in toxic effects on preimplantation embryo development. Reactive oxygen species (ROS) and endocannabinoids, a particular group of endogenously produced cannabinoids, have been reported to have an inhibitory effect on sperm motility. While ROS exert this negative effect by damaging the sperm membrane, the effect of endocannabinoids is mediated through the activation of the cannabinoid receptor subtype 1, which has been shown to be expressed in mature sperm.8 It has been suggested that the ␦ and -opioid receptors which have been identified in sperm participate in regulating sperm motility. Progressive sperm motility was significantly reduced after incubation with the -receptor agonist morphine, whereas this effect was antagonized in the presence of the corresponding antagonist naloxone. The ␦-receptor antagonist naltrindole significantly decreased progressive motility immediately after its addition.9 These findings support further research of interventions involving ROS as well as the cannabinoid and opioid systems as tools for the treatment of male infertility. In this issue of The Journal Hatakeyama et al (page 767) present their investigation of the effect of the trophinin binding peptide GWRQ on human sperm motility. Trophinin is an integral membrane protein that has parts in the cytoplasm and the cell surface. Previous studies have shown that the cytoplasmic domain of trophinin is connected through certain intermediate proteins to the light chain of the microtubule associated adenosine triphosphatase (ATPase) dynein.10 Activation of dynein ATPase by phosphorylation leads to adenosine triphosphate hydrolysis, which is converted into force, causing microtubules to slide against each other with resultant sperm movement. Hatakeyama et al demonstrated that human sperm incubated with GWRQ showed enhanced motility in sperm counting and swim-down Transwell™ assays. Furthermore, spermatozoa incubated with GWRQ showed reduced adenosine triphosphate levels and increased intracellular calcium levels, suggesting that trophinin has a role in regulating
S
0022-5347/08/1802-0442/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
442
Vol. 180, 442-443, August 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.05.077
ENHANCEMENT OF HUMAN SPERM MOTILITY ATPase in human sperm. Interestingly the findings of this study suggest that sperm motility enhancement by GWRQ is limited to short distances. This limitation has an important impact on the potential clinical use of GWRQ, suggesting that this peptide may be useful for IVF but may have limited potential use for IUI, during which much longer sperm movement is required. Impaired sperm motility may interfere not only with the achievement of natural conception but may also require more invasive, sophisticated and expensive ARTs. Improvement of sperm motility could obviate the need for intracytoplasmic sperm injection and potentially even allow for IUI. Hatakeyama et al present an important extension of the investigational effort in this field as it suggests a role for the trophinin binding peptide GWRQ in enhancing human sperm motility. This interesting method, as well as other approaches based on cellular sperm physiology, may be further investigated to evaluate its clinical usefulness in the treatment of infertility associated with asthenospermia. Moshe Wald Department of Urology University of Iowa Iowa City, Iowa
2.
3.
4.
5.
6. 7.
8. 9.
REFERENCES 1.
van Weert JM, Repping S, Van Voorhis BJ, van der Veen F, Bossuyt PM and Mol BW: Performance of the postwash total motile sperm count as a predictor of pregnancy at the time of intrauterine insemination: a meta-analysis. Fertil Steril 2004; 82: 612.
10.
443
Repping S, van Weert JM, Mol BW, de Vries JW and van der Veen F: Use of the total motile sperm count to predict total fertilization failure in in vitro fertilization. Fertil Steril 2002; 78: 22. Van Voorhis BJ, Barnett M, Sparks AE, Syrop CH, Rosenthal G and Dawson J: Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization. Fertil Steril 2001; 75: 661. Bajpai M and Doncel GF: Involvement of tyrosine kinase and cAMP-dependent kinase cross-talk in the regulation of human sperm motility. Reproduction 2003; 126: 183. Yunes R, Fernández P, Doncel GF and Acosta AA: Cyclic nucleotide phosphodiesterase inhibition increases tyrosine phosphorylation and hyper motility in normal and pathological human spermatozoa. Biocell 2005; 29: 287. Mostafa T: Tadalafil as an in vitro sperm motility stimulant. Andrologia 2007; 39: 12. Luconi M, Torcia S, Grillo D, Fiorenza MT, Forti G, Mangia F et al: Enhancement of mouse sperm motility by the PI3kinase inhibitor LY294002 does not result in toxic effects on preimplantation embryo development. Hum Reprod 2005; 20: 3500. Tremellen K: Oxidative stress and male infertility–a clinical perspective. Hum Reprod Update 2008; 14: 243. Agirregoitia E, Valdivia A, Carracedo A, Casis L, Gil J, Subiran N et al: Expression and localization of delta-, kappa-, and mu-opioid receptors in human spermatozoa and implications for sperm motility. J Clin Endocrinol Metab 2006; 91: 4969. Nadano D, Nakayama J, Matsuzawa S, Sato TA, Matsuda T and Fukuda MN: Human tastin, a proline-rich cytoplasmic protein, associates with the microtubular cytoskeleton. Biochem J 2002; 364: 669.