Can We Do Better? CRYPTORCHIDISM is one of the most common congenital anomalies, occurring in 1% to 4% of all full-term newborns with an increased incidence in preterm neonates.1 The etiology of isolated cryptorchidism is unknown but likely involves genetic and environmental factors that disrupt normal testicular descent and subsequent development. One of the major pathological outcomes of cryptorchidism is testicular maldevelopment with associated decreased spermatogonia and increased subfertility potential.2 Although there is variability in testicular maldevelopment in the biopsy data of children with cryptorchid testes, significant evidence shows that impaired development of spermatogonia is present at an early age in children with cryptorchidism. Testicular biopsy studies demonstrated that increased age at intervention and higher testicular position may worsen the degree of testicular dysfunction.3,4 Older age at orchiopexy and an intra-abdominal location appeared to increase the degree of germ cell depletion and Leydig cell loss, and decrease the diameter of the seminiferous tubules. These and other data support the notion that earlier age at orchiopexy may improve measures of fertility. The current therapy recommendation is to perform orchiopexy as early as age 6 months since the testicle is unlikely to descend and testicular growth may be restored with early intervention.5 Although strong data show that cryptorchidism can lead to degrees of subfertility and early intervention may improve measures of fertility and testicular function, the long-term impact of early intervention on the final outcome of paternity is unclear and challenging to measure. In the best studies of paternity in men with cryptorchidism (a series of case-control studies using questionnaire, hormone, semen analysis and paternity data) investigators found that of men with cryptorchidism who attempted paternity 65% (32 of 49) with bilateral and 90% (322 of 359) with unilateral cryptorchidism as well as 93% of controls (413 of 443) were successful.6 In these studies age at orchiopexy and testicular position did not appear to affect overall paternity.
0022-5347/14/1914-0893/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
Further complicating decision making regarding the timing of surgical intervention is the controversial but increasing body of literature suggesting that early exposure to general anesthesia impairs neurocognitive development.7 Although the studies are primarily retrospective and have definite methodological limitations, they suggest that anesthetic exposure before age 3 years may increase the long-term risk of neurocognitive dysfunction. Ongoing prospective studies will hopefully provide valuable answers in the near future. Beyond early surgical intervention is there another option to improve fertility potential in the cryptorchid testis? In this issue of The Journal Uyeturk et al (page 1168) from Turkey propose that administering the antioxidant N-acetyl cysteine (NAC) decreases damage to spermatogonia in undescended testicles by decreasing reactive oxidative species (ROS) created by the increased abdominal temperature exposure.8 They used a rodent model of induced neonatal bilateral cryptorchidism and measured histological and biochemical end points in undescended testes treated with and without intraperitoneally delivered NAC compared to respective controls. In rodents treated with NAC there was significant histological improvement in overall spermatogonia density per tubule compared to that in untreated rodents with undescended testicles. Biochemically malonyl dialdehyde and glutathione peroxidase, each a biochemical measure of ROS, were associated with significant improvement in the NAC treated group compared to the untreated group, indicating a decrease in overall ROS activity in undescended testes treated with NAC. Although histological and biochemical measures did not attain the values of normal nonaffected controls, overall there appeared to be significant improvement in these fertility measures compared to those in the nontreated cryptorchid group. Oxidative stress has been implicated as a potential cause for male factor infertility. All cellular components of the testicle are at risk for damage depending on the extent and duration of ROS exposure.9 Various antioxidants have been used in
http://dx.doi.org/10.1016/j.juro.2014.01.090 Vol. 191, 893-894, April 2014 Printed in U.S.A.
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CAN WE DO BETTER?
reproductive technologies to protect sperm as well as in other animal models of cryptorchidism and testicular torsion. NAC itself is a weak antioxidant. NAC best functions as an antioxidant by increasing glutathione synthesis since glutathione is a powerful detoxifier and antioxidant of ROS.10 The intracellular concentration of glutathione is the critical driver of NAC efficacy as an antioxidant. Future studies should consider incorporating tissue level measurements of glutathione as further supportive evidence of the efficacy of NAC. Overall, the utilization of antioxidant therapy as preventive therapy to preserve fertility in children with cryptorchidism is highly compelling and may
provide a new weapon to improve the overall longterm care of these children. Antioxidant therapy may prove to be extremely beneficial, particularly in children with bilateral or intra-abdominal cryptorchidism. If future data demonstrate that early exposure to anesthesia truly increases the risk of neurotoxicity, the need for such nonsurgical therapies to protect fertility in these children will be needed even more. Richard S. Lee Department of Urology Harvard Medical School Boston Children’s Hospital Boston, Massachusetts
REFERENCES 1. Sijstermans K, Hack WW, Meijer RW et al: The frequency of undescended testis from birth to adulthood: a review. Int J Androl 2008; 31: 1. 2. Cortes D, Thorup JM and Visfeldt J: Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res 2001; 55: 21. 3. Tasian GE, Hittelman AB, Lim GE et al: Age at orchiopexy and testis palpability predict germ and Leydig cell loss: clinical predictors of adverse histological features of cryptorchidism. J Urol 2009; 182: 704.
4. AbouZeid AA, Mousa MH, Soliman HA et al: Intra-abdominal testis: histological alterations and significance of biopsy. J Urol 2011; 185: 269. 5. Kollin C, Karpe B, Hesser U et al: Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchiopexy at age 9 months or 3 years. J Urol 2007; 178: 1589. 6. Lee PA: Fertility after cryptorchidism: epidemiology and other outcome studies. Urology 2005; 66: 427. 7. Olsen EA and Brambrink AM: Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the
developing brain. Curr Opin Anaesthesiol 2013; 26: 677. 8. Uyeturk U, Cetinkaya A, Ozyalvacli G et al: Protective effects of N-acetylcysteine on experimentally undescended testis. J Urol 2014; 191: 1168. 9. Agarwal A, Makker K and Sharma R: Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol 2008; 59: 2. 10. Rushworth GF and Megson IL: Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014; 141: 150.
0022-5347/14/1914-0893/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
Further complicating decision making regarding the timing of surgical intervention is the controversial but increasing body of literature suggesting that early exposure to general anesthesia impairs neurocognitive development.7 Although the studies are primarily retrospective and have definite methodological limitations, they suggest that anesthetic exposure before age 3 years may increase the long-term risk of neurocognitive dysfunction. Ongoing prospective studies will hopefully provide valuable answers in the near future. Beyond early surgical intervention is there another option to improve fertility potential in the cryptorchid testis? In this issue of The Journal Uyeturk et al (page 1168) from Turkey propose that administering the antioxidant N-acetyl cysteine (NAC) decreases damage to spermatogonia in undescended testicles by decreasing reactive oxidative species (ROS) created by the increased abdominal temperature exposure.8 They used a rodent model of induced neonatal bilateral cryptorchidism and measured histological and biochemical end points in undescended testes treated with and without intraperitoneally delivered NAC compared to respective controls. In rodents treated with NAC there was significant histological improvement in overall spermatogonia density per tubule compared to that in untreated rodents with undescended testicles. Biochemically malonyl dialdehyde and glutathione peroxidase, each a biochemical measure of ROS, were associated with significant improvement in the NAC treated group compared to the untreated group, indicating a decrease in overall ROS activity in undescended testes treated with NAC. Although histological and biochemical measures did not attain the values of normal nonaffected controls, overall there appeared to be significant improvement in these fertility measures compared to those in the nontreated cryptorchid group. Oxidative stress has been implicated as a potential cause for male factor infertility. All cellular components of the testicle are at risk for damage depending on the extent and duration of ROS exposure.9 Various antioxidants have been used in
http://dx.doi.org/10.1016/j.juro.2014.01.090 Vol. 191, 893-894, April 2014 Printed in U.S.A.
www.jurology.com
j
893
894
CAN WE DO BETTER?
reproductive technologies to protect sperm as well as in other animal models of cryptorchidism and testicular torsion. NAC itself is a weak antioxidant. NAC best functions as an antioxidant by increasing glutathione synthesis since glutathione is a powerful detoxifier and antioxidant of ROS.10 The intracellular concentration of glutathione is the critical driver of NAC efficacy as an antioxidant. Future studies should consider incorporating tissue level measurements of glutathione as further supportive evidence of the efficacy of NAC. Overall, the utilization of antioxidant therapy as preventive therapy to preserve fertility in children with cryptorchidism is highly compelling and may
provide a new weapon to improve the overall longterm care of these children. Antioxidant therapy may prove to be extremely beneficial, particularly in children with bilateral or intra-abdominal cryptorchidism. If future data demonstrate that early exposure to anesthesia truly increases the risk of neurotoxicity, the need for such nonsurgical therapies to protect fertility in these children will be needed even more. Richard S. Lee Department of Urology Harvard Medical School Boston Children’s Hospital Boston, Massachusetts
REFERENCES 1. Sijstermans K, Hack WW, Meijer RW et al: The frequency of undescended testis from birth to adulthood: a review. Int J Androl 2008; 31: 1. 2. Cortes D, Thorup JM and Visfeldt J: Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res 2001; 55: 21. 3. Tasian GE, Hittelman AB, Lim GE et al: Age at orchiopexy and testis palpability predict germ and Leydig cell loss: clinical predictors of adverse histological features of cryptorchidism. J Urol 2009; 182: 704.
4. AbouZeid AA, Mousa MH, Soliman HA et al: Intra-abdominal testis: histological alterations and significance of biopsy. J Urol 2011; 185: 269. 5. Kollin C, Karpe B, Hesser U et al: Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchiopexy at age 9 months or 3 years. J Urol 2007; 178: 1589. 6. Lee PA: Fertility after cryptorchidism: epidemiology and other outcome studies. Urology 2005; 66: 427. 7. Olsen EA and Brambrink AM: Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the
developing brain. Curr Opin Anaesthesiol 2013; 26: 677. 8. Uyeturk U, Cetinkaya A, Ozyalvacli G et al: Protective effects of N-acetylcysteine on experimentally undescended testis. J Urol 2014; 191: 1168. 9. Agarwal A, Makker K and Sharma R: Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol 2008; 59: 2. 10. Rushworth GF and Megson IL: Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014; 141: 150.
